Pediatric Lung Transplant Recipients Research Articles

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course. This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507). An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.

Gastrointestinal complications in pediatric lung transplant recipients: Incidence, risk factors, and effects on patient outcomes.

Gastrointestinal (GI) complications in lung transplant recipients can occur any time during the post-operative period, leading to prolonged morbidity and mortality. Despite the negative association between GI complications and patient outcomes, little is known about their incidence and risk factors for their development in pediatric lung transplant recipients. We performed a retrospective chart review at one pediatric tertiary center to describe the frequency of GI complications in lung transplant recipients. We identified potential risk factors for the diagnosis of gastroparesis, gastroesophageal reflux disease (GERD) and aspiration in the post-transplant period. Lastly, we investigated the association of these complications with mortality and graft survival. 84.3% of lung transplant recipients experienced at least one GI complication in the post-transplant period. Gastroparesis (52.9%), GERD (41.2%), and oropharyngeal dysphagia/laryngeal penetration (33.3%) were the most common complications diagnosed. Post-operative opioid exposure was a risk factor for gastroparesis, with the odds increasing 3.0% each day a patient was prescribed opioids (p = .021). The risk of death or retransplant in individuals who experienced gastroparesis was 2.7 times higher than those not diagnosed with gastroparesis (p = .027). Exposure to opioids in the post-operative period is a risk factor for gastroparesis and a prolonged hospitalization placed patients at risk for aspiration. Gastroparesis was associated with increased patient mortality and graft failure, while aspiration and GERD had no effect on long term outcomes. Future prospective studies investigating the relationship between opioid use and the development of a gastroparesis are necessary to improve patient outcomes.

Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients

This retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application. Overall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan-Meier analysis. The use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF. The real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.

Body mass index percentage and survival in pediatric patients listed for lung transplantation: A modern-era multi-institutional analysis

Prior studies suggest that being underweight by body mass index percentiles (BMI%) or thinness grade did not affect post-transplant survival in pediatric lung transplant (LTx) recipients regardless of cystic fibrosis (CF) or non-CF diagnosis. Graft and overall survival from the time of listing was instead evaluated based on listing BMI%, the current standard of practice for BMI definitions in pediatrics, to ascertain the impact of a "severely low" subcategory. The UNOS registry was queried for children listed for LTx (aged 2 to <18 years) from January 1986 to March 2020. BMI% at listing and transplant were calculated per CDC guidelines according to age in years, sex, and reported BMI%. Patients were divided by listing BMI%: severely low (<3rd), low (3-<5th), normal (5-<85th), overweight (85-<95th), and obese (≥95th). Kaplan-Meier curves were generated to assess differences in overall survival since listing based on BMI% classes. Cox proportional-hazards models were developed to assess risk factors for overall and graft survival, including listing BMI%, transplant listing era (≥2005), and listing age, by reporting hazard ratios (HR). Listing BMI% was calculable for 1,876 patients. The proportion of patients with CF differed significantly between BMI% groups (p<0.001). Patients listed with a non-CF diagnosis comprised 34% of those in the severely low category, and 88% of those listed with an obese BMI%. Compared to patients with a normal listing BMI%, the cohort with severely low BMI% had worse overall survival regardless of LTx (p=0.009) and graft survival (p=0.034). Compared to patients with a low BMI%, those with a severely low BMI% had significantly poorer graft survival as well (p=0.040). Mean graft survival was not significantly different between groups that remained at listing BMI% versus those that improved in category despite an overall small sample size. Independent predictors of poorer survival from the time of listing include severely low vs low-normal BMI% (HR=1.20) and listing age (HR=1.02). The proportion of children listed at severely low BMI% has steadily decreased with time, yet pediatric LTx candidates listed with a severely low BMI% had poorer graft and overall survival compared to those of normal BMI%. Severely low listing BMI% was an independent prognostic factor for higher mortality risk from the time of placement on the waitlist. BMI% may be a modifiable target for improving survival regardless of transplantation.

Center volume effect on acute cellular rejection and outcomes in pediatric lung transplant recipients

Acute cellular rejection (ACR) is common after lung transplant (LTx). We sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. The United Network for Organ Sharing (UNOS) Registry was queried for patients <18-years-of-age who underwent LTx 1987-2020. Cohorts were children who survived the first-year post transplant and were treated for ACR within that first year (ACR group) and those not treated for ACR (non-ACR). LTx center volume was defined as: high volume center (HVC) (>5LTxs/year), medium volume center (MVC) (>1≤5 LTxs/year), and low volume center (LVC) (≤1LTxs/year). 1320 patients were enrolled into the study; 269 (20.4%) did not experience ACR. The ACR cohort was older (median 14 [11-16] vs 13 [7-16] years, p < 0.001), female (65.3% vs 57.3%, p=0.016), had cystic fibrosis (62.3% vs 45.5%, p < 0.001), and had a higher lung allocation score (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). The ACR cohort trended (p=0.06) towards lower survival at 5-year (37% vs 47%) and 10-year (25% vs 34%) post-LTx. Among children at HVCs, ACR occurred in 17% of recipients (n=98/574), compared to 18.5% (n=73/395) at MVCs and 27% (n=100/369) at LVCs. Children treated for ACR at HVCs had higher survival than LVCs at 5-years (52% vs 29%) and 10-years (36% vs 15%) (p < 0.001) but similar survival to MVCs at 5-years (52% vs 43%) and 10-years (36% vs 24%) (p=0.081). No survival differences were detected in MVCs vs LVCs (p=0.14). ACR treated within the first post-LTx year influence survival of children. ACR incidence was lowest at higher volume centers whereas post-ACR treatment survival outcomes were also superior.

(672) Donor Derived Cell-Free DNA as a Marker of Allograft Dysfunction in Pediatric Lung Transplant Recipients

(672) Donor Derived Cell-Free DNA as a Marker of Allograft Dysfunction in Pediatric Lung Transplant Recipients

(101) Nine-Year Experience with Treatment of Early Detectable Donor Specific Anti-HLA Antibodies in Pediatric Lung Transplant Recipients

(101) Nine-Year Experience with Treatment of Early Detectable Donor Specific Anti-HLA Antibodies in Pediatric Lung Transplant Recipients

COVID-19 in pediatric lung transplant recipients: Clinical course and outcome

COVID-19 causes high morbidity and mortality in adult lung transplant (LTX) recipients. Data on COVID-19 in children after LTX is limited. We report the clinical presentation and outcome of SARS-CoV-2 infection in 19 pediatric LTX recipients. Between March 2020 and June 2022, SARS-CoV-2 testing was performed on all pediatric LTX patients with COVID-19 symptoms or contact with a SARS-CoV-2 infected person. Positive patients were prospectively evaluated for symptoms, treatment and outcome. Vaccination status and immune response were recorded. Nineteen out of 51 pediatric LTX recipients had a SARS-CoV-2 infection. Mean age was 12.3 years (IQR 9-17), 68% were female, 84% had preexisting comorbidities. Mean time between LTX and SARS-CoV-2 infection was 4.8 years (IQR 2-6). No patients experienced severe COVID-19: 11% were asymptomatic, and 89% had mild symptoms, primarily rhinitis (74%), fever (47%), and cough (37%). One SARS-CoV-2 positive patient was hospitalized due to combined fungal and bacterial infection. Mean duration of symptoms was 10.5 days (IQR 3-16), whereas mean period of positivity by antigen test was 21 days (IQR 9-27, p=0.013). Preventive antiviral therapy was initiated in 3 patients. After a mean follow-up of 2.5 months (IQR 1.1-2.4), no patient reported persistent complaints related to COVID-19. Lung function tests remained stable. Unlike adult LTX recipients, children and adolescents are at low risk for severe COVID-19, even with risk factors beyond immunosuppression. Our findings cast doubt on the necessity of excessive isolation for these patients and should reassure clinicians and caregivers of LTX patients.

Monitoring practices of chronic lung allograft dysfunction in pediatric lung transplantation.

Chronic lung allograft dysfunction (CLAD) continues to negatively impact the survival of pediatric lung transplant (LTx) recipients. Current consensus guidelines are adult-focused. We sought to examine CLAD detection and monitoring practices at pediatric LTx programs. We conducted a survey among the International Pediatric Lung Transplant Collaborative. Questions consisted of practitioner's experience, LTx program demographics, and querying tests used for CLAD surveillance and detection. Investigations queried included: chest x-ray (CXR), chest computed tomography (CT), lung magnetic resonance imaging (MRI), ventilation/perfusion scanning, conventional pulmonary function testing (PFT), multiple breath washout (MBW), infant/preschool PFT, bronchoalveolar lavage, transbronchial biopsies (TBBx), or other tissue sampling techniques. Preferences for certain modalities over others were questioned based on a five-point Likert scale. Twenty-four of 25 programs responded. Chest CT and CXR are used generally for both CLAD surveillance and detection. No programs use lung MRI clinically, it may have some utility in the future. While all centers use conventional PFT, MBW, and infant/preschool PFT are used in one-fifth and one-third of centers, respectively. While the majority of programs use TBBx, only 41.7% would obtain a diagnosis based on tissue histopathology over noninvasive techniques if CLAD is suspected. Utilization of biomarkers is still limited. Our results indicate continued use of conventional PFT along with chest CT and less so CXR for CLAD detection and monitoring in the large majority of centers. Infant/preschool PFTand novel methods such as MBW are used in a few centers only. Respondents agreed there is a timely need for pediatric consensus guidelines on CLAD detection and monitoring.

Optimization of initial dose regimen of tacrolimus in paediatric lung transplant recipients based on Monte Carlo simulation.

The initial tacrolimus dose regimen in paediatric lung transplant recipients is unknown. The present study optimized the initial tacrolimus dose regimen for paediatric lung transplant recipients. This study was based on a published population pharmacokinetic model of tacrolimus in lung transplant recipients and used Monte Carlo simulations to recommend an initial dose regimen of tacrolimus in paediatric lung transplant recipients. Without voriconazole, the tacrolimus doses recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers were 0.02, 0.03, and 0.04 mg/kg/day, split into two doses, for weights of 10-16, 16-30, and 30-40 kg, respectively. For paediatric lung transplant recipients who were CYP3A5*1 carriers, the tacrolimus doses of 0.03, 0.04, 0.05, and 0.06 mg/kg/day, split into two doses, were recommended for weights of 10-16, 16-25, 25-30, and 30-40 kg, respectively. With voriconazole, the tacrolimus dose recommended for paediatric lung transplant recipients who were not CYP3A5*1 carriers was 0.02 mg/kg/day, split into two doses, for weights of 10-40 kg. For paediatric lung transplant recipients who were CYP3A5*1 carriers, tacrolimus doses of 0.02 and 0.03 mg/kg/day, split and two doses, were recommended for weights of 10-24 and 24-40 kg, respectively. This study developed tacrolimus dose regimens for the first time for paediatric lung transplant recipients using Monte Carlo simulation and optimized initial dosage in paediatric lung transplant recipients.

Role of Open Lung Biopsy After Pediatric Lung Transplant in Current Era

<h3>Purpose</h3> With the advent of transbronchial biopsy (TBB), open lung biopsy (OLB) has played a smaller role in surveillance of pediatric lung transplant recipients. We review our experience with diagnostic OLB at a high-volume institution. <h3>Methods</h3> Pediatric lung transplant recipients undergoing OLB from 2008-2020 were reviewed to identify preoperative characteristics, indications, and outcomes. Patients requiring intubation or increased oxygen were deemed "respiratory failure". We performed Cox univariate analysis to identify risk factors for one-year retransplant-free survival. Data are expressed as percent or median (interquartile range). <h3>Results</h3> Of 128 patients transplanted from 2008-2020, 32(25%) had subsequent OLB. The most common indications were respiratory failure (15/32, 46.9%) and bronchiolitis obliterans (9/32, 28.1%) (Table). 28 patients (87.5%) had a median of 5 (2-9) TBB prior to OLB. 28/32 (87.5%) patients' treatments were adjusted following OLB, with most requiring immunosuppression changes. 5/32 (15.6%) of patients died in-hospital; one died 3 days after discharge. Mechanical ventilation at OLB was associated with decreased one-year transplant-free survival. 24 patients were followed up for 2.3 (0.6-4.9) years. One-year transplant-free survival was 44% (30-65%) (Figure). Only 7 (29.2%) remained alive at latest follow-up, including one retransplanted patient. <h3>Conclusion</h3> Although OLB is useful for making new diagnoses and treatment adjustments, it is currently used in sicker children in whom less invasive diagnostic approaches have failed. 66% of patients undergoing OLB were retransplanted or died within 1 year.

Long Term Outcome After Pediatric Lung Transplantation

<h3>Purpose</h3> Pediatric lung transplantation is an infrequent, but potentially life-saving procedure for patients with end-stage pulmonary disease. While survival has been increasing over the last decades, there is a lack of data regarding long-term survivors after pediatric lung. The Vienna transplant center is unique in having a high re-transplant rate in children, leading to a high median overall survival with a large number of long-term survivors. Aim of the present retrospective single-center study was to describe the post-transplant organ function, survival, medical complications and social status of patients that survived at least 5 years after lung transplantation in pediatric age. <h3>Methods</h3> Long term outcome of 30 pediatric lung transplant recipients was assessed retrospectively. Primary outcome contained medical status five years after transplantation (growth, BMI, lung function), complications (osteopenia, diabetes mellitus, post-transplant malignomas, psychiatric and neurological complications) five or more years after transplantation including educational status, occupation and living situation. Secondary outcome contained association of pre-transplant patient specific parameters to post transplant outcome. <h3>Results</h3> Out of the 73 pediatric patients, who underwent lung transplantation between 1993 and 2013 at Medical University Vienna, 30 patients survived at least 5 years after transplantation. Median survival of these patients was 192.3 months, 10-year and 15-years survival 85% and 54%, respectively. Mean FEV1%pred 5 years after transplantation was 61%, after 10 years 54%. A statistically significant increase of the median BMI percentile rank from time of transplantation to five years post transplantation was observed. From 1993 to 2002 the 10-year survival rate was 63%, whereas from 2003 to 2013 it was 100%, underlining the improvement in pediatric lung transplantation. No significant differences could be detected analyzing the influence of specific parameters (e.g. gender, underlying disease, age) on survival. <h3>Conclusion</h3> We did not only observe a remarkably high long term survival rate, but also very satisfying results regarding health state in pediatric lung transplant recipients surviving at least five years after transplantation. Complications are considerable, however most importantly the majority of complications is temporary and/or are manageable.

High Volume Centers Have Lower Incidence of Acute Cellular Rejection in Pediatric Lung Transplant Recipients and Better Survival After Treatment

Purpose Acute cellular rejection (ACR) is a common form of allograft rejection in pediatric recipients after lung transplant (LTx). ACR most commonly occurs during the 1st post-transplant year. This study sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. Methods The United Network for Organ Sharing (UNOS) Registry was queried for patients <18 years who underwent LTx in 1987-2020. Cohorts were patients who were treated for ACR during the 1st post-LTx year (ACR group) and who did not experience ACR (non-ACR). Survival of patients who had ACR was compared by LTx center volume defined as average of LTx/year: >5LTx/year (high), >1-≤5LTx/year (medium) and 1LTx/year (low). Results 1338 patients were included in our analysis with 271 (20.3%) identified as having ACR. Compared to non-ACR, the ACR cohort were older (median 14 [11-16] vs 13 [7-16] years, p<0.001), more commonly female (65.3% vs 57.3%, p=0.016), more commonly diagnosed with cystic fibrosis (62.3% vs 45.5%, p<0.001), and had a higher lung allocation score at LTx (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). Kaplan-Meier survival of ACR vs non-ACR cohorts trended towards lower survival at 5-yr (37% vs 47%) & 10-yr (25% vs 34%) post-LTx, p=0.06. ACR occurred in 17% of patients at high (n=98/574), 18.5% (n=73/395) at medium, and 27% (n=100/369) at low volume centers. Patients treated for ACR at high volume centers had better post-transplant survival than low volume centers (p<0.001) but similar survival to those at medium volume centers (p=0.081; Figure). No significant difference in survival was observed in medium vs low volume centers (p=0.14). Conclusion ACR treated within the 1st post-LTx year influences survival of pediatric LTx recipients. ACR incidence was lowest at higher volume centers where post-ACR treatment survival outcomes were also superior. More analysis is needed to determine factors affecting differences in center outcomes regarding ACR. Acute cellular rejection (ACR) is a common form of allograft rejection in pediatric recipients after lung transplant (LTx). ACR most commonly occurs during the 1st post-transplant year. This study sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. The United Network for Organ Sharing (UNOS) Registry was queried for patients <18 years who underwent LTx in 1987-2020. Cohorts were patients who were treated for ACR during the 1st post-LTx year (ACR group) and who did not experience ACR (non-ACR). Survival of patients who had ACR was compared by LTx center volume defined as average of LTx/year: >5LTx/year (high), >1-≤5LTx/year (medium) and 1LTx/year (low). 1338 patients were included in our analysis with 271 (20.3%) identified as having ACR. Compared to non-ACR, the ACR cohort were older (median 14 [11-16] vs 13 [7-16] years, p<0.001), more commonly female (65.3% vs 57.3%, p=0.016), more commonly diagnosed with cystic fibrosis (62.3% vs 45.5%, p<0.001), and had a higher lung allocation score at LTx (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). Kaplan-Meier survival of ACR vs non-ACR cohorts trended towards lower survival at 5-yr (37% vs 47%) & 10-yr (25% vs 34%) post-LTx, p=0.06. ACR occurred in 17% of patients at high (n=98/574), 18.5% (n=73/395) at medium, and 27% (n=100/369) at low volume centers. Patients treated for ACR at high volume centers had better post-transplant survival than low volume centers (p<0.001) but similar survival to those at medium volume centers (p=0.081; Figure). No significant difference in survival was observed in medium vs low volume centers (p=0.14). ACR treated within the 1st post-LTx year influences survival of pediatric LTx recipients. ACR incidence was lowest at higher volume centers where post-ACR treatment survival outcomes were also superior. More analysis is needed to determine factors affecting differences in center outcomes regarding ACR.

Assessment of Cardiac Contribution to Exercise Intolerance in Pediatric Bilateral Lung Transplant Recipients

<h3>Purpose</h3> Exercise intolerance is common among lung transplant (LTx) recipients. However, there is limited data in pediatrics. Since the heart and lungs work in concert with each other, we aim to assess the cardiac contribution to exercise intolerance in pediatric LTx recipients by examining the prevalence of traditional cardiac risk factors (CRFs) and their performance on cardiopulmonary exercise testing (CPET). <h3>Methods</h3> All pediatric LTx recipients followed at a single center who had a resting echocardiogram (echo), were able to exercise, and had a routine CPET in the last 2 years were included. CRFs including hypertension, hyperlipidemia, diabetes mellitus (DM), body mass index (BMI), activity level, and smoking history were assessed. CPET-derived maximal oxygen consumption (VO2_max) and % predicted peak VO2 (ppVO2_max) were used to assess exercise tolerance. Left ventricular (LV) systolic and diastolic function were also assessed on resting echo. <h3>Results</h3> 11 bilateral LTx patients (7M, 4F, and median age 21 years, range 17-28 years) formed the cohort. Median time since LTx is 6 years, range 2-10 years. The majority of patients (8, 73%) had multiple CRFs: 7 (64%) had hypertension, 7 (64%) hyperlipidemia, 6 (55%) DM, 2 with BMI ≥25 kg/m², and 6 (55%) sedentary lifestyle. None had a smoking history. On resting echo, all had normal LV systolic function. 5 (45%) had LV diastolic dysfunction. On CPET, 9 (82%) had abnormal ppVO2_max ≤85%, even with maximal patient effort. None had ischemia. Surprisingly, only 2 of the 9 had a pulmonary limitation to exercise with abnormal breathing reserve (<25%) to account for abnormal ppVO2_max. 6 had a cardiac limitation to exercise attributed to inability to augment stroke volume (decreased % predicted peak O2 pulse). 1 had an abnormal respiratory exchange ratio (RER <1.10), with a normal % predicted peak O2 pulse and a chronotropic deficit (achieving 60% predicted peak heart rate). Of note, 2 patients had normal exercise tolerance with ppVO2_max >85%. <h3>Conclusion</h3> Despite maximal effort, low exercise tolerance is common among pediatric LTx recipients. The high prevalence of CRFs, diastolic dysfunction, and inability to augment stroke volume suggest a potential cardiac contribution to exercise intolerance for this cohort. Further studies are needed to define potential cardiac issues in exercise tolerance in pediatric LTx recipients.

Anti-HLA DQ Antibodies Are Associated with Chronic Lung Allograft Dysfunction in a Pediatric Lung Transplant Population

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) limits long term survival after lung transplantation. Antibody mediated rejection (AMR) has been associated with earlier CLAD development, but studies are limited in children. Clinical AMR can exist on a spectrum from subclinical to definite AMR based on the presence of anti-HLA donor specific antibodies (DSA), allograft dysfunction, and histopathologic findings, with DSA development first to appear. This study aims to describe the relationship of elevated DSA with clinical outcomes in a single center pediatric lung transplant population. <h3>Methods</h3> This was a single center, retrospective study. Pediatric bilateral lung transplant recipients were included from 2002-2020 if they had longitudinal HLA and lung function data for at least 6 months after transplantation. Preliminary analyses with chi-squared or Fisher's exact test for categorical variables and ANOVA or Kruskal-Wallis for continuous variables were used. DSA were detected with single-antigen bead arrays, and elevated DSA was defined as a mean fluorescence intensity level above 500. <h3>Results</h3> 34 patients were included: 19 with elevated DSA and 15 without. Most patients had subclinical AMR (n=10) without allograft dysfunction and two patients had definite AMR, based on the 2018 Banff consensus statement. The proportion of patients who developed CLAD was significantly higher in the elevated DSA group and had an earlier onset of CLAD. Average graft longevity and rates of acute cellular rejection, while not significant, trended towards shorter survival and higher rates of rejection in the elevated DSA group. All persistently elevated DSA were directed against HLA Class II DQ (6 of 14 patients) epitopes. Survival analysis and the significance of different HLA antigens remains ongoing. <h3>Conclusion</h3> The development of persistently elevated HLA Class II DQ DSA is associated with CLAD and likely decreased survival in the pediatric lung transplant population.

Cardiovascular Burden Is High in Pediatric Lung Transplant Recipients.

Cardiovascular morbidity is common in adults after lung transplantation (LTx) but has not been described for pediatric LTx recipients. Early subclinical cardiovascular damage is reflected by increases in pulse wave velocity (PWV; indicating arteriosclerosis), intima-media thickness (IMT; indicating atherosclerosis), and left ventricular mass index (LVMI; indicating left ventricular hypertrophy). We annually assessed 47 pediatric LTx recipients in a prospective longitudinal study (144 observations, mean 3.1 visits/patient, range of 1-4 visits, mean follow-up 2.2 y). At inclusion, increased PWV and IMT were detected in 13% and 30%, respectively, and elevated LVMI was detected in 33%. Higher PWV was associated with male sex, longer time since LTx, higher diastolic blood pressure, and lower glomerular filtration rate. Male sex and lower hemoglobin levels were associated with higher IMT, and the presence of diabetes was associated with higher LVMI. Pediatric LTx recipients suffer from a high and sustained burden of subclinical cardiovascular damage. In light of improving long-term outcomes, cardiovascular morbidity needs to be addressed. Our analysis identified classical and nonclassical risk factors to be associated with the measures for cardiovascular damage, which could serve as targets for intervention.

CTOTC-08: A multicenter randomized controlled trial of rituximab induction to reduce antibody development and improve outcomes in pediatric lung transplant recipients

We conducted a randomized, placebo-controlled, double-blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti-thymocyte globulin induction would reduce de novo donor-specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n=15) or placebo (n=12). No rituximab-treated subjects versus five placebo-treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0-p, obliterative bronchiolitis or listing for retransplant). A post-hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0-p showed no difference in outcome (p=.118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).

Remote intervention engagement and outcomes in the Clinical Trials in Organ Transplantation in Children consortium multisite trial

Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre- and 180days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy-five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180days postenrollment (2.9±1.29) compared with pre-enrollment (4.6±2.10), p=.02. At 180days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p=.054). Participants successfully engaged in a long-term remote intervention, and their medication blood levels stabilized. NCT02266888.

Racial/Ethnic Disparities in Receipt of Lung Transplant and In-Hospital Mortality among Pediatric and Adolescent Patients in the United States

The purpose of this study was to analyze racial/ethnic disparity in inpatient mortality among pediatric and adolescent lung transplant recipients (≤19 years old) in the United States (US). The Nationwide Inpatient Sample (NIS) dataset from 2003-2017 was used for this analysis. Survey logistic regression model was utilized to find the association between lung transplant and inpatient mortality among various racial/ethnic groups. The overall inpatient mortality rate was 3.92 per 100 lung transplant hospitalizations. Overall, when adjusted for covariates, those who received lung transplants were 8.49 times as likely to experience inpatient mortality (95% CI: 5.66-12.73) compared to those who did not receive it. The likelihood of inpatient mortality was highest among Hispanics (OR=10.11, 95% CI=4.93-14.95) relative to the findings among other racial/ethnic groups. Our findings may guide healthcare providers when caring for pediatric and adolescent populations from different racial/ethnic backgrounds who need a lung transplant. Copyright © 2021 Salihu, et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

Low Rates of Growth in Paediatric Lung and Heart-Lung Transplant Recipients and Effects on Spirometry

Purpose A retrospective study of paediatric lung and heart-lung transplant (LTx) recipients to assess growth and its relationship with spirometric indices. Methods Analyses of relationships between serially assessed age, height, weight, forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were undertaken. Serial spirometry at identical heights were analysed as means. Percentile height-for-age was calculated from the CDC 2000 dataset.1 95% confidence intervals are presented in parentheses after values. Results 42 LTx recipients ≤17 years (median at LTx = 13.6 years, 62% female) had spirometry and biometric data available. LTx indications included Cystic Fibrosis (n = 20) and Obliterative Bronchiolitis (n = 6). Median follow-up was 1.24 years (0.13-2.35). There was no significant difference between median biometric or spirometry value changes if recipients with 10cm. The median increase in FVC was 0.94L (0.15-1.72). Median predicted FVC and FEV1 were 67.8% (37.5-98.2) and 58.3% (27.8-88.8) of predicted respectively. Growth was not above expected for age with median change in height for age of -2.9 percentiles (-36.2-30.4). LTx recipients 1year follow-up) had a median height change of 7.5cm (-2.1-17.1 and median age-matched height percentile change of-4.55 percentiles (-22.6-13.47). Conclusion Most paediatric LTx recipients did not significantly change height after LTx. Unlike other solid organ Tx, where growth catch-up is expected, this does not occur.2 Additionally, graft function does not appear to impact growth trajectory. While significant steroid exposure contributes, further research will need to delineate the interplay of LTx on pubertal growth, immunosuppression and the effects of underlying conditions.