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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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

BACKGROUND: 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. METHODS: 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). RESULTS: 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% vs 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). CONCLUSION: 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.

Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency.

ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease. However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression. Additionally, monoallelic ABCA3 variants have been reported in infants and children with ABCA3-deficient phenotypes. The effects of most ABCA3 variants identified in patients have not been characterized at the RNA level. ABCA3 allele-specific expression occurs in some cell types due to epigenetic regulation. We obtained lung tissue at transplant or autopsy from 16 infants and children with ABCA3 deficiency due to compound heterozygous ABCA3 variants for biologic characterization of the predicted effects of ABCA3 variants at the RNA level and determination of ABCA3 allele expression. We extracted DNA and RNA from frozen lung tissue and reverse-transcribed cDNA from mRNA. We performed Sanger sequencing to assess allele-specific expression by comparing the heights of variant nucleotide peaks in amplicons from genomic DNA and cDNA. We found similar genomic and cDNA variant nucleotide peak heights and no evidence of allele-specific expression among explant or autopsy samples with biallelic missense ABCA3 variants (n = 6). We observed allele-specific expression of missense alleles in trans with frameshift (n = 4) or nonsense (n = 1) variants, attributable to nonsense-mediated decay. The missense variant c.53 A > G;p.Gln18Arg, located near an exon-intron junction, encoded abnormal splicing with skipping of exon 4. Biologic characterization of ABCA3 variants can inform discovery of variant-specific disease mechanisms.

Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation.

BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD). METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients. RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival. CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

Infections Within the First Month After Pediatric Lung Transplantation: Epidemiology and Impact on Outcomes.

BACKGROUND: Despite successes in lung transplantation, with infection as the leading cause of death in the first year following lung transplantation, there remains a lag in survival compared with other solid organ transplants. Infections that occur early after transplantation may impact short- and long-term outcomes in pediatric lung transplant recipients (LTRs). METHODS: We performed a retrospective review of pediatric LTRs at a large quaternary-care hospital from January 2009 to March 2016 to evaluate both epidemiologic features of infection in the first 30 days post-transplantation and mortality outcomes. The 30 days were divided into early (0-7 days) and late (8-30 days) periods. RESULTS: Among the 98 LTRs, there were 51 episodes of infections. Cystic fibrosis (CF) was associated with early bacterial infections (P = .004) while non-CF was associated with late viral (P = .02) infections. Infection after transplantation was associated with worse survival by Kaplan-Meier analysis (P value log rank test = .007). Viral infection in the late period was significantly associated with 3-year mortality after multivariable analysis (P = .02). CONCLUSIONS: Infections in pediatric LTRs were frequent in the first 30 days after transplant, despite perioperative antimicrobial coverage. The association of 3-year mortality with late viral infections suggests a possible important role in post-transplant lung physiology and graft function. Understanding the epidemiology of early post-lung transplant infections can help guide post-operative management and interventions to reduce their incidence and the early- and long-term impact in this population.

Inhaled hypertonic saline after pediatric lung transplant-Caution required?

Management of pulmonary infection following lung transplant is multifaceted and includes respiratory physiotherapy. Inhaled hypertonic saline (HTS) has been introduced as an adjunct to physiotherapy in pediatric transplant patients. There are no published studies investigating the use of HTS in this population. This study aimed to evaluate the effect of inhaled HTS, in the acute post-operative period, in pediatric lung transplant patients. A retrospective case-note review was completed at a single UK pediatric transplant center. An intervention group who received HTS was compared to a historical control group. Participants were frequency matched for age, gender, and diagnosis (14 per group); median age in years was 13.7(IQR 12.7-15.3) in the controls and 14.8(IQR 12.4-16.1) in the intervention group. Primary outcome was the requirement of invasive and non-invasive ventilation. Secondary outcomes included oxygen use and length of stay. Median days of invasive ventilation were shorter in the control group (1, 95% CI 1-1) compared to the intervention group (2, 95% CI 1-2.5) (P < .05). Days of non-invasive ventilation and oxygen were higher in the HTS group, but this was not statistically significant. The controls displayed shorter median length of stay (23 days, 95% CI 20-24) compared to the intervention group (31 days, 95% CI 24.5-39) (P < .05). The results of this small study provide uncertainty regarding the safety of inhaled hypertonic saline after lung transplant. There was a trend of poorer acute outcomes in patients who received HTS. However, the findings should be interpreted with caution and further investigation using larger samples is required.

Neuropsychological outcomes following pediatric lung transplantation.

OBJECTIVE: Lung transplantation (LTx) is a treatment option for eligible children with end-stage pulmonary diseases. Improving our understanding of longer-term developmental outcomes in pediatric LTx recipients is important for strategized interventions targeting cognitive difficulties. METHODS: Neuropsychological assessments were completed for children who received LTx at our center (2009-2017). Assessments comprised tasks of general intellect, memory, visual-perception, academics, and executive functioning as well as caregiver questionnaires of adaptive, executive, emotional, and behavioral functioning. Results were compared to age-matched population norms. Between-group nonparametric tests were performed pre-LTx vs post-LTx and for children with a primary diagnosis of cystic fibrosis (CF) vs other diagnoses (non-CF). RESULTS: Neuropsychological outcomes were assessed for 21 children post-LTx, with a median age (interquartile range) at the time of transplant of 11.52 (6.89, 14.12) years. Eleven children completed pre- and post-transplant assessments and within this group, improvements for verbal learning (P = .02), aspects of mood, behavior, and adaptive functioning were observed over time (all P < .05). Post-transplant whole group analysis suggested age-appropriate abilities across most cognitive domains, with a relative weakness for executive functioning. Emotional or behavioral difficulties were not endorsed by caregivers. Across pulmonary diagnoses, higher levels of emotional, behavioral, and executive functioning difficulty were reported in the non-CF group (all P < .05). CONCLUSIONS: Overall, LTx has a positive impact on cognitive functioning, particularly learning, adaptive functioning, mood, and behavior. Children transplanted for non-CF related diseases demonstrated greater challenges, highlighting the need for targeted assessments and interventions across the transplant process to support the complex needs of this population.

Waiting list outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs.

BACKGROUND: Low case volume has been associated with lower survival after pediatric lung transplantation. Our aim was to analyze waitlist outcomes among pediatric lung transplant centers in the USA. METHODS: We studied a cohort of 1,139 pediatric candidates listed in the Organ Procurement and Transplantation Network for lung transplantation between 2002 and 2014. Of these candidates, 720 (63.2%) received a transplant. Candidates were divided into groups according to the clinical activity of the center of listing: high-volume pediatric (≥4 transplants per year); low-volume pediatric (<4 transplants per year); and adult (transplant volume predominantly in adults). We used multivariate Cox regression analysis to identify independent risk factors for waitlist mortality. We also determined the transplant rate-or likelihood of transplant after listing-over the study period. RESULTS: Fifty-eight percent of the children and adolescents were listed in adult centers where the resultant transplant rate was low-only 42% received a transplant compared with 93% in pediatric programs. Listing in an adult program was also the most significant risk factor for death on the waiting list (hazard ratio 15.6, 95% confidence interval 5.8 to 42.1). CONCLUSIONS: Most children (58%) are listed for lung transplantation in adult centers and have a reduced rate of transplantation and a greater chance of waitlist mortality.

Lung clearance index is sensitive to small airway disease in pediatric lung transplant recipients.

BACKGROUND: The principal obstacle to long-term survival after lung transplant is chronic lung allograft dysfunction (CLAD), which primarily affects the small airways. After transplant, patients are monitored with spirometry, which is a generally insensitive detector of small airways obstruction. The lung clearance index (LCI) is a measure obtained during multiple breath washout (MBW) maneuvers. We hypothesized that among lung allograft recipients, LCI would detect small airways disease not detected with spirometry. METHODS: This study enrolled 15 patients, 5 of whom already had a diagnosis of CLAD. We added MBW as an additional index of peripheral airway function to the established post-transplant routine care protocol. RESULTS: Of trials, 87.9% yielded valid measurements, and single maneuvers were 2-8 minutes. LCI did not yield any false-negative findings-no patients were considered obstructed by forced expiratory volume in 1 second (FEV1) but normal by LCI. At enrollment, 6 patients without CLAD had an elevated LCI, and 4 progressed to CLAD. Only 2 of these 4 patients would have been identified by a decrease in FEV1. CONCLUSIONS: LCI identified lung allograft dysfunction in more patients than the use of standardized spirometric measures, including patients with abnormal FEV1. These data suggest that LCI from MBW may be a more sensitive means to detect allograft peripheral airway disease than standard methods for measurement of small airways function.