Pseudomonas aeruginosa Infection and Inflammation in Cystic Fibrosis: A Pilot Study With Lung Explants and a Novel Histopathology Scoring System.

PURPOSE: Pseudomonas aeruginosa is the predominant bacterial pathogen colonizing the cystic fibrosis (CF) lung. Mixed populations of nonmucoid and mucoid variants of P. aeruginosa have been isolated from the CF airway. While the association between mucoid variants and pulmonary function decline is well-established, their impact on inflammation and tissue damage in advanced CF lung disease remains unclear. METHODS: This pilot study utilized 1 non-CF and 3 CF lung explants to examine lobar distribution, inflammation, and histopathology related to nonmucoid and mucoid P. aeruginosa infection. To study tissue damage, we developed a novel lung histopathology scoring system, the first applied to human CF lung biopsies, which is comprised of five indicators: bronchiolar epithelial infiltrate, luminal inflammation, peribronchial/bronchiolar infiltrate, peribronchiolar fibrosis, and alveolar involvement. RESULTS: Mucoid P. aeruginosa variants were distributed throughout the CF lung but associated with greater concentrations of proinflammatory cytokines, IL-1ß, TNF-α, IL-6, IL-8, and IFN-γ, and one anti-inflammatory cytokine, IL-10, compared to nonmucoid variants. CF lung explants exhibited higher histopathology scores compared to a non-CF lung control. In mixed-variant infection, nonmucoid constituents associated with increased bronchiolar epithelial infiltration, one indicator of histopathology. CONCLUSION: This pilot study suggests ongoing interplay between host and bacterial elements in late-stage CF pulmonary disease. Mucoid P. aeruginosa infection correlates with inflammation regardless of lung lobe, whereas nonmucoid P. aeruginosa is associated with increased inflammatory cell infiltration. The development of a novel lung histopathology scoring system lays the groundwork for future large-cohort investigations.

xTrends in racial and ethnic disparities in pediatric lung transplantation in the United States.

BACKGROUND: Racial and ethnic disparities in pediatric lung transplantation (LTx) related to the shifting cystic fibrosis (CF) population receiving highly effective modulator therapy (HEMT) has not been well investigated. METHODS: The UNOS Registry was queried for patients age 1-25 years undergoing bilateral LTx between 1 January 2012 and 31 December 2021. Race and ethnicity were classified as non-Hispanic White, non-Hispanic Black, Hispanic, or none of the above. The primary outcome was posttransplant mortality. Trends in the association between race/ethnicity and mortality were examined using transplant year as a continuous variable and stratifying year based on introduction of HEMT (triple combination therapy) in November 2019. RESULTS: In the study sample (N = 941), 7% of patients were non-Hispanic Black, 15% were Hispanic, and 2% were some other racial or ethnic group. One hundred (11%) received LTx after approval of triple combination therapy, and 407 (43%) died during follow-up. We identified a statistically significant disparity in mortality hazard (hazard ratio: 1.91; 95% confidence interval: 1.31, 2.80) in non-Hispanic Black compared to non-Hispanic White patients in the pre-triple combination therapy era. CONCLUSIONS: We found higher mortality hazard among non-Hispanic Black compared to non-Hispanic White children undergoing LTx in the United States. Further monitoring of LTx outcomes to identify and address disparities is needed in the current era of triple combination therapy for CF.

Outcomes of Concomitant Cardiac Surgical Procedures Performed During Pediatric Lung Transplantation in the United States.

Data on concomitant cardiac surgery (CCS) performed during pediatric lung transplantation (LTx) is limited. Therefore, we conducted a multi-institutional analysis to identify the incidence and outcomes of CCS in pediatric (< 18 years) LTx recipients by merging data (2004-2023) from the United Network for Organ Sharing (UNOS) and Pediatric Health Information System (PHIS) databases. Of the total of 596 pediatric LTx recipients, 87 (15%) underwent CCS. The majority of these cardiac surgeries were atrial septal defect (ASD) closure (90%) followed by aortic arch/descending aortic repair (3%), atrial repair (3%), ventricular septal defect closure (2%), patent ductus arteriosus ligation (2%), and tricuspid valve repair (2%). The median age at LTx was 3 years (IQR: 0-12). Pulmonary hypertension (PHT) was the predominant indication for LTx (54%). Survival to discharge was 94% and 5-years survival was 64%. Our findings indicate CCS in children undergoing LTx has acceptable outcomes.

Flexible bronchoscopy in pediatric lung transplantation.

Pediatric lung transplantation represents a treatment option for children with advanced lung disease or pulmonary vascular disorders who are deemed an appropriate candidate. Pediatric flexible bronchoscopy is an important and evolving field that is highly relevant in the pediatric lung transplant population. It is thus important to advance our knowledge to better understand how care for children after lung transplant can be maximally optimized using pediatric bronchoscopy. Our goals are to continually improve procedural skills when performing bronchoscopy and to decrease the complication rate while acquiring adequate samples for diagnostic evaluation. Attainment of these goals is critical since allograft assessment by bronchoscopic biopsy is required for histological diagnosis of acute cellular rejection and is an important contributor to establishing chronic lung allograft dysfunction, a common complication after lung transplant. Flexible bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy plays a key role in lung transplant graft assessment. In this article, we discuss the application of bronchoscopy in pediatric lung transplant evaluation including historical approaches, our experience, and future directions not only in bronchoscopy but also in the evolving pediatric lung transplantation field. Pediatric flexible bronchoscopy has become a vital modality for diagnosing lung transplant complications in children as well as assessing therapeutic responses. Herein, we review the value of flexible bronchoscopy in the management of children after lung transplant and discuss the application of novel techniques to improve care for this complex pediatric patient population and we provide a brief update about new diagnostic techniques applied in the growing lung transplantation field.

ECMO Bridge to Lung Transplant in Children with Idiopathic Pulmonary Arterial Hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) represents an important clinical indication for lung transplant (LTx) in children. Recent trends show fewer children with IPAH are undergoing LTx nowadays compared to previous time periods, including those with most severe form of the disease. Using the UNOS Registry, we investigated if ECMO at the time of transplant impacts post-transplant survival in children with IPAH. A total of 74 LTx recipients while on ECMO at the time of transplant were identified (IPAH: N = 12). Children with IPAH who underwent LTx while on ECMO had shown comparable survival rates to those who were on ECMO for other conditions. This analysis provides encouraging results, supporting the potential expansion of LTx for this patient population. Given the low number of children undergoing LTx, we think there should be a consensus document to provide better guidance for referring and selecting the high-risk pediatric population with IPAH on ECMO for lung transplant.

Magnetic Resonance Elastography and Computational Modeling Identify Heterogeneous Lung Biomechanical Properties during Cystic Fibrosis.

The lung is a dynamic mechanical organ and several pulmonary disorders are characterized by heterogeneous changes in the lung's local mechanical properties (i.e. stiffness). These alterations lead to abnormal lung tissue deformation (i.e. strain) which have been shown to promote disease progression. Although heterogenous mechanical properties may be important biomarkers of disease, there is currently no non-invasive way to measure these properties for clinical diagnostic purposes. In this study, we use a magnetic resonance elastography technique to measure heterogenous distributions of the lung's shear stiffness in healthy adults and in people with Cystic Fibrosis. Additionally, computational finite element models which directly incorporate the measured heterogenous mechanical properties were developed to assess the effects on lung tissue deformation. Results indicate that consolidated lung regions in people with Cystic Fibrosis exhibited increased shear stiffness and reduced spatial heterogeneity compared to surrounding non-consolidated regions. Accounting for heterogenous lung stiffness in healthy adults did not change the globally averaged strain magnitude obtained in computational models. However, computational models that used heterogenous stiffness measurements predicted significantly more variability in local strain and higher spatial strain gradients. Finally, computational models predicted lower strain variability and spatial strain gradients in consolidated lung regions compared to non-consolidated regions. These results indicate that spatial variability in shear stiffness alters local strain and strain gradient magnitudes in people with Cystic Fibrosis. This imaged-based modeling technique therefore represents a clinically viable way to non-invasively assess lung mechanics during both health and disease.

Preventive service utilization among adults with cystic fibrosis covered by private insurance is comparable to the general population.

BACKGROUND: As the life expectancy of the cystic fibrosis (CF) population is lengthening with modulator therapies, diligent age-appropriate screening and preventive care are increasingly vital for long-term health and wellbeing. METHODS: We performed a retrospective analysis comparing rates of receiving age- and sex-appropriate preventive services by commercially insured adult people with CF (PwCF) and adults without CF from the general population (GP) via the Truven Health MarketScan database (2012-2018). RESULTS: We captured 25,369 adults with CF and 488,534 adults from the GP in the United States. Comparing these groups, we found that 43% versus 39% received an annual preventive visit, 28% versus 28% were screened for chlamydia, 38% versus 37% received pap smears every 3 years (21-29-year-old females), 33% versus 31% received pap smears every 5 years (30-64-year-old females), 55% versus 44% received mammograms, 23% versus 21% received colonoscopies, and 21% versus 20% received dyslipidemia screening (all screening rates expressed per 100 person-years). In age-stratified analysis, 18-27-year-old PwCF had a lower rate of annual preventive visits compared to adults in the same age group of the GP (27% versus 42%). CONCLUSIONS: We discovered a comparable-to-superior rate of preventive service utilization in adults with CF relative to the GP, except in young adulthood from 18-27 years. Our findings establish the importance of meeting the primary care needs of adults with CF and call for development of strategies to improve preventive service delivery to young adults.

Lung Transplantation for Pulmonary Vascular Disease in Children: A United Network for Organ Sharing Analysis.

Pulmonary vascular disease (PVD) represents an important clinical indication for lung transplant (LTx) in infants, children, and adolescents. There is limited information on LTx outcomes in these patients. We explored LTx volumes and post-LTx survival in children with PVD compared to other diagnoses. The UNOS Registry was queried from 1989 to 2020 to identify first-time pediatric LTx recipients (< 18 yo). PVD was categorized as idiopathic pulmonary arterial hypertension (IPAH) and non-idiopathic arterial hypertension (non-IPAH) and compared to all other patients as other diagnoses. Univariate and multivariate regression models were performed. 984 pediatric LTx patients (593 before 2010 and 391 during/after 2010) were identified, of which 145 (14.7%) had PVD. There has been no significant change in annual rate of all LTxs over comparative eras. However, there has been a decrease in rate of LTxs for PVD patients. Children with PVD had similar survival to other LTx groups in the early era (p = 0.2) and the latter era (p = 0.9). Univariate Cox models, showed that LTx in patients with PVD was associated with a significantly less risk of mortality for children aged 6-11 years compared to younger and older cohorts (HR = 0.4 [0.17-0.98]; p = 0.045), whereas multivariate analysis showed a trend toward higher mortality in 11-17-year-olds (HR = 1.54 [0.97-2.45]; p = 0.06). For PVD patients, oxygen supplementation and ventilator support at LTx were associated with worse post-transplant survival (p = 0.029 and p = 0.01). There has been a decrease in LTx volume for pediatric patients with PVD in the modern era. Post-LTx outcomes for children with PVD are similar to those of other diagnoses in both eras, with children aged 6-11 years having the best survival. Given these findings, LTx should be considered for this patient population.

Lung Transplantation for Pulmonary Vascular Disease in Children: A United Network for Organ Sharing Analysis.

Background: Pulmonary vascular disease (PVD) represents an important clinical indication for lung transplant (LTx) in infants, children, and adolescents. There is limited information on LTx outcomes in these patients. We explored LTx volumes and post-LTx survival in children with PVD compared to other diagnoses. Methods: The UNOS Registry was queried from 1989-2020 to identify first-time pediatric LTx recipients (<18 yo). PVD was categorized as idiopathic pulmonary arterial hypertension (IPAH) and non-idiopathic arterial hypertension (non-IPAH) and compared to all other patients as other diagnoses. Univariate and multivariate regression models were performed. Results: 984 pediatric LTx patients (593 before 2010 and 391 during/after 2010) were identified, of which 145 (14.7%) had PVD. There has been no significant change in annual rate of all LTxs over comparative eras. However, there has been a decrease in rate of LTxs for PVD patients. Children with PVD had similar survival to other LTx groups in the early era (p=0.2) and the latter era (p=0.9). Univariate Cox models, showed that LTx in patients with PVD was associated with a significantly less risk of mortality for children aged 6-11 years compared to younger and older cohorts (HR=0.4 [0.17-0.98];p=0.045), whereas multivariate analysis showed a trend towards higher mortality in 11-17-year-olds (HR=1.54 [0.97-2.45];p=0.06). For PVD patients, oxygen supplementation and ventilator support at LTx were associated with worse post-transplant survival (p=0.029 and p=0.01). Conclusions: There has been a decrease in LTx volume for pediatric patients with PVD in the modern era. Post-LTx outcomes for children with PVD are similar to those of other diagnoses in both eras, with children aged 6-11 years having the best survival. Given these findings, LTx should be considered for this patient population.

Improved donor lung size matching by estimation of lung volumes based on chest X-ray measurements.

RATIONALE: Organ size matching is an important determinant of successful allocation and outcomes in lung transplantation. While computed tomography (CT) is the gold standard, it is rarely used in an organ-donor context, and chest X-ray (CXR) may offer a practical and accurate solution in estimating lung volumes for donor and recipient size matching. We compared CXR lung measurements to CT-measured lung volumes and traditional estimates of lung volume in the same subjects. METHODS: Our retrospective study analyzed clinically obtained CXR and CT lung images of 250 subjects without evidence of lung disease (mean age 9.9 ± 7.8 years; 129 M/121F). From CT, each lung was semi-automatically segmented and total lung volumes were quantified. From anterior-posterior CXR view, each lung was manually segmented and areas were measured. Lung lengths from the apices to the mid-basal regions of each lung were measured from CXR. Quantified CT lung volumes were compared to the corresponding CXR lung lengths, CXR lung areas, height, weight, and predicted total lung capacity (pTLC). RESULTS: There are strong and significant correlations between CT volumes and CXR lung areas in the right lung (R2 = .89, p < .0001), left lung (R2 = .87, p < .0001), and combined lungs (R2 = .89, p < .0001). Similar correlations were seen between CT volumes and CXR measured lung lengths in the right lung (R2 = .79, p < .0001) and left lung (R2 = .81, p < .0001). This correlation between anatomical lung volume (CT) and CXR was stronger than lung-volume correlation to height (R2 = .66, p < .0001), weight (R2 = .43, p < .0001), or pTLC (R2 = .66, p < .0001). CONCLUSION: CXR measures correlate much more strongly with true lung volumes than height, weight, or pTLC. The ability to obtain efficient and more accurate lung volume via CXR has the potential to change our current listing practices of using height as a surrogate for lung size, with a case example provided.

The Many Hosts of Mycobacteria 9 (MHM9): A conference report.

The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.

Extracorporeal membrane oxygenation bridge to pediatric lung transplantation: Modern era analysis.

BACKGROUND: Survival outcomes of children on extracorporeal membrane oxygenation (ECMO) at time of lung transplant (LTx) remain unclear. METHODS: Pediatric first-time LTx recipients transplanted between January 2000 and December 2020 were identified in the United Network for Organ Sharing Registry to compare post-transplant survival according to ECMO support at time of transplant. For a comprehensive analysis of the data, univariate analysis, multivariable Cox regression, and propensity score matching were performed. RESULTS: During the study period, 954 children under 18 years of age underwent LTx with 40 patients on ECMO. We did not identify a post-LTx survival difference between patients receiving ECMO when compared to those that did not. A multivariable Cox regression model (Hazard ratio = 0.83; 95% confidence interval: 0.47, 1.45; p = .51) did not demonstrate an increased risk for death post-LTx. Lastly, a propensity score matching analysis, retaining 33 ECMO and 33 non-ECMO patients, further confirmed no post-LTx survival difference comparing ECMO to no ECMO cohorts (Hazard ratio = 0.98; 95% confidence interval: 0.48, 2.00; p = .96). CONCLUSIONS: In this contemporary cohort of children, the use of ECMO at the time of LTx did not negatively impact post-transplant survival.

Atrial arrhythmias following lung transplant: a single pediatric center experience.

Background: Outcomes after lung transplant (LTx) in children have slowly improved. Although atrial arrhythmia (AA) is a common and adverse complication following LTx among adults, there is limited data on pediatric recipients. We detail our pediatric single-center experience while providing further insights on occurrence and management of AA following LTx. Methods: A retrospective analysis of LTx recipients at a pediatric LTx program from 2014 to 2022 was performed. We investigated timing of occurrence and management of AA following LTx, and its effect on post-LTx outcome. Results: Three out of nineteen (15%) pediatric LTx recipients developed AA. The timing of occurrence was 9-10 days following LTx. Those patients in the older age group (age >12 years old) were the only ones who developed AA. Developing AA did not have a negative effect on hospital stay duration or short-term mortality. All LTx recipients with AA were discharged home on therapy that was discontinued at 6 months for those who was on mono-therapy without recurrence of AA. Conclusions: AA is an early post-operative complication in older children and younger adults undergoing LTx at a pediatric center. Early recognition and aggressive management can mitigate any morbidity or mortality. Future investigations should explore factors that place this population at risk for AA in order to prevent this complication post-operatively.

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.

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

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Lung Transplantation for Bronchopulmonary Dysplasia.

BACKGROUND: Patients with bronchopulmonary dysplasia (BPD) have poor respiratory trajectories and are at increased risk of lung function decline with age. Lung transplant (LTx) is a possible treatment option for this growing patient population, but little has been published on LTx in this patient group. RESEARCH QUESTION: What are the characteristics of patients with BPD who are listed for LTx? How do waitlist and post-LTx outcomes for BPD compare with LTx for other diagnoses? STUDY DESIGN AND METHODS: The United Network for Organ Sharing (UNOS) registry was queried for patients of all ages listed for or who underwent LTx (2000-2020). Descriptive analysis, waitlist outcomes, and post-LTx survival at 1, 5, and 10 years were assessed comparing patients with BPD vs LTx patients with other diagnoses. Post-LTx survival for patients with BPD born in the pre-surfactant era (pre-SE, before 1990) and those born in the post-surfactant era (post-SE) was compared. Propensity score matching was performed to control for the risk factors and match patients with BPD with other LTx patients on a 1:1 ratio. RESULTS: BPD was reported in 65 patients, of whom 32 (49.2%) underwent LTx. Patients with BPD at listing were younger than those with other diagnoses (median age, 21 [interquartile range, 5-31] years vs 57 [45-63] years; P < .001), and more were likely to receive mechanical ventilation at listing (23% vs 3.7%; P < .001). Patients with BPD had an FEV1 of 17% compared with 34% predicted in other patients (P = .002). Patients with BPD had an overall similar post-LTx survival compared with patients with other diagnoses (P = .106), even following propensity score matching (P = .41). INTERPRETATION: LTx for BPD has increased over the last 20 years. Patients with BPD have similar post-LTx outcomes compared with those of other patient populations in the modern era. Thus, LTx could be considered for patients with BPD experiencing progressive respiratory deterioration.