Faculty Bibliography

Lung transplantation remains the only available therapy for many patients with end-stage lung disease. The number of lung transplants performed has increased significantly, but development of the field was slow compared with other solid-organ transplants. This delayed growth was secondary to the increased complexity of transplanting lungs; the continuous needs for surgical, anesthetics, and critical care improvements; changes in immunosuppression and infection prophylaxis; and donor management and patient selection. The future of lung transplant remains promising: expansion of donor after cardiac death donors, improved outcomes, new immunosuppressants targeted to cellular and antibody-mediated rejection, and use of xenotransplantation or artificial lungs.

Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting.

The benefits of bilateral lung transplantation (BLT) versus single lung transplantation (SLT) are still debated. One impediment to clinical recommendations is that BLT vs. SLT advantages may vary based on underlying disease. Since both options are clinically tenable in patients with emphysema, we conducted a comprehensive assessment of lung allograft survival in this population. Using U.S. registry data, we studied time to all-cause allograft failure in 8,092 patients 12 years or older transplanted from 2006 to 2022, adjusting for recipient, donor, and transplant factors by inverse propensity weighting. Median allograft survival was 6.6 years in BLT compared to 5.3 years in SLT, a 25% risk-adjusted survival advantage of _0.81.3_1.8 years. Risk-adjusted bilateral survival advantages varied between 0.9 and 2.4 years across eleven subgroups. Median allograft survival in BLT was 1.2 years greater than right SLT and 2.0 years greater than left SLT. During the 16-year study period, allograft survival steadily improved for BLT but not for SLT. Although the 25% BLT survival advantage pre-dated the pandemic, COVID-19 may have contributed to an apparent SLT survival decline. Recognizing the possible influence of residual confounding due to selection biases, these findings may aid offer decision-making when both donor lungs are available.

Primary graft dysfunction (PGD) is a major source of morbidity and mortality following lung transplantation, presenting as acute lung injury within 72 hours post-transplantation. Despite advances in surgical techniques and perioperative care, the complex interplay of donor, recipient, and perioperative factors contributes to its development, underscoring the multifactorial nature of PGD. Clinical management of recipients with PGD relies on supportive care strategies, including lung-protective ventilation, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO). Severe cases of PGD may result in significant short- and long-term adverse outcomes, including early mortality. Even for patients who recover from PGD, there is also an associated increased risk of chronic lung allograft dysfunction, further compounding its clinical impact. This review provides a brief review of current knowledge regarding PGD, detailing risk factors, diagnostic criteria, and management approaches while identifying critical gaps in understanding its pathophysiology. Ongoing research is essential to develop innovative therapeutic strategies and improve outcomes for lung transplant recipients.

RATIONALE/BACKGROUND:Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. METHODS:Lower airway samples from 96 LT recipients with varying degrees of PGD were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS:Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference did not reach statistical significance (p=0.06). PGD severity associated with increased BAL neutrophil concentration (p=0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p<0.05). Furthermore, microbial signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p<0.05). C-SPT exhibited differential expression of TNF, SERPINE1 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. CONCLUSIONS:Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.

Cystic degeneration of thymoma can occur, although rarely to the extent that the lesion appears entirely cystic. We present a case of a 26-year-old man with a large anterior mediastinal cyst that was resected with histopathologic examination revealing a cystic thymoma.

OBJECTIVE/UNASSIGNED:Anticoagulation monitoring in patients supported on extracorporeal membrane oxygenation is challenging given the risks of both bleeding and thrombotic complications. Based on our early clinical experience, we revised our heparin protocol by reducing our target anti-factor Xa assay from 0.3 to 0.7 U/mL to 0.15 to 0.5 U/mL, while instituting a partial thromboplastin time cutoff of 70 seconds. We evaluated the impact of this change on bleeding/thrombotic complications. METHODS/UNASSIGNED:A single-center retrospective study of adult patients on extracorporeal membrane oxygenation support was conducted from January 2015 to August 2022. Patients were stratified into groups based on protocol revision: Pre-Revision (2015-2018) or Post-Revision (2019-2022). Our primary end point was the incidence of bleeding/thrombotic complications. Time in therapeutic range was calculated to determine protocol adherence. Poisson regression was performed to correlate time in therapeutic range with the likelihood of complication. RESULTS/UNASSIGNED:008). CONCLUSIONS/UNASSIGNED:A modified heparin monitoring protocol defined by a lower therapeutic anti-factor Xa assay target and a set partial thromboplastin time cutoff correlated with decreases in bleeding/thrombotic complications in patients on extracorporeal membrane oxygenation.