Faculty Bibliography

OBJECTIVES/OBJECTIVE:To examine perioperative lactate and its association with survival and postoperative complications following lung transplantation (LTx). DESIGN/METHODS:Single-center retrospective cohort study. SETTING/METHODS:Academic tertiary-care transplant center. PARTICIPANTS/METHODS:Adult patients undergoing LTx between February 2018 and January 2023. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Serum lactate was measured at 6-hour intervals from the start of surgery, and the maximum value within the first 0 to 6 hours was recorded. Patients were categorized into the high-lactate group (upper quartile, ≥4.2 mmol/L) and low-lactate group (lower 3 quartiles). Primary outcomes were 1-year and overall survival. Secondary outcomes included renal failure, venous thromboembolism (VTE), primary graft dysfunction grade 3 (PGD3), mechanical ventilation duration, intensive care unit (ICU) and post-transplant length of stay, and in-hospital mortality. Among 225 recipients (median age, 62.3 years; 34.2% female), high lactate was not associated with 1-year or overall survival. However, recipients with high lactate had higher rates of PGD3 at 72 hours (42.1% v 13.1%, p < 0.001), longer mechanical ventilation duration (3 days v 2 days, p = 0.003), longer ICU stay (11.6 days v 7 days, p = 0.013), and higher in-hospital mortality rate (7% v 0.6%, p = 0.019). No significant differences were observed in renal failure, VTE, or post-transplant length of stay. CONCLUSIONS:Elevated perioperative serum lactate was associated with PGD3 at 72 hours, prolonged mechanical ventilation, longer ICU stay, and in-hospital mortality but not 1-year or overall survival following LTx. These findings suggest that perioperative lactate may aid in identifying high-risk patients early in their postoperative course despite its lack of association with long-term survival.

BACKGROUND:The role of the lower airway microbiome in COVID-19-associated mortality remains poorly understood despite evidence implicating secondary pathogens and non-airway commensals. The influence of prior immunosuppression on the lower airway microbiome and its contribution to mortality in mechanically ventilated patients has been largely unexplored. Given that host-microbiome interactions are dynamic, we assessed longitudinal patterns in the respiratory microbiome associated with mortality and immunosuppression status. RESULTS:We conducted longitudinal forecasting, differential abundance, and comparative network analyses of metatranscriptomic data from 604 upper and lower airway samples collected from 243 mechanically ventilated COVID-19 patients to profile key microbial factors associated with immunosuppression and clinical outcome. SARS-CoV-2 was enriched over time in immunosuppressed patients and in both immunosuppressed and immunocompetent patients who died, highlighting the need for aggressive viral infection control early in the disease course. Using longitudinal forecasting and differential abundance analyses, we observed a progressive increase in opportunistic pathogens, such as Staphylococcus aureus and Escherichia coli, among the taxa most predictive of mortality. Concurrently, immunosuppressed individuals exhibited a significant decrease in typical airway commensals alongside a restructuring and marked destabilization of the microbial community compared with their immunocompetent counterparts. CONCLUSIONS:These findings indicate that loss of airway microbiome stability in immunosuppressed patients constitutes an independent factor contributing to increased susceptibility to opportunistic pathogens and poor clinical outcomes. Video Abstract.

BACKGROUND:Fewer than 20% of donated lungs are transplanted. We examined the impacts of donor management and recovery at an in-hospital donor care unit (DCU) established in 2021 versus the donor hospital (DH). METHODS:(P/F ratio) were examined as a hypothesized effect modifier. We projected the national impact of improved utilization on lung transplant volume. RESULTS:After adjusting for donor differences, lung utilization was 88% higher (aRR: 1.88; 95% CI: 1.40, 2.53) in the DCU versus DH setting. Median P/F ratio increased from 275 to 348 mmHg (p<0.0001) in the DCU and explained approximately 38% of the improvement in lung utilization. Non-lung organ utilization was either improved or non-inferior in the DCU. Lung graft survival and pulmonary function were similar for recipients of DCU versus DH-managed donors. Nationally, an 88% improvement in lung utilization among donors not currently transferred to a DCU could theoretically result in ≥300 more lung transplants per year. CONCLUSIONS:Lung transplantation can be nearly doubled through lung-centric donor management in a DCU, without sacrificing recipient outcomes nor the utilization of other organs. Donor management practices to optimize lung utilization should be proliferated by establishing more DCUs and, where feasible, applying lung-centric protocols in donor hospitals.

BACKGROUND/UNASSIGNED:Efforts to reduce waitlist mortality in lung transplantation have been hindered by a high donor lung non-use rate, with approximately one-fifth of deceased organ donors ultimately providing lungs for transplantation. Rationale for organ decline varies across individual providers and transplant centers. Greater donor lung utilization could significantly reduce waitlist mortality and improve clinical outcomes for adult lung transplant candidates. OBJECTIVE/UNASSIGNED:This study aimed to evaluate whether machine learning models can successfully predict donor lung non-use and characterize donor factors associated with current utilization patterns, with the long-term goal of informing more consistent and data-driven donor lung evaluation. METHODS/UNASSIGNED:Using U.S. national registry data collected between 2012 and 2022, we generated five machine learning models - logistic regression, decision tree, random forest, XGBoost, and Naive Bayes - all of which were trained with 19 donor variables to predict donor lung non-use. Models were tested with both full donor feature sets and restricted donor feature sets comprised of the top 15, 10, and 5 predictors. Performance metrics, including area under the receiver operating characteristic curve (AUROC), accuracy, precision, recall, and F1 score, were assessed using cross-validation. RESULTS/UNASSIGNED:ratio, donor age, body mass index, and serum aspartate aminotransferase levels. More restricted random forest models (i.e., those that only included 5 or 10 predictors) and any of the restricted logistic regression and XGBoost models had inferior but still acceptable performance (AUROC 0.867-0.958). CONCLUSION/UNASSIGNED:Machine learning models, particularly random forest, XGBoost, and logistic regression, accurately predicted donor lung non-use. Restricted models using fewer predictors also maintained strong performance, demonstrating technical feasibility for future evaluation in time-sensitive workflows. Because the models were trained on historical utilization decisions rather than recipient outcomes or independent measures of donor suitability, prospective validation is needed to determine whether they can improve appropriate donor lung utilization or support acceptance decisions without reinforcing practice-pattern bias.

IMPORTANCE/UNASSIGNED:Bronchoscopic biopsy is conventionally performed with forceps, which can result in small specimen sizes and poor specimen quality due to crush artifact. Cryoprobe use localizes freezing at the probe tip, enabling retrieval of larger, more intact biopsy specimens. OBJECTIVE/UNASSIGNED:To evaluate the diagnostic yield of a 1.1-mm cryoprobe for transbronchial biopsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This open-label, outcome assessor-masked, multicenter randomized clinical trial included 500 patients aged 18 years or older scheduled to undergo transbronchial biopsy for lung nodules or masses, lung transplant, or diffuse parenchymal lung disease. The trial was conducted in 9 US medical centers and enrolled patients between February 27, 2023, and September 11, 2024. The date of last follow-up was October 12, 2024. INTERVENTION/UNASSIGNED:Patients were randomized 1:1 to transbronchial biopsy using a 1.1-mm cryoprobe (n = 250) or 2.0-mm forceps (n = 250). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was diagnostic yield, defined as the percentage of patients for whom the transbronchial biopsy sample led to a specific diagnosis based on histologic examination. Of the 8 prespecified secondary analyses, key secondary analyses were the diagnostic yield for each of the 3 conditions (lung nodules or masses, lung transplant, and diffuse parenchymal lung disease) and complication rates. RESULTS/UNASSIGNED:Of 774 patients assessed for eligibility, 609 provided consent, 500 were randomized, and 490 were included in the primary analysis; the mean age was 62.6 years (SD, 12.7 years) and 252 of 500 (50.4%) were male. The primary outcome of diagnostic yield was significantly higher in patients randomized to transbronchial biopsy with cryoprobes vs forceps (217 of 245 [88.6%] vs 193 of 245 [78.8%]; absolute difference, 9.8%; 95% CI, 3.3%-16.3%; P = .003). For the key secondary analyses, compared with that of forceps, the diagnostic yield of cryoprobes was significantly higher among patients with pulmonary nodules or masses (79 of 95 [83.2%] vs 68 of 97 [70.1%]; absolute difference, 13.1%; 95% CI, 1.0%-24.6%; P = .04) and lung transplant (120 of 125 [96.0%] vs 110 of 124 [88.7%]; absolute difference, 7.3%; 95% CI, 0.6%-14.4%; P = .03) but did not differ significantly in diffuse parenchymal lung disease (18 of 25 [72.0%] vs 15 of 24 [62.5%]; absolute difference, 9.5%; 95% CI, -16.0% to 33.6%; P = .55). For the secondary safety analysis, there were 4 pneumothoraces requiring chest tube placement in the forceps group (1.6%) vs none in the cryoprobe group; no patients experienced significant bleeding or respiratory failure events. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Transbronchial lung biopsy performed with a 1.1-mm cryoprobe had a significantly higher diagnostic yield compared with 2.0-mm forceps in a group of patients with lung nodules or masses, lung transplant, and diffuse parenchymal lung disease. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05751278.

Primary graft dysfunction (PGD) is a proinflammatory syndrome occurring within the first days following lung transplantation. It is initiated by ischemia-reperfusion injury and perpetuated by donor and recipient immunologic factors, resulting in alveolar damage and progressive hypoxemic respiratory failure.¹ PGD is a known risk factor for both early allograft failure and chronic lung allograft dysfunction (CLAD).² Incidence of severe PGD remains high at 10-25%, though is variable; risk factors for PGD include center experience, underlying recipient disease type, size matching, donor lung storage conditions, operative time, and post-operative management.² Strategies to prevent PGD or mitigate the long -term consequences after it develops, are sorely needed. However, lack of specificity of the current PGD definition may hamper further progress in the field, especially as it pertains to the development of robust and relevant clinical trials. We propose that future modifications of the PGD definition incorporate more objective surrogates of allograft injury and subsequent diffuse alveolar damage, which may improve our ability to accurately study disease pathogenesis and improve outcomes.

We describe the case of a 36-year-old woman who underwent redo lung transplantation AFTER a heart-lung transplant 3.5 years prior. The retransplantation was performed through sequential left posterolateral thoracotomy followed by right anterior thoracotomy, without sternal division and without the use of extracorporeal membrane oxygenation or cardiopulmonary bypass support. The patient was found to have undergone an extensive pericardiectomy at the time of the initial heart-lung transplant. The patient recovered uneventfully and complete healing of the airway anastomosis was demonstrated. This novel technique avoids some potential pitfalls of redo lung transplantation after heart-lung transplant.

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.

Tacrolimus is highly effective at preventing allograft rejection and prolonging survival after lung transplantation. However, erratic pharmacokinetics may limit efficacy and predispose to greater adverse effects. We conducted a prospective, open-label trial of lung transplant recipients who underwent early conversion (within 30 days) to LCP tacrolimus (LCPT, n = 40) and compared first-year outcomes to an historical control of patients who remained on immediate-release tacrolimus (IRT, n = 24). Subjects were converted 1:1 from IRT to LCPT. The first dose of LCPT overlapped with the last morning dose of IRT. Conversion to LCPT occurred at a median of 17.5 [IQR 12-25] days. The conversion dose ratio was 1.0 mg:mg [IQR 0.75-1.50] at 14 days. At 1 year, there were no differences between LCPT and IRT in the incidence of biopsy-proven (12.5% vs. 25.0%, p = 0.30) or clinically treated (20.0% vs. 25.0%, p = 0.64) acute cellular rejection. However, the severity of any biopsy-proven rejection was significantly higher in the IRT cohort (27.5% vs. 54.2%, p = 0.03). Although not achieving statistical significance, de novo donor-specific antibodies were more commonly observed in the LCPT group (20.0% vs. 4.2%, p = 0.14). Despite this, the incidence of antibody-mediated rejection (7.5% vs. 0.0%, p = 0.29) and early-onset chronic lung allograft dysfunction (7.5% vs. 9.1%, p = 1.00) were similar. The incidence of chronic kidney disease stage 4 or greater at 1-year was similar (7.5% vs. 12.5%, p = 0.66). In conclusion, early conversion to LCPT was feasible and similarly efficacious to IRT in a cohort of lung transplant recipients. Trial Registration: ClinicalTrials.gov identifier: NCT04420195.

Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.