Faculty Bibliography

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.

BACKGROUND:Donor pool expansion is critical as lung candidates suffer high mortality, yet older donor lungs remain underutilized. We evaluated whether accepting an older donor (defined 4 ways: donor age 30-39, 40-49, 50-59, or 60-69 y) lung transplant was associated with a survival benefit over waiting for a younger donor offer. METHODS:Adult candidates who received a lung offer were identified using Scientific Registry of Transplant Recipients data, 2015-2022. Offers were categorized by donor age and candidate lung allocation score (LAS; <40, 40-55, >55). Postoffer mortality was compared between candidates for whom the offer was accepted ("acceptors") versus declined ("decliners") within each age-LAS category using weighted Cox regression. RESULTS:A total of 21 426 candidates received an offer from a donor age ≥30 y; 11 679 accepted. For LAS >55 candidates, a survival benefit was observed for acceptors of donors ages 30-39 y (weighted hazard ratio [wHR] of mortality: 0.450.520.59), 40-49 y (wHR: 0.610.700.79), and 50-59 y (wHR: 0.670.770.88); P < 0.001. For candidates with LAS 40-55, results suggest a survival benefit of accepting lung offers from donors age 30-39 y (wHR: 0.770.870.99) and 40-49 y (wHR: 0.760.870.99); P = 0.03. However, for candidates with LAS <40, a survival benefit was not observed for accepting any older donor transplant, with possible harm in accepting an age 50+ donor offer. CONCLUSIONS:Compared with declining and waiting for a younger donor offer, accepting an older donor lung transplant was associated with a survival advantage in candidates with high LAS in the precontinuous distribution era. Decision makers should consider these findings while recognizing potential changes in waiting time dynamics in the current era.

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.