Joshua M. Diamond

Rationale: Primary graft dysfunction (PGD) after lung transplant is associated with increased mortality. Whether PGD increases mortality via long-term effects on allograft function is poorly understood. Objective: Evaluate the association of PGD with potential lung function and chronic lung allograft dysfunction (CLAD). Methods: We included lung transplant recipients enrolled in an 8-center prospective cohort study from 2007-2018. PGD was defined by ISHLT criteria. Linear mixed effects and logistic regression models evaluated the association between PGD and maximum potential forced expiratory volume in 1 second (FEV1) and whether Global Lung Function Initiative defined (GLI) predicted FEV1 was attained, respectively. Flexible parametric survival models evaluated the association between PGD and CLAD, accounting for confounding and mortality as a competing risk. Measurements and Main Results: Among 2419 recipients, 510 had PGD. Recipients with PGD had lower maximum potential FEV1 (-311 ml, 95% CI -245 to -377 ml) and were less likely to achieve GLI-predicted FEV1 (probability difference -12.5%, 95% CI -17 to -8%). 930 recipients developed CLAD (405 obstructive, 525 restrictive) over median (IQR) 5.9 (3.0-8.0 years). The 5-year cumulative incidence of CLAD did not differ by PGD (cumulative difference: -2.2%, 95% CI - 6.4% to 1.9%). This association was not modified by age, sex, BMI, pretransplant diagnosis, or transplant type. PGD was not associated with a difference in cumulative incidence of obstructive or restrictive CLAD (cumulative difference -1.2% and -0.8%, respectively). Conclusion: PGD is associated with reduced lung function and lower likelihood of achieving GLI-predicted maximum potential lung function but not CLAD.

Introduction: Prolonged invasive mechanical ventilation (IMV) after lung transplantation is an appealing early prognostic outcome as it can be reproducibly assessed both prospectively and retrospectively. Whether use of IMV at 72 h after lung transplantation is associated with post‐transplant graft survival is unknown. Methods: We performed a retrospective cohort study of 1511 participants in the multi‐center Lung Transplant Outcomes Group cohort (2011–2018). Using Cox proportional hazards models and restricted mean survival time, we investigated whether IMV at 72 h was associated with post‐transplant graft survival. We secondarily evaluated whether IMV at 72 h was concordant with severe primary graft dysfunction (PGD). Results: Participants requiring IMV at 72 h after transplant were sicker at transplantation (higher lung allocation score [LAS], increased extracorporeal membrane oxygenation, or IMV bridge) and more likely to have severe PGD. Use of IMV at 72 h was associated with 55% (95% CI 26%–92%) increased hazards of death or re‐transplantation after adjustment for age, ECMO, diagnosis, LAS, and intra‐operative transfusion. The association between IMV and graft survival was modified by severe PGD ( p ‐for interaction 0.002) but not by pre‐transplant ECMO ( p ‐for interaction 0.88) or pre‐transplant IMV ( p ‐for interaction 0.92). IMV was associated with increased risk of death or re‐transplantation among those with PGD (HR 2.35, 95% CI 1.43–3.85) but not among those without PGD (HR 1.04, 95% CI 0.77‐1.41). Conclusion: Requirement of IMV at 72 h is an important early post‐transplant outcome associated with post‐transplant survival. This appears driven by those with severe PGD.

Severe lung injury causes airway basal stem cells to migrate and outcompete alveolar stem cells, resulting in dysplastic repair. We found that this “stem cell collision” generates an injury-induced tissue niche containing keratin 5 ⁺ epithelial cells and plastic Pdgfra ⁺ mesenchymal cells. Single-cell analysis revealed that the injury-induced niche is governed by mesenchymal proliferation and Notch signaling, which suppressed Wnt/Fgf signaling in the injured niche. Conversely, loss of Notch signaling rewired alveolar signaling patterns to promote functional regeneration and gas exchange. Signaling patterns in injury-induced niches can differentiate fibrotic from degenerative human lung diseases through altering the direction of Wnt/Fgf signaling. Thus, we have identified an injury-induced niche in the lung with the ability to discriminate human lung disease phenotypes.