Background:
Lung transplant (LTx) recipients have low long-term survival and a high incidence of bronchiolitis-obliterans syndrome (BOS). However, few long-term, multicenter, and precise estimates of BOS-free survival (a composite outcome of death and BOS) incidence exist.
Methods:
This retrospective cohort study of primary LTx recipients (1994–2011) reported to the ISHLT Thoracic Transplant Registry assessed outcomes through 2012. For the composite primary outcome of BOS-free survival, we used Kaplan-Meier survival and Cox proportional hazards regression, censoring for loss-to-follow-up, end-of-study, and retransplantation. While standard Registry analyses censor at the last consecutive annual complete BOS status report, our analyses allowed for partially missing BOS data.
Results:
Due to BOS reporting standards, 99.1% of the cohort received LTx in North America. During 79,896 person-years of follow-up, single LTx (6,599/15,268; 43%) and bilateral LTx (8,699/15,268; 57%) recipients had a median BOS-free survival of 3.16 (95% CI, 2.99–3.30) years and 3.58 (95% CI, 3.53–3.72) years, respectively. Almost 90% of the single and bilateral LTx recipients developed the composite outcome within 10 years of transplantation. Standard Registry analyses “overestimated” median BOS-free survival by 0.42 years and “underestimated” the median survival after BOS by about a half-year for both single and bilateral LTx (p<0.05).
Conclusions:
A majority of LTx recipients die or develop BOS within 4 years, and very few remain alive and free from BOS at 10 years post-transplantation. Less inclusive Registry analytic methods tend to overestimate BOS-free survival. The Registry would benefit from improved international reporting of BOS and other chronic lung allograft dysfunction (CLAD) events.
Primary graft dysfunction (PGD) is a major limitation in short-and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mt-DAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.
K E Y W O R D Sanimal models, basic (laboratory) research/science, cellular biology, clinical research/practice, immunobiology, innate immunity, ischemia-reperfusion injury (IRI), lung (allograft) function/ dysfunction, lung transplantation/pulmonology, mouse | 1465 SCOZZI et al.
Rationale: Allosensitization may be a barrier to lung transplant. Currently, consideration is not given to allosensitization when assigning priority on the lung transplant waiting list. Objectives: We aimed to examine the association between allosensitization and waiting list outcomes. Methods: We conducted a retrospective single-center cohort study of adults listed for lung transplant at our center between January 1, 2006, and December 31, 2016. We screened candidates for human leukocyte antigen antibodies before listing and examined the association between allosensitization and waiting list outcomes, including likelihood of transplant and death on the waiting list, using a competing risk model. Calculated panel-reactive antibody (CPRA) was used as a continuous measure of allosensitization. Results: Among 746 candidates who were listed for lung transplant during the study period, 263 (35%) were allosensitized, and 483 (65%) were not. In unadjusted analysis, allosensitized candidates had a decreased likelihood of transplant compared with nonallosensitized candidates (subhazard ratio [sHR], 0.71; 95% confidence interval [CI], 0.60-0.83; P , 0.001) and were more likely to die on the waiting list (sHR, 1.66; 95% CI, 1.08-2.58; P , 0.001). In multivariable modeling, increasing CPRA was associated with an increased risk of death and a decreased likelihood of transplant (sHR for death, 1.15 per 10% increase in CPRA; 95% CI, 1.07-1.22; P , 0.001; sHR for transplant, 0.89 per 10% increase in CPRA; 95% CI, 0.86-0.91; P , 0.001). Conclusions: Broad allosensitization was associated with longer waiting times, decreased likelihood of transplant, and increased risk of death among candidates on the waiting list for lung transplant. Consideration of allosensitization in organ allocation strategies might help mitigate this increased risk in highly allosensitized candidates.
Although neutropenia is a common complication following lung transplantation, its relationship to recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and Granulocyte Colony Stimulating Factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (ANC 1000-1499), moderate (500-999) or severe (<500) and also as a timevarying continuous variable. Association with survival, acute rejection (ACR) and chronic lung allograft dysfunction (CLAD) were assessed by Cox proportional hazards regression. GCSF therapy impact on survival, CLAD and ACR development was analyzed by propensity score matching. 101 of 228 patients (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality when compared to recipients with no (adjusted hazard ratio (aHR) 2.97, 95%
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