The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Contemporary trends in PGD incidence, outcomes, and therapies.

BACKGROUND: We sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation. METHODS: Patients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders. RESULTS: A total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p = .0002), median LAS (38.0-47.7 p = .009) and the use of ECMO salvage for PGD (5.7%-20.9%, p = .007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p = .0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p = .66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p = .0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]). CONCLUSIONS: PGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.

First lung and kidney multi-organ transplant following COVID-19 Infection.

As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

Estimated impact of hepatitis C-positive lung donor utilization on US donor lung supply.

The availability of highly effective direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection has led to reports of safely transplanting HCV+ donor lungs into HCV- candidates. However, it remains unclear how the ability to use HCV+ donor lungs for lung transplant could affect the number of donor lungs available for transplant. Using Scientific Registry of Transplant Recipient data, we identified all deceased organ donors within the United States from March 1, 2015, to February 28, 2018, and stratified by HCV status. A donor prediction model for lung donation was derived and validated within HCV- donors and applied to HCV+ donors to estimate the number of acceptable HCV+ lung donors. Of 29 481 eligible donors, 2054 (7.0%) were HCV+ donors with 82 HCV+ donors' lungs being used for transplant during the study period. The prediction model for donor lung donation (specificity 92.6%, sensitivity 65.6%) estimated 248 HCV+ donors (75 nonviremic, 173 viremic) were acceptable for lung transplant during the study period, suggesting that 166 acceptable HCV+ lung donors were discarded. The ability to transplant lungs from HCV+ organ donors would lead to an estimated nationwide increase of at least 55 donor lungs per year, including 44 from HCV viremic donors.

Fortification of Preservation Solution With Nitroprusside Does Not Alter Lung Allograft Survival in Clinical Human Lung Transplantation.

Background: Nitric oxide improves gas exchange following primary lung allograft dysfunction. Nitroprusside, a potent nitric oxide donor, has reduced reperfusion injury and improved oxygenation in experimental lung transplantation. Methods: We sought to study the effect on lung allograft outcomes of fortifying the preservation solution with nitroprusside. We conducted a single-center clinical study of 46 consecutive lung recipients between 1998 and 2000: 24 patients received donor organs preserved in modified Euro-Collins solution with prostaglandin E1 (PGE1) (control group), and 22 patients received organs preserved in modified Euro-Collins with PGE1 and nitroprusside (NP group). The primary endpoint was overall survival. Results: Baseline characteristics were similar between the groups except for a significantly longer graft ischemic time in the NP group vs the control group (253.3 ± 52 vs 225.3 ± 41 minutes, respectively, P=0.04). No significant differences were found in partial pressure arterial oxygen to fraction inspired oxygen ratio at ≤48 hours, primary graft dysfunction, or bronchiolitis obliterans-free days. Overall survival at 1, 3, and 5 years was 89%, 73%, and 63% in the control group and 76%, 38%, and 23% in the NP group. Log-rank survival analysis showed that the NP group had a significantly increased risk of mortality (P=0.034) compared to the control group. Conclusion: The addition of nitroprusside to the lung transplant perfusate in this clinical trial did not improve survival; however, a large randomized trial would likely reduce confounding ischemia times and increase the power of the study.

Effect of broader geographic sharing of donor lungs on lung transplant waitlist outcomes.

BACKGROUND: The United States lung allocation system prioritizes allocation based on medical urgency and benefit but does not address a federal mandate for broader geographic organ sharing. It is unknown whether broader geographic sharing of donor lungs would improve lung transplant waitlist outcomes. METHODS: A discrete event microsimulation model simulated donor lung allocation according to different geographic lung-sharing policies, including the historic local donor service area (DSA)-based policy and hypothetical policies that prioritize candidates to donors within 500-mile or 1,000-mile geographic radii. Candidate waitlist mortality, number of transplants, and 1-year survival were compared across organ allocation policies. Waitlist mortality rates were further stratified by diagnosis, Lung Allocation Score (LAS) threshold, ABO blood type, and region. RESULTS: Under broader geographic lung sharing, the proportion of chronic obstructive pulmonary disease transplant recipients decreased, whereas the proportion of pulmonary fibrosis recipients increased. Waitlist mortality decreased with broader geographic lung sharing with a 21.3% decrease in waitlist mortality with 500-mile lung sharing and a 31.8% decrease in waitlist mortality with 1,000-mile lung sharing. The decrease in waitlist deaths occured across all U.S. geographic regions and was greatest in candidates with pulmonary fibrosis and/or high medical urgency. CONCLUSIONS: Broader geographic sharing of donor lungs could reduce waitlist mortality, particularly among pulmonary fibrosis and high-medical-urgency candidates.

Multiple listing in lung transplant candidates: A cohort study.

Lung transplant candidates can be waitlisted at more than one transplant center, a practice known as multiple listing. The factors associated with multiple listing and whether multiple listing modifies waitlist mortality or likelihood of lung transplant is unknown. US lung transplant waitlist candidates were identified as either single or multiple listed using data from the Scientific Registry of Transplant Recipients. Characteristics of single and multiple listed candidates were compared and multivariable logistic regression was used to estimate associations with multiple listing. Multiple listed candidates were matched to single listed candidates using a combination of exact and propensity score matching methods. Cox proportional hazard models were used to estimate the relationship of multiple listing on waitlist mortality and receiving a transplant. Multiple listing occurred in 2.3% of lung transplant waitlist candidates. Younger age, female gender, white race, short stature, high antibody sensitization, college or postcollege education, lower lung allocation score, and a cystic fibrosis diagnosis were independently associated with multiple listing. Multiple listing was associated with an increased likelihood of lung transplant (adjusted hazard ratio [aHR] 2.74, 95% CI 2.37 to 3.16) but was not associated with waitlist mortality (aHR 0.99, 95% CI 0.68 to 1.44).

Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation.

Invasive pulmonary disease due to the mold Aspergillus fumigatus can be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant of A. fumigatus invasion and, consequently, its virulence. Invasive growth was increased during progressive alloimmune-mediated graft rejection associated with high concentrations of ferric iron in the graft. The role of iron in A. fumigatus invasive growth was further confirmed by showing that this invasive phenotype was increased in tracheal transplants from donor mice lacking the hemochromatosis gene (Hfe-/- ). The invasive phenotype was also increased in mouse syngrafts treated with topical iron solution and in allograft recipients receiving deferoxamine, a chelator that increases iron bioavailability to the mold. The invasive growth of the iron-intolerant A. fumigatus double-knockout mutant (ΔsreA/ΔcccA) was lower than that of the wild-type mold. Alloimmune-mediated microvascular damage and iron overload did not appear to impair the host's immune response. In human lung transplant recipients, positive staining for iron in lung transplant tissue was more commonly seen in endobronchial biopsy sections from transplanted airways than in biopsies from the patients' own airways. Collectively, these data identify iron as a major determinant of A. fumigatus invasive growth and a potential target to treat or prevent A. fumigatus infections in lung transplant patients.

Racial and ethnic disparities in lung transplant listing and waitlist outcomes.

BACKGROUND: The United States lung transplant registry data demonstrate differences in adult waitlist mortality by race/ethnicity. It is unknown whether these differences persist after risk adjustment or occur secondary to disparities in disease severity at the time of listing. METHODS: Adult lung transplant waitlist candidates between May 4, 2005 and March 5, 2015 were identified and compared by non-Hispanic white (NHW), non-Hispanic black (NHB), Hispanic and Asian race/ethnicity. A competing risk proportional hazards model was used to assess the association of race/ethnicity with the unadjusted and adjusted risk of waitlist death or removal for too sick, transplant, or removal for other reason. Disease illness severity at transplant listing was compared by race/ethnicity. RESULTS: There were 20,684 lung transplant candidates identified (82% NHW, 9% NHB, 6% Hispanic, 2% Asian and 1% other). Non-white candidates had higher unadjusted waitlist mortality, which was fully mitigated by adjusting for other risk factors (NHB: hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.93 to 1.18; Hispanic: HR 1.02, 95% CI 0.99 to 1.18; Asian: HR 0.90, 95% CI 0.70 to 1.16). Adjusted waitlist access to transplant was lower in non-white candidates (NHB: HR 0.88, 95% CI 0.83 to 0.94; Hispanic: HR 0.87, 95% CI 0.81 to 0.94; Asian: HR 0.83, 95% CI 0.73 to 0.96). NHW candidates with obstructive lung disease and pulmonary fibrosis were older with less illness severity at listing than non-white candidates. CONCLUSIONS: Within the current lung allocation system, there is no difference in risk-adjusted waitlist mortality by race/ethnicity, but non-white waitlist candidates have lower risk-adjusted access to lung transplant. Non-white candidates are generally younger with greater disease-specific illness severity at the time of lung transplant listing.

Leukotriene B4 antagonism ameliorates experimental lymphedema.

Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B4 (LTB4). LTB4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB4 was functionally bimodal: Lower LTB4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB4 stimulated, whereas high concentrations of LTB4 inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1-/- mice were refractory to the beneficial effects of LTB4 antagonism, suggesting that LTB4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB4 was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB4 is a promising drug target for the treatment of acquired lymphedema.

Effect of Transplant Center Volume on Cost and Readmissions in Medicare Lung Transplant Recipients.

RATIONALE: Although lung transplant recipient survival is better at higher volume centers, the effect of center volume on admission cost and early hospital readmission is unknown. OBJECTIVES: To understand the association between transplant center volume and recipient risk-adjusted transplant admission cost, in-hospital mortality, and early hospital readmission in lung transplant recipients. METHODS: Medicare lung transplant recipients from May 4, 2005 to December 31, 2011 were identified through linkage of transplant registry and Medicare administrative claims. Transplant admission cost was extracted, adjusted for regional price variation, and compared across low-, intermediate-, and high-volume centers. A multivariable hierarchical generalized linear regression model was used to assess the effect of transplant center volume on recipient adjusted cost. Modified Poisson regression models were used to assess adjusted in-hospital mortality and early hospital readmission by transplant center volume. MEASUREMENTS AND MAIN RESULTS: There were 3,128 Medicare lung transplant recipients identified. Unadjusted transplant cost was lower at high-volume centers (mean, $131,352 [SD, ±$106,165]; median, $90,177; interquartile range [IQR], $79,165-$137,915) than at intermediate-volume (mean, $138,792 [SD, ±$106,270]; median, $93,024; IQR, $82,700-$154,857) or low-volume (mean, $143,609 [SD, ±$123,316]; median, $95,234; IQR, $83,052-$152,149) centers (P < 0.0001). After adjusting for recipient health risk, low-volume centers had an 11.66% greater transplant admission cost (P = 0.040), a 41% greater risk for in-hospital mortality (P = 0.015), and a 14% greater risk for early hospital readmission (P = 0.033) compared with high-volume centers. There was no significant difference in transplant cost, in-hospital mortality, or early hospital readmission between intermediate- and high-volume centers. CONCLUSIONS: Lung transplant admission cost, in-hospital mortality, and early hospital readmission rate are lower at high-volume centers compared with low-volume centers.

Heart-lung vs. double-lung transplantation for idiopathic pulmonary arterial hypertension.

Patients with idiopathic pulmonary arterial hypertension (IPAH) have improved survival after heart-lung transplantation (HLT) and double-lung transplantation (DLT). However, the optimal procedure for patients with IPAH undergoing transplantation remains unclear. We hypothesized that critically ill IPAH patients, defined by admission to the intensive care units (ICU), would demonstrate improved survival with HLT vs. DLT. All adult IPAH patients (>18 yr) in the Scientific Registry of Transplant Recipients (SRTR) database, who underwent either HLT or DLT between 1987 and 2012, were included. Baseline characteristics, survival, and adjusted survival were compared between the HLT and DLT groups. Similar analyses were performed for the subgroups as defined by the recipients' hospitalization status. A total of 928 IPAH patients (667 DLT, 261 HLT) were included in this analysis. The HLT recipients were younger, more likely to be admitted to the ICU, and have had their transplant in previous eras. Overall, the adjusted survivals after HLT or DLT were similar. For recipients who were hospitalized in the ICU, DLT was associated with worse outcomes (HR 1.827; 95% CI 1.018-3.279). In IPAH patients, the overall survival after HLT or DLT is comparable. HLT may provide improved outcomes in critically ill IPAH patients admitted to the ICU at time of transplantation.

Increased resource use in lung transplant admissions in the lung allocation score era.

RATIONALE: In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1-year survival. Its effect on resource use is unknown. OBJECTIVES: To determine changes in resource use over time in lung transplant admissions. METHODS: Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 [$53,229] vs. $407,489 [$28,360]) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89). CONCLUSIONS: LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.

Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined. METHODS: Survival and BOS-free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database. RESULTS: When compared with the first control group, BOS-free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p-value = 0.004) and multivariate (HR 3.49, p-value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five-yr survival of clarithromycin group was similar (p-value = 0.24). CONCLUSIONS: Routine use of clarithromycin does not delay development of BOS or improve survival.

Lung transplant airway hypoxia: a diathesis to fibrosis?

RATIONALE: Chronic rejection, manifested pathologically as airway fibrosis, is the major problem limiting long-term survival in lung transplant recipients. Airway hypoxia and ischemia, resulting from a failure to restore the bronchial artery (BA) circulation at the time of transplantation, may predispose patients to chronic rejection. To address this possibility, clinical information is needed describing the status of lung perfusion and airway oxygenation after transplantation. OBJECTIVES: To determine the relative pulmonary arterial blood flow, airway tissue oxygenation and BA anatomy in the transplanted lung was compared with the contralateral native lung in lung allograft recipients. METHODS: Routine perfusion scans were evaluated at 3 and 12 months after transplantation in 15 single transplant recipients. Next, airway tissue oximetry was performed in 12 patients during surveillance bronchoscopies in the first year after transplant and in 4 control subjects. Finally, computed tomography (CT)-angiography studies on 11 recipients were reconstructed to evaluate the post-transplant anatomy of the BAs. MEASUREMENTS AND MAIN RESULTS: By 3 months after transplantation, deoxygenated pulmonary arterial blood is shunted away from the native lung to the transplanted lung. In the first year, healthy lung transplant recipients exhibit significant airway hypoxia distal to the graft anastomosis. CT-angiography studies demonstrate that BAs are abbreviated, generally stopping at or before the anastomosis, in transplant airways. CONCLUSIONS: Despite pulmonary artery blood being shunted to transplanted lungs after transplantation, grafts are hypoxic compared with both native (diseased) and control airways. Airway hypoxia may be due to the lack of radiologically demonstrable BAs after lung transplantation.

Impact of hepatitis B core antibody positive donors in lung and heart-lung transplantation: an analysis of the United Network For Organ Sharing Database.

BACKGROUND: The availability of suitable lung and heart-lung allografts for transplantation remains poor. Accepting organs from donors with positive serological studies for hepatitis B could potentially expand the donor pool. The aim of this study was to assess the impact of donor hepatitis B core antibody (HBcAb) status on outcomes of lung and heart-lung transplant recipients. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we compared outcomes of 13,233 recipients of HBcAb negative organs with 333 recipients of HBcAb positive donor organs. RESULTS: We found that the unadjusted 1-year survival of recipients of HBcAb positive donor was worse, but there was no difference in survival after adjusting for baseline donor and recipient differences. On multivariate analysis, recipient and donor age, procedure type, era of transplant, baseline medical condition, diagnosis, and donor hepatitis C antibody status impacted 1- and 5-year survival. However, donor HBcAb status did not impact 1- or 5-year survival posttransplant. CONCLUSIONS: Lung and heart-lung allografts from HBcAb positive donors may be safely used, which would increase the number of transplants performed without compromising recipient outcomes.