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).

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120.

Development and validation of primary graft dysfunction predictive algorithm for lung transplant candidates.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making. METHODS: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination. RESULTS: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort. CONCLUSION: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials.

Critical Care Management of the Lung Transplant Recipient.

Lung transplantation is often the only treatment option for patients with severe irreversible lung disease. Improvements in donor and recipient selection, organ allocation, surgical techniques, and immunosuppression have all contributed to better survival outcomes after lung transplantation. Nonetheless, lung transplant recipients still experience frequent complications, often necessitating treatment in an intensive care setting. In addition, the use of extracorporeal life support as a means of bridging critically ill patients to lung transplantation has become more widespread. This review focuses on the critical care aspects of lung transplantation, both before and after surgery.

Survival difference between high-risk and low-risk CFTR genotypes after lung transplant.

BACKGROUND: While cystic fibrosis transmembrane conductance regulator (CFTR) genotypes are associated with clinical outcomes in cystic fibrosis patients, it is unknown if genotype impacts lung transplant outcomes. We sought to compare lung transplant survival and time to bronchiolitis obliterans syndrome (BOS) between high-risk, low-risk, and not yet classified CFTR genotypes. METHODS: We used merged data from the Organ Procurement and Transplantation Network (2005-2017) and United States Cystic Fibrosis Foundation Patient Registry (2005-2016). Cox Proportional Hazards models compared graft failure after lung transplant and time to BOS among high-risk, low-risk, and not yet classified risk CFTR genotype classes. RESULTS: Among 1,830 cystic fibrosis lung transplant recipients, median survival for those with low-risk, high-risk, and not yet classified genotype was 9.83, 6.25, and 5.75 years, respectively. Adjusted Cox models showed recipients with a low-risk genotype had 39% lower risk of death or re-transplant compared to those with high-risk genotype (adjusted HR 0.61, 95% CI = 0.40, 0.91). A subset of 1,585 lung transplant recipients were included in the BOS subgroup analysis. Adjusted analyses showed no significant difference of developing BOS among high-risk, low-risk, or not yet classified genotypes. CONCLUSIONS: Lung transplant recipients with low-risk CFTR genotype have better survival after transplant compared to recipients with high-risk or not yet classified genotypes. Given these differences, future studies evaluating the mechanism by which CFTR genotype affects post-transplant survival could identify potential targets for intervention.

Infection prophylaxis and management of viral infection.

Viral infections are associated with significant morbidity and mortality in lung transplant recipients. Importantly, several viral infections have been associated with the development of chronic lung allograft dysfunction (CLAD). Community-acquired respiratory viruses (CARV) such as influenza and respiratory syncytial virus (RSV), are frequently associated with acute and chronic rejection. Cytomegalovirus (CMV) remains a significant burden in regards to morbidity and mortality in lung transplant recipients. Epstein-Barr virus (EBV) is mostly involved with the development of post-transplant lymphoproliferative disorder (PTLD), a lymphoid proliferation that occurs in the setting of immunosuppression. On the other hand, the development of direct acting antivirals for hepatitis C virus (HCV) is changing the use of HCV-positive organs in transplantation. In this article we will focus on reviewing common viral infections that have a significant impact on lung transplant recipients looking at epidemiology, prevention and potential treatment.