Outcomes In Lung Transplant Recipients Research Articles

Lung transplant and severe coronary artery disease: results from a single-centre experience.

The management of severe coronary artery disease at the time of a lung transplant remains a challenge. We analysed the short- and long-term outcomes of lung transplant recipients with severe coronary artery disease. Records of adult patients who received transplants at our institution between April 2010 and February 2021 were reviewed retrospectively. Severe coronary artery disease was defined as coronary stenosis ≥70% (main stem ≥50%) seen on the coronary angiographic scans performed before or at the time of listing. Patient characteristics, perioperative and long-term outcomes were compared between patients with and without severe coronary artery disease. Among 896 patients who received lung transplants who had undergone coronary angiography before the transplant, 77 (8.5%) had severe coronary artery disease; the remaining 819 (91.5%) did not. Patients with severe coronary artery disease were older (p < 0.0001), more often male (p < 0.0001) and received transplants more often for pulmonary fibrosis (p = 0.0007). The median (interquartile range) follow-up was 46 (20-76) months. At the Cox multivariable analysis, severe coronary artery disease was not associated with death. Patients with pretransplant percutaneous transluminal coronary angioplasty and patients with coronary artery bypass graft surgery concomitant to a transplant had survival equivalent to that of patients without severe coronary artery disease (p = 0.513; p = 0.556). Severe coronary artery disease was not associated with decreased survival after a lung transplant. Concomitant coronary artery bypass graft surgery and pretransplant percutaneous transluminal coronary angioplasty can be used for revascularization.

Perioperative diabetes mellitus affects the outcomes of lung transplant recipients.

Identifying the risks for chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx) is beneficial to the patient. We hypothesized that diabetes mellitus (DM) is relevant to CLAD development. Our study aimed to clarify if DM is a risk for poor post-LTx outcomes. The records of patients first undergoing LTx in our institution between 2010 and 2018 were reviewed retrospectively. Patient characteristics and postoperative outcomes were analysed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and CLAD development. To identify perioperative DM, we evaluated the patient for DM at 6 months post-LTx. A total of 172 patients were investigated. DM and CLAD occurred in 76 and 39 patients, respectively, and 40 died. At 6 months post-LTx, the unadjusted and adjusted hazard ratios of DM for OS were 3.36 [95% confidence interval (CI) = 1.67-6.73] and 2.78 (95% CI = 1.35-5.75), respectively. The unadjusted and adjusted hazard ratios of DM for CLAD-free survival were 2.20 (95% CI = 1.27-3.80) and 2.15 (95% CI = 1.24-3.74). The patients with DM were older and had a higher body mass index and more incidents of post-LTx malignant disease than the non-DM patients. The 5-year OS and CLAD-free survival rates of the patients with or without DM were 57.2% vs 86.5% and 50.1% vs 72.9%, respectively. Perioperative DM was identified as an independent adverse factor for OS and CLAD-free survival. Perioperative management of DM should be emphasized in the clinical setting of LTx.

Outcomes of lung transplantation from organ donation after medical assistance in dying: First North American experience

Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n=33) and end stage organ failure (n=5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p=.0009). Median ventilation period and 30day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1day [1-3] vs 2days [1-3]; p=.37, deaths 0% [0/33] vs. 2% [11/560], p=.99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Pulmonary Endotoxin is Associated with Reflux, Inflammation, and Adverse Outcomes in Lung Transplant Recipients

Purpose Gastroesophageal reflux disease (GERD) and aspiration are risk factors for poor long-term outcomes in lung transplant recipients. However, the mechanisms underlying this relationship are poorly understood. We have previously shown that bile acids and bacterial density in the lung allograft are associated with GERD. As such, we hypothesized that products of the gut microbiome, including pathogen associated molecular patterns (PAMPs), are aspirated into the airways of lung transplant recipients resulting in lung injury. Herein, we measure endotoxin, a bacterial PAMP, in large airway bronchial washes (LABW) of lung transplant recipients and assess the association with GERD, aspiration, inflammation, and allograft survival. Methods Endotoxin was measured using the Limulus amebocyte lysate assay in LABW obtained 2-7 months post-transplant in 61 lung transplant recipients. Proximal and total reflux episodes were measured using 24h pH-impendence testing. Bile acids were measured using mass spectrometry and soluble markers of inflammation were measured with multiplex assay. Results LABW endotoxin was higher in samples that had a positive bacterial culture (p=0.08). Among samples that did not have a positive bacterial culture (n=49), endotoxin concentration was associated with proximal reflux episodes (r=0.312; p=0.02), total reflux episodes (r=0.321; p=0.03), total bile acid concentration (r=0.260; p=0.04), and inflammatory mediators IL-6, IL-8, IL-1ß, and CCL5 (Figure A). Among all 61 lung transplant recipients, those with LABW endotoxin levels in the highest tertile were at increased risk of chronic lung allograft dysfunction (CLAD) [HR: 3.35 (1.43-7.84); p=0.003] (Figure B) and death/retransplant [HR: 4.24 (1.38-13.01); p=0.01]. Conclusion In the absence of overt bacterial infection, endotoxin concentration in LABW was associated with reflux, aspiration, and inflammation. Aspiration of PAMPs may explain why reflux is a risk factor for CLAD. Gastroesophageal reflux disease (GERD) and aspiration are risk factors for poor long-term outcomes in lung transplant recipients. However, the mechanisms underlying this relationship are poorly understood. We have previously shown that bile acids and bacterial density in the lung allograft are associated with GERD. As such, we hypothesized that products of the gut microbiome, including pathogen associated molecular patterns (PAMPs), are aspirated into the airways of lung transplant recipients resulting in lung injury. Herein, we measure endotoxin, a bacterial PAMP, in large airway bronchial washes (LABW) of lung transplant recipients and assess the association with GERD, aspiration, inflammation, and allograft survival. Endotoxin was measured using the Limulus amebocyte lysate assay in LABW obtained 2-7 months post-transplant in 61 lung transplant recipients. Proximal and total reflux episodes were measured using 24h pH-impendence testing. Bile acids were measured using mass spectrometry and soluble markers of inflammation were measured with multiplex assay. LABW endotoxin was higher in samples that had a positive bacterial culture (p=0.08). Among samples that did not have a positive bacterial culture (n=49), endotoxin concentration was associated with proximal reflux episodes (r=0.312; p=0.02), total reflux episodes (r=0.321; p=0.03), total bile acid concentration (r=0.260; p=0.04), and inflammatory mediators IL-6, IL-8, IL-1ß, and CCL5 (Figure A). Among all 61 lung transplant recipients, those with LABW endotoxin levels in the highest tertile were at increased risk of chronic lung allograft dysfunction (CLAD) [HR: 3.35 (1.43-7.84); p=0.003] (Figure B) and death/retransplant [HR: 4.24 (1.38-13.01); p=0.01]. In the absence of overt bacterial infection, endotoxin concentration in LABW was associated with reflux, aspiration, and inflammation. Aspiration of PAMPs may explain why reflux is a risk factor for CLAD.

BMI Change and Outcomes in Lung Transplant Recipients

Purpose Lung transplantation is a lifesaving therapy in patients with advanced lung disease. A body mass index (BMI) >30 is associated with worse outcomes after lung transplantation. Therefore, a BMI above 30 is considered a relative contraindication for lung transplantation in many centers. However, it is not clear how BMI changes after lung transplantation affects outcomes. Here we investigated how BMI changes after lung transplantation affect outcomes of lung transplant recipients. Methods We retrospectively assessed BMI and several post-transplant outcomes in 118 consecutive lung transplant recipients. The data was analyzed using R 4.0.2 (The R Foundation for Statistical Computing http://www.R-project.org). Packages Performance Analytics and ggplot2 were used in addition to core R. We evaluated impact of BMI change on mortality by running a Wilcoxon Sum-Rank test. We also did regression analysis controlling for impact of age, gender, race, type of lung transplant and length of stay. Results We evaluated 118 lung transplant recipients, 58 of whom were female. The average age was 56.06 years. Using traditional BMI categories, 7% of patients were underweight, 47% normal weight, 37% overweight, and 9% obese. Decrease in BMI of 2 or more points at 6 months after lung transplant was associated with increase mortality with odds ratio of death 5.13 and p=0.014. This effect was preserved when controlled for age, length of stay, gender, race, and type of transplant (p=0.02534). Interestingly, longer length of stay (LOS) was also associated with increased mortality independent from change in BMI, age, gender, race and type of transplant (p=0.00316). Conclusion A rather large proportion of lung transplant candidates are overweight by BMI criteria. A higher BMI was associated with a longer LOS after transplant and longer length of stay was associated with increased mortality. This effect was independent from change in age, gender, race and type of lung transplant. Patients who lost weight resulting in >2 points decrease in BMI at 6 months post-transplant also had increased mortality. This effect was independent from age, gender, race, length of stay and type of lung transplant. Larger studies are needed to confirm these findings and better understand the impact of weight change on outcomes after lung transplant. Lung transplantation is a lifesaving therapy in patients with advanced lung disease. A body mass index (BMI) >30 is associated with worse outcomes after lung transplantation. Therefore, a BMI above 30 is considered a relative contraindication for lung transplantation in many centers. However, it is not clear how BMI changes after lung transplantation affects outcomes. Here we investigated how BMI changes after lung transplantation affect outcomes of lung transplant recipients. We retrospectively assessed BMI and several post-transplant outcomes in 118 consecutive lung transplant recipients. The data was analyzed using R 4.0.2 (The R Foundation for Statistical Computing http://www.R-project.org). Packages Performance Analytics and ggplot2 were used in addition to core R. We evaluated impact of BMI change on mortality by running a Wilcoxon Sum-Rank test. We also did regression analysis controlling for impact of age, gender, race, type of lung transplant and length of stay. We evaluated 118 lung transplant recipients, 58 of whom were female. The average age was 56.06 years. Using traditional BMI categories, 7% of patients were underweight, 47% normal weight, 37% overweight, and 9% obese. Decrease in BMI of 2 or more points at 6 months after lung transplant was associated with increase mortality with odds ratio of death 5.13 and p=0.014. This effect was preserved when controlled for age, length of stay, gender, race, and type of transplant (p=0.02534). Interestingly, longer length of stay (LOS) was also associated with increased mortality independent from change in BMI, age, gender, race and type of transplant (p=0.00316). A rather large proportion of lung transplant candidates are overweight by BMI criteria. A higher BMI was associated with a longer LOS after transplant and longer length of stay was associated with increased mortality. This effect was independent from change in age, gender, race and type of lung transplant. Patients who lost weight resulting in >2 points decrease in BMI at 6 months post-transplant also had increased mortality. This effect was independent from age, gender, race, length of stay and type of lung transplant. Larger studies are needed to confirm these findings and better understand the impact of weight change on outcomes after lung transplant.

Malnutrition in Lung Transplant Recipients: Weighing the Outcomes

<h3>Purpose</h3> Malnutrition negatively impacts outcomes post-lung transplantation. Therefore, nutrition status is routinely considered in the selection criteria for lung transplant candidates. Malnourishment is often present in patients with end-stage lung disease, and unfortunately, it cannot always be resolved before surgery. The impact of malnutrition on lung transplant outcomes has been assessed in the literature using a variety of different methods. However, the standard of care used by nutrition experts and Registered Dietitians, the Academy of Nutrition and Dietetics/American Society of Parenteral and Enteral Nutrition (AND/ASPEN) criteria, has not been considered. Here we investigated how malnutrition identified by these criteria can affect outcomes of lung transplant recipients. <h3>Methods</h3> We retrospectively assessed twenty-two patients who met criteria for moderate or severe malnutrition at the time of transplant using the AND/ASPEN criteria between Jan 1st 2018 and June 1st 2021. We used a control group of twenty-two non-malnourished patients that had similar age and transplant type (single vs bilateral) and compared several different outcome measures using a Kruskal-Wallis test. The data was analyzed using R 4.0.2 (The R Foundation for Statistical Computing http://www.R-project.org). <h3>Results</h3> The average age of both groups was 54.4 years, and 50% of the population was female. We found a significant increase in length of stay (LOS) for the malnourished group (p=0.045) as well as an increased need for return to the intensive care unit (ICU) within 60 days of transplant (p=0.021). Interestingly, no differences were found between the two groups regarding days on a ventilator, days in ICU, the number of rejections in the first six months, or the need for acute inpatient rehabilitation (AIR) following the transplant admission. <h3>Conclusion</h3> Malnutrition identified by AND/ASPEN criteria does seem to impact outcomes following lung transplant, specifically overall LOS and the need for return to ICU within 60 days of transplant. However, there were no significant differences with days on a ventilator, days in ICU, number of rejections in the first 6 months, or need for AIR after transplant. If possible, malnutrition should be improved before lung transplantation. Larger studies are needed to better understand the impact of malnutrition on outcomes after lung transplant.

Obese Lung Recipients May Be Susceptible to Severe COVID-19 Outcomes Compared to Controls

PurposeObesity is thought to increase COVID-19 (C19) related morbidity and mortality in nontransplant patients; however, the data in lung transplant literature are lacking. We aimed to study impact of body mass index (BMI) on outcomes of lung transplant recipients (LTR) with C19.MethodsFrom March 2020 to August 2021, 91 lung recipients with C19 were included and classified as controls (BMI <30 kg/m2) and obese (BMI ≥30 kg/m2) at the time of LT listing. Primary outcome was death. Secondary outcome was C19-related medical morbidity. Cox proportional hazard analysis and Kaplan-Meier method were used.ResultsControls (69%, n=63) and obese (31%, n=28) subjects were comparable in terms of baseline characteristics before C19 onset. Compared to controls, obese subjects tended to have more severe inflammation and a higher prevalence of hypoxemia, requirement of ICU, mechanical ventilation, and death (Table 1). Also compared to controls, the risk of death tended to be higher and probability of survival tended to be lower in obese subjects (HR: 1.971 [0.956-4.065], p=0.066 and 73% vs 53.6%, p=0.061, respectively; Figure 1). However, coinfections and post-C19 allograft function were comparable between the two groups (Table 1). Of note, mycophenolate was stopped or reduced upon/during hospitalization in both groups alike.ConclusionIn our study, obese LTRs trended toward an increased risk of death from C19 compared to controls. This is the first data on the impact of obesity on C19 in LTRs. The role of leptin as a pro-inflammatory substance can be speculated.

Neutropenia and Outcomes in Lung Transplant Recipients

<h3>Purpose</h3> Lung transplantation is a lifesaving therapy for patients with advanced lung disease. However, graft rejection, neutropenia, and subsequent infection are common complications in patients' postoperative courses. While neutropenia is common post-transplant, its relationship to outcomes remains ill-defined. We investigated the relationship between severity and timing of neutropenia and outcomes after lung transplantation. <h3>Methods</h3> We retrospectively assessed absolute neutrophil values in the 12-month postoperative period of 209 lung transplant recipients at Northwestern Memorial Hospital from 2014-2021. Neutropenia is defined as an absolute neutrophil count <1500 cells/uL. We evaluated the correlation between neutropenia and the following outcomes: death within 1 year, presence of graft rejection, the severity of rejection, and infection with <i>Aspergillus</i>. The data was analyzed using R 4.0.2 (The R Foundation for Statistical Computing http://www.R-project.org). Packages Performance Analytics and ggplot2 were used in addition to core R. <h3>Results</h3> We evaluated 209 lung transplant recipients with an average age of 60. Neutropenia was present in 133(64%) patients during the 12-month postoperative period. There was no clear relationship between neutropenia and 1 year mortality(p=0.52), presence of graft rejection(p=0.75), severity of rejection(p=0.41) and <i>Aspergillus</i> infection(p=0.75). <h3>Conclusion</h3> Neutropenia is highly prevalent in lung transplant recipients, representing nearly 2/3 of our cohort. However, the clinical significance of this finding is not clear because we showed that the incidence of neutropenia had no significant relationship with the postoperative outcomes. Additional analysis of current data to determine if the severity of neutropenia (mild vs. moderate vs. severe), the timing of first neutropenic episode post-transplant, and frequency within the first year will be conducted to fully establish the impact of neutropenia on patients outcomes after lung transplantation.

Prior and Perioperative Revascularization Impact on Survival in Lung Transplant Patients

<h3>Purpose</h3> Survival outcomes of lung transplant recipients with concomitant coronary artery disease who had prior or perioperative revascularization remains a topic of conversation. We hypothesized concomitant-CABG can be a safe and viable option during lung transplantation in a select group of patients. <h3>Methods</h3> A retrospective analysis of all single and double lung transplant patients from Feb-2012 to Aug-2021 (n=868) was performed. Patients were split into 4 groups: (1) those who received a preoperative percutaneous coronary intervention (n=58), (2) those who received pre-operative coronary artery bypass grafting (CABG) (n=39), (3) those who received concomitant CABG during transplantation (n=51), and (4) those who had lung transplantation without revascularization (n=720). Groups were compared for demographics, surgical procedure, and survival outcomes using STATA Inc. P-value <0.05 was considered significant. <h3>Results</h3> Throughout all groups, a majority of patients receiving LTx were males (p<0.01) and ethnically white (p<0.01). The no revascularization group was significantly younger than the other groups (p<0.01). The diagnosis of IPF constituted the largest portion of all groups except the no revascularization group (p<0.01). In terms of transplant type, the pre-CABG group had a higher portion of single LTx procedures (p=0.014). The antero-axillary thoracotamy approach was the most utilized approach in all groups except Con-CABG (p=0.014). Kaplan-Meier analysis showed that survival rates post-LTx were not significantly different between the groups (p=0.471). Cox Regression analysis showed diagnosis significantly impacted survival rates (p=0.009). <h3>Conclusion</h3> These results continue to suggest that preoperative or intraoperative revascularization did not affect survival outcomes in lung transplant patients. Select patients with coronary artery disease may benefit when intervened during lung transplant procedure with similar outcomes to patients without intervention.

Treatment of De Novo DSA with IVIG Monotherapy After Lung Transplantation

<h3>Purpose</h3> The development of de novo donor-specific anti-HLA antibodies (DSA) is associated with worse outcomes in lung transplant recipients (LTxR). The purpose of this study is to evaluate IVIG monotherapy for de novo DSA in the absence of allograft dysfunction or clinical antibody-mediated rejection (AMR). <h3>Methods</h3> Adult LTxR between 2/2013 and 3/2021 treated with IVIG monotherapy for de novo DSA with no evidence of AMR were included. IVIG was initiated at 2g/kg followed by 1g/kg monthly for a minimum of 3 months or until clearance (up to 6 months). HLA Ab is routinely checked by Luminex SAB post-transplant at day 14, months 1, 3, 6, 9, 12, and 18, and monthly during IVIG treatment. Primary outcome was change in DSA after IVIG therapy. DSA clearance was defined as sum MFI less than 1000. <h3>Results</h3> 32 LTxR developed de novo DSA at a median of 33 days (18,143) post-transplant and were treated with IVIG. Mean follow-up time was 1330 days (861-1910). The median sum MFI for DSA at baseline was 4782 (2927,7490). DQ was the immunodominant DSA in 24 (75%) and only 2 (6%) patients had isolated class I DSA. MFI of sum DSA decreased by a median of 2993 (2051, 6358) after IVIG therapy; p < 0.0001. Eighteen (56%) cleared de novo DSA (Group 1) versus 14 (44%) did not clear (Group 2) at the end of IVIG therapy. There was no significant difference in age, gender, race, transplant indication or type, cPRA, HLA mismatch, or PGD. ACR and AMR tended to be more frequent in Group 2; ACR: 92.9% vs 61.1%, p=0.053; and AMR: 35.7% vs 5.6%, p=0.063. Overall survival for the entire cohort at 1, 3 and 5 years was 100%, 86%, 60%, respectively. There was no significant difference in chronic lung allograft dysfunction (CLAD) or survival between Groups (Table 1). <h3>Conclusion</h3> In LTxR, IVIG monotherapy is associated with significant reduction in de novo DSA. DSA clearance may result in less acute rejection. Randomized controlled trials are needed to determine the optimal strategy for managing de novo DSA.

One Year Into the Pandemic: Evolving COVID-19 Outcomes in Lung Transplant Recipients, a Single-center Experience.

Background.In the early months of the coronavirus disease 2019 (COVID-19) pandemic, our center reported a mortality rate of 34% in a cohort of 32 lung transplant recipients with COVID-19 between March and May 2020. Since then, there has been evolving knowledge in prevention and treatments of COVID-19. To evaluate the impact of these changes, we describe the clinical presentation, management, and outcomes of a more recent cohort of lung transplant recipients during the second surge and provide a comparison with our first cohort.Methods.We conducted a retrospective cohort study that included all consecutive lung transplant recipients who tested positive for severe acute respiratory syndrome coronavirus 2 between November 2020 and February 28, 2021. We compared baseline demographics and major outcomes between the first- and second-surge cohorts.Results.We identified 47 lung transplant recipients (median age, 60; 51% female) who tested positive for severe acute respiratory syndrome coronavirus 2 between November 2020 and February 28, 2021. The current cohort had a higher proportion of patients with mild disease (34% versus 16%) and fewer patients with a history of obesity (4% versus 25%). Sixty-six percent (n = 31) required hospitalization and were treated with remdesivir (90%) and dexamethasone (84%). Among those hospitalized, 77% (n = 24) required supplemental oxygen, and 22% (n = 7) required invasive mechanical ventilation. The overall 90-d mortality decreased from 34% to 17% from the first cohort to the second (adjusted odds ratio, 0.26; 95% confidence interval, 0.08-0.85; P = 0.026).Conclusions.Although COVID-19–associated mortality rate in lung transplant recipients at our center has decreased over time, COVID-19 continues to be associated with significant morbidity and mortality.

The impact of cytochrome P450 3A5 genotype on early tacrolimus metabolism and clinical outcomes in lung transplant recipients.

Background Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx). It shows great inter-individual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors. Aim We aim to investigate the influence of cytochrome P450 3A5 (CYP3A5) genotypes on early post-LTx Tac metabolism and whether it is affected by concomitant use of azole antifungals. Also, we explored the association between CYP3A5 genotype and clinical outcomes. Method 90 recipients who underwent LTx from 2017 to 2019 were enrolled in the study. The effect of CYP3A5 genotype on Tac metabolism and interaction with azole antifungals were assessed during week 1-4 after transplantation. Associations between CYP3A5 genotype and the incidence of acute kidney injury (AKI), length of hospital stay and mortality were analyzed. ResultsCYP3A5*1 carriers had lower dose adjusted concentration (C/D) than CYP3A5*3/*3 group at all time points (p < 0.05). The dose ratio of CYP3A5*1 carriers to CYP3A5*3/*3 was between 1.3 and 2.4 when comparable concentrations were reached. Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration ≥ 7.5 ng/mL at week 1 was associated with higher incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay. Kaplan-Meier analysis showed no statistically significant difference between 30-day or 1-year mortality and CYP3A5 genotype. Conclusion CYP3A5 genotype could affect Tac metabolism early after LTx. However, it had no influence on the incidence of AKI, length of hospital stay and mortality.

Foregut Dysmotility in the Lung Transplant Patient.

To explore the role of upper gastrointestinal disease in the clinical course of lung transplant patients - including its pathophysiology, diagnostic testing, and treatment options. Gastroesophageal reflux disease (GERD) and foregut motility disorders are more prevalent among end-stage lung disease patients and are associated with poorer outcomes in lung transplant recipients. A proposed mechanism is the exposure of the lung allograft to aspirated contents, resulting in inflammation and rejection. Diagnostic tools to assess for these disorders include multichannel intraluminal impedance and pH (MII-pH) testing, high resolution esophageal manometry (HREM), and gastric emptying scintigraphy. The main treatment options are medical management with acid suppressants and/or prokinetic agents and anti-reflux surgery. In particular, data support the use of early anti-reflux surgery to improve outcomes. Newer diagnostic tools such as MII-pH testing and HREM allow for the identification of both acid and non-acid reflux and esophageal motility disorders, respectively. Recent studies have demonstrated that early anti-reflux surgery within six months post-transplant better protects against allograft injury and pulmonary function decline when compared to late surgery. However, further prospective research is needed to evaluate the short and long-term outcomes of these diagnostic approaches and interventions.

Impact of COVID-19 on Lung Allograft and Clinical Outcomes in Lung Transplant Recipients: A Case-control Study.

The impacts of COVID-19 on lung allograft function, rejection, secondary infection, and clinical outcomes in lung transplant recipients (LTRs) remain unknown. A 1:2 matched case-control study was performed to evaluate rehospitalization, lung allograft function, and secondary infections up to 90 d after COVID-19 diagnosis (or index dates for controls). Twenty-four LTRs with COVID-19 (cases) and 48 controls were identified. Cases and controls had similar baseline characteristics and lung allograft function. LTRs with COVID-19 had higher incidence of secondary bacterial infection (29.2% versus 6.3%, P = 0.008), readmission (29.2% versus 10.4%, P = 0.04), and for-cause bronchoscopy (33.3% versus 12.5%, P = 0.04) compared with controls. At d 90, mortality in cases versus controls was 8.3% versus 2.1% (P = 0.21), incidence of invasive fungal infections in cases versus controls was 20.8% versus 8.3% (P = 0.13) and forced expiratory volume in 1 s (FEV1) decline ≥10% from baseline occurred in 19% of cases versus 12.2% of controls (P = 0.46). No acute cellular rejection, acute antibody-mediated rejection, or new donor-specific anti-HLA antibodies were observed among cases or controls within 90 d post index date. We found LTRs with COVID-19 were at risk to develop secondary infections and rehospitalization post COVID-19, compared with controls. While we did not observe post viral acute cellular rejection or antibody-mediated rejection, further studies are needed to understand if LTRs with COVID-19 who did not recover baseline lung function within 90 d have developed chronic lung allograft dysfunction stage progression.

The respiratory microbiome after lung transplantation: Reflection or driver of respiratory disease?

With the introduction of high-throughput sequencing methods, our understanding of the human lower respiratory tract's inhabitants has expanded significantly in recent years. What is now termed the "lung microbiome" has been described for healthy patients, as well as people with chronic lung diseases and lung transplants. The lung microbiome of lung transplant recipients (LTRs) has proven to be unique compared with nontransplant patients, with characteristic findings associated with disease states, such as pneumonia, acute rejection, and graft failure. In this review, we summarize the current understanding of the lung microbiome in LTRs, not only focusing on bacteria but also highlighting key findings of the viral and the fungal community. Based on our knowledge of the lung microbiome in LTRs, we propose multiple opportunities for clinical use of the microbiome to improve outcomes in this population.

Death Rate in Lung Transplant Recipients during the COVID-19 Outbreak in France

PurposeData on outcomes in lung transplant recipients with SARS-CoV-2 infection remains limited. Given the potential higher COVID-19 severity in lung recipients, the Agence de la biomedecine has limited the transplant program to patients with high-urgency status during the first epidemic wave. The program has been fully restored where possible during the second epidemic wave. This study aimed to assess the impact of COVID-19 on lung recipient mortality in France.MethodsAll lung recipients with COVID-19 reported in the French national registry CRISTAL between February 1st and September 30th 2020 were included in the study. Patient characteristics were extracted from CRISTAL. Cumulative number of cases by month since February (Figure 1) and case fatality rate (CFR) were calculated. Mortality rates from February to September in the whole 2019 and 2020 recipient cohorts were compared. Survival curves were estimated using Kaplan-Meier method and compared using the log-rank test.ResultsOf the 46 patients (median age (IQR) 51 years (39-60), 54% female, median time from transplantation 3.5 years (0.8-7.1)) 88% required hospitalization including 21% in ICU. Eight patients died (CFR: 17.4%). No difference in 3-month survival was observed between 2020 and 2019 recipient cohorts (98.6% 95%CI [98.0%-99.0%] vs 98.4% [97.8%-98.8%], respectively) (Figure 2).ConclusionCOVID-19 was associated with lower fatality rate in lung recipients than in other organ transplant recipients and did not result in an excess mortality. These findings suggest that continuing lung transplant activity during the COVID-19 pandemic was a reasonable option.

CYP3A4 Polymorphisms and Acute Cellular Rejection in Lung Transplant Patients

Purpose Tacrolimus is the main component of the immunosuppressive regimen used in patients with solid organ transplants. Genetic polymorphism in CYP3A4 and CYP3A5 enzyme expression contributes to differences in tacrolimus metabolism with potential impact on allograft function. Although genetic factors influencing immunosuppressive response have been studied in kidney, heart and liver transplant patients, data regarding lung transplant patients are more limited. The aim of our study was to determine the relationship between CYP3A4 and CYP3A5 polymorphisms and acute rejection. Methods 41 lung transplant recipients were included. We retrospectively reviewed clinical and pathology data of patients. CYP3A5 polymorphisms were defined as intermediate, normal, or poor metabolizers. CYP3A4 polymorphisms were defined as rapid, intermediate, normal, or poor metabolizers. The diagnosis of acute cellular rejection was based on histopathology results. Chi-square statistic was used to compare categorical continuous variables (CYP3A5, CYP3A4 and acute rejection). Results The mean age of the patients was 59±13 years (mean ± SD) with an age range between 21 to 75 years. Among patients included in the analysis there were 51% males . There was a statistically significant increased rate of rejection in patients with normal CYP3A4 polymorphisms (68%) as compared to patients with poor and intermediate CYP3A4 polymorphisms (20%) (p 0.036). There was no association between CYP3A5 phenotype and acute rejection (p= 0.33). Conclusion Although this was a small study, our data suggest that CYP3A4 phenotype may influence the occurrence of acute rejection. Patients with normal CYP3A4 phenotype might require closer monitoring and higher tacrolimus concentrations to avoid rejection. Additional studies are needed to confirm these results and determine whether genotype-based tacrolimus dosing could improve outcomes in lung transplant recipients.

Lung Transplant Outcomes with Concomitant Heart Donation

<h3>Purpose</h3> Concomitant heart and lung donation may adversely affect outcomes in lung transplant recipients. In this study we characterized donor characteristics and examined the outcomes of lung transplantation from donors with concomitant heart donation. <h3>Methods</h3> This retrospective cohort study used the UNOS SRTR database and identified donors as lung only (LO) or heart and lung (HL) donors. Recipients from 5/01/05-03/31/19 were identified and compared. Redo and multi-organ transplants were excluded. Characteristics and outcomes were compared using the Kruskal-Wallis and chi-square tests. Survival was analyzed with Kaplan-Meier analysis and Cox proportional-hazard (CPH) model. <h3>Results</h3> We identified 24,393 lung transplant recipients. 6,412 were in the HL group and 17,981 in the LO donor group. HL recipients were older, male, and had shorter waitlist times (Table, p<0.01 for all). HL donors were younger and had a significantly lower incidence of coronary disease, smoking, diabetes, and hypertension (Table, p<0.01 for all). HL recipients were more likely to be single lung transplants, have shorter ischemic times, and have shorter length of stay (Table, p<0.01 for all). No significant difference in survival was noted with unadjusted analysis (p=0.09), or with the CPH (HL hazard ratio 0.956, 95% confidence interval 0.91-1.00, p=0.06). <h3>Conclusion</h3> No survival difference was noted in recipients of LO and HL donors. Given comparable survival outcomes HL donors should be viewed as equivalent to LO donors. Further investigation should be directed into the reasons behind increased use of single lung transplantation of HL donors and whether both lungs are utilized.

Differential Outcomes of Lung Transplant Recipients as They Age: Is over 70 Too Old? No!

PurposeLung transplantation (LTX) is generally reserved for the young due to perioperative complications & organ utilization. We sought to evaluate the long-term outcomes of LTX in the septuagenarian.MethodsRetrospectively, LTX recipients in the UNOS transplant registry (May 1, 2005 to June 12, 2020) were stratified into 18-59, 60-69, and >=70 years of age. Recipient and transplant characteristics were evaluated for survival, cause of death (COD), length of stay (LOS) and complications. A Kaplan-Meier analysis examined long-term survival for all patients stratified by age, specifically looking at COD.ResultsA total of 27,632 recipients met inclusion criteria. As recipients aged, we found a decrease in proportion of cystic fibrosis & an increase in restrictive disease while obstructive disease peaked in the 60-69yo cohort (p<0.001). Recipient to donor age difference significantly increased with older recipients (p<0.001). >=70yo had higher rates of single LTX, male gender and white race (p<0.001). Older recipients had significantly longer recovery distances traveled with paradoxical shorter ischemic times, shorter LOS and were transplanted at higher volume centers. There was no difference with in-hospital mortality (p=0.5). Rejection during initial hospitalization and within 1 year and post-transplant dialysis incidence decreased with age. Graft and pulmonary failure were common COD in younger patients while malignancy and cardio/cerebrovascular diseases were common COD in >= 70yo (Figure).ConclusionSeptuagenarian LTX candidates may be safely transplanted with relatively few complications. Young transplant recipients appear more vulnerable to rejection and die more often of graft failure complications. Malignancy and cardio/cerebrovascular etiologies were more common COD in older recipients. Immuno-senescence and conditions of the aged are likely contributing factors to the less rejection and graft failure observations. The >=70yo should be considered a good LTX candidate. Lung transplantation (LTX) is generally reserved for the young due to perioperative complications & organ utilization. We sought to evaluate the long-term outcomes of LTX in the septuagenarian. Retrospectively, LTX recipients in the UNOS transplant registry (May 1, 2005 to June 12, 2020) were stratified into 18-59, 60-69, and >=70 years of age. Recipient and transplant characteristics were evaluated for survival, cause of death (COD), length of stay (LOS) and complications. A Kaplan-Meier analysis examined long-term survival for all patients stratified by age, specifically looking at COD. A total of 27,632 recipients met inclusion criteria. As recipients aged, we found a decrease in proportion of cystic fibrosis & an increase in restrictive disease while obstructive disease peaked in the 60-69yo cohort (p<0.001). Recipient to donor age difference significantly increased with older recipients (p<0.001). >=70yo had higher rates of single LTX, male gender and white race (p<0.001). Older recipients had significantly longer recovery distances traveled with paradoxical shorter ischemic times, shorter LOS and were transplanted at higher volume centers. There was no difference with in-hospital mortality (p=0.5). Rejection during initial hospitalization and within 1 year and post-transplant dialysis incidence decreased with age. Graft and pulmonary failure were common COD in younger patients while malignancy and cardio/cerebrovascular diseases were common COD in >= 70yo (Figure). Septuagenarian LTX candidates may be safely transplanted with relatively few complications. Young transplant recipients appear more vulnerable to rejection and die more often of graft failure complications. Malignancy and cardio/cerebrovascular etiologies were more common COD in older recipients. Immuno-senescence and conditions of the aged are likely contributing factors to the less rejection and graft failure observations. The >=70yo should be considered a good LTX candidate.

Weight Change and Outcomes in Lung Transplant Recipients

Purpose Lung transplantation is a lifesaving therapy in patients with advanced lung disease. A body mass index (BMI) >30 is associated with worse outcomes after lung transplantation. Therefore, a BMI above 30 is considered a relative contraindication for lung transplantation. However, it is not clear how weight change after lung transplantation affects outcomes. We investigated the impact of weight change after lung transplantation on outcomes. Methods We retrospectively assessed BMI and several post-transplant outcomes in 78 consecutive lung transplant recipients. The data was analyzed using R 4.0.2 (The R Foundation for Statistical Computing http://www.R-project.org). Packages Performance Analytics and ggplot2 were used in addition to core R. FVC was modeled as a linear regression against BMI at transplant. To show a different approach, FEV1 was modeled by group of BMI, breaking the BMI values in three equal sets. We checked our hypothesis that people with lower BMI had better lung function when their weight increased from consult to one year after transplant by running a Wilcoxon Sum-Rank test. Results We evaluated 78 lung transplant recipients, 39 of whom were female. The average age was 55 years. The average transplant BMI was 24.3 with a range from 16.8 to 32.2. At one year post transplant, the average BMI was 25.7. By BMI, 33% of recipients were overweight at the time of transplant and 5% were obese. Higher BMI was associated with increased length of stay (LOS) and decreased FVC and FEV1 at 1 year post transplant compared to those with normal BMIs. More than half the patients who needed to lose weight for transplant re-gained the weight by 1 year post transplant. Underweight recipients who gained weight after transplant had increased FVC and FEV1 compared to those who didn't gain weight. Conclusion A rather large proportion of lung transplant candidates are overweight by BMI criteria. A higher BMI was associated with a longer LOS after transplant. One year pulmonary function (PFT) data was also worse in patients with higher BMIs compared to those with normal BMIs. Interestingly, underweight patients who gained weight after lung transplant had a strong trend for statistically significant improvement in PFT one year after lung transplant. Larger studies are needed to better understand the impact of weight change on outcomes after lung transplant.