Post-lung Transplant Research Articles

Driving pressure association with mortality in post-lung transplant patients: A prospective observational study.

To investigate the association between driving pressure (ΔP) and 90-day mortality in patients following lung transplantation (LTx) in patients who developed primary graft dysfunction (PGD). This prospective, observational study involved consecutive patients who, following LTx, were admitted to our intensive care unit (ICU) from January 2022 to January 2023. Patients were separated into two groups according to ΔP at time of admission (i.e., low, ≤15 cmH2O or high, >15 cmH2O). Postoperative outcomes were compared between groups. In total, 104 patients were involved in the study, and of these, 69 were included in the low ΔP group and 35 in the high ΔP group. Kaplan-Meier analysis of 90-day mortality showed a statistically significant difference between groups with survival better in the low ΔP group compared with the high ΔP group. According to Cox proportional regression model, the variables independently associated with 90-day mortality were ΔP and pneumonia. Significantly more patients in the high ΔP group than the low ΔP group had PGD grade 3 (PGD3), pneumonia, required tracheostomy, and had prolonged postoperative extracorporeal membrane oxygenation (ECMO) time, postoperative ventilator time, and ICU stay. Driving pressure appears to have the ability to predict PGD3 and 90-day mortality of patients following LTx. Further studies are required to confirm our results.

EPS8.06 “’Snot a problem”: physiotherapy outcomes from initiating elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis post-lung transplant

EPS8.06 “’Snot a problem”: physiotherapy outcomes from initiating elexacaftor/tezacaftor/ivacaftor in adults with cystic fibrosis post-lung transplant

Treatment of Patients After Lung Transplantation With Covid Infection During Long-Term Follow-Up

BackgroundPatients undergoing lung transplantation are routinely managed with lifelong immunosuppression associated with heightened risk for infections. This study delves into the therapeutic challenges and strategies employed in managing lung transplant recipients (LTRs) who were infected with COVID-19 during long-term follow-up. Patients and MethodsThe study is conducted as a case series analysis, among which non-standard therapies consisting of either targeted antibody treatment or antiviral drugs or anti-IL-6 drugs were applied in patients after lung transplantation. Additional analysis of laboratory test results for systemic inflammation and imaging studies was also carried out. The study was limited to a dedicated COVID-19 center, commonly known as a temporary hospital and included patients infected with Covid-19 in the late post-lung transplant period (home related infection). Results15 patients after LTx (lung transplantation) with current COVID-19 infection were treated with antibodies like tocilizumab, casirivimab and imdevimab and regdanvimab. 6,7 % (n=1) of the patients were given tocilizumab, 53,3% (n=8) casirivimab and imdevimab and 13,3 % (n=2) regdanvimab. Of the 15 LTRs studied, 53,3 % presented COVID-19 associated lung changes in CT scans. Common clinical manifestations included dyspnea, fever, and fatigue. Antiviral agents, like remdesivir, were employed in the remaining 26,7% (n:4) cases, and adjunctive therapies, such as corticosteroids and anticoagulants, were utilized selectively. All treated patients survived the infection without complications; the treatment proved to be effective and safe.

Acute rejection post lung transplant.

To review what is currently known about the pathogenesis, diagnosis, treatment, and prevention of acute rejection (AR) in lung transplantation. Epigenomic and transcriptomic methods are gaining traction as tools for earlier detection of AR, which still remains primarily a histopathologic diagnosis. Acute rejection is a common cause of early posttransplant lung graft dysfunction and increases the risk of chronic rejection. Detection and diagnosis of AR is primarily based on histopathology, but noninvasive molecular methods are undergoing investigation. Two subtypes of AR exist: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Both can have varied clinical presentation, ranging from asymptomatic to fulminant ARDS, and can present simultaneously. Diagnosis of ACR requires transbronchial biopsy; AMR requires the additional measuring of circulating donor-specific antibody (DSA) levels. First-line treatment in ACR is increased immunosuppression (pulse-dose or tapered dose glucocorticoids); refractory cases may need antibody-based lymphodepletion therapy. First line treatment in AMR focuses on circulating DSA removal with B and plasma cell depletion; plasmapheresis, intravenous human immunoglobulin (IVIG), bortezomib, and rituximab are often employed.

Metabolic complications in lung transplantation for cystic fibrosis - A case control study

BackgroundMetabolic complications post-lung transplant are poorly understood and little is known about how these complications differ between patients with or without cystic fibrosis (pwCF and pwoCF). This study compared post-lung transplant outcomes between pwCF and pwoCF relating to survival and incidence of diabetes, dyslipidaemia, hypertension, and renal impairment. MethodsA retrospective (2004–2017) case-control study involving 90 pwCF and 90 pwoCF (age, sex and year of transplant matched) was conducted. Demographic variables, pre/post-transplant metabolic diseases, blood investigations and medications were extracted. Descriptive statistics were used to describe the cohort. Mann-Whitney U and Chi-squared tests were used to analyse morbidity and mortality data. Regression analyses were used to identity independent variables that impacted clinical outcomes. Kaplan Meier analysis with log-rank testing was used to compare survival. ResultsPwCF were younger, had lower BMIs, and were less likely to have pre-transplant extracorporeal membrane oxygenation (ECMO) use. A total of 37 pwCF and 41 pwoCF died (p = 0.65) during the period of observation with no differences in survival. Adjusting for covariates of age, sex and BMI via multiple logistic regression, CF status was associated with a dramatic increased risk of new-onset diabetes post-transplant (adjusted odds ratio 28.7; 95 % CI, 28.76 to 108.7). No other differences in adjusted risk were found. ConclusionsAs pwCF had a greater adjusted risk of developing new post-transplant diabetes and experienced metabolic complications at similar rates as pwoCF, the findings highlight the need for rigorous monitoring of pwCF for possible metabolic complications post-transplant.

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course. This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507). An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.

Improved kidney function and one-year survival with transitioning from intravenous to enteral tacrolimus in lung transplant recipients

BackgroundAcute kidney injury (AKI) is common after lung transplant and may increase risk of chronic kidney disease (CKD). Calcineurin inhibitors (CNIs) such as tacrolimus contribute to AKI risk. This study evaluated outcomes among lung transplant recipients administered enteral or oral versus intravenous (IV) tacrolimus immediately post-lung transplant. MethodsWe performed a single-center retrospective study of lung transplant recipients from 2011 to 2019. Tacrolimus concentrations, rates of perioperative AKI, CKD, and one-year survival were compared between those that received IV versus oral tacrolimus post-LT. ResultsA total of 153 patients were included; 110 and 43 received IV tacrolimus and enteral or oral tacrolimus, respectively. AKI within 14 days post-LT occurred more frequently in patients that received IV tacrolimus versus enteral administration (84.5 vs 44.1 %, p = <0.001). Additionally, those patients that received IV tacrolimus had supratherapeutic tacrolimus concentrations for more days than those that received enteral (3 days, IQR 1–5 vs 1 day, IQR 0–1; p < 0.001). CKD rates at 1 year were not significantly different between groups. One year survival was 97.7 % in group that received enteral tacrolimus compared to 82.7 % in IV tacrolimus group (p = 0.01) ConclusionIV tacrolimus in the initial period post-LT was associated with higher AKI rates and lower 1-year survival compared to enteral tacrolimus. There was no difference in CKD rates at 1 year.

Risk Factors for and Outcomes Following Early Acquisition of Mycobacterium abscessus Complex After Lung Transplantation.

Lung transplant recipients are at increased risk of Mycobacterium abscessus complex (MABC) acquisition and invasive infection. We analyzed risk factors and outcomes of early post-lung transplant MABC acquisition. We conducted a retrospective matched case-control study of patients who underwent lung transplant from 1/1/2012 to 12/31/2021 at a single large tertiary care facility. Cases had de novo MABC isolation within 90 days post-transplant. Controls had no positive MABC cultures and were matched 3:1 with cases based on age and transplant date. Recipient demographics and pre-/peri-operative characteristics were analyzed, and a regression model was used to determine independent risk factors for MABC acquisition. We also assessed 1-year post-transplant outcomes, including mortality. Among 1145 lung transplants, we identified 79 cases and 237 matched controls. Post-transplant mechanical ventilation for >48 hours was independently associated with MABC acquisition (adjusted odds ratio, 2.46; 95% CI, 1.29-4.72; P = .007). Compared with controls, cases required more days of hospitalization after the MABC index date (28 vs 12 days; P = .01) and had decreased 1-year post-transplant survival (78% vs 89%; log-rank P = .02). One-year mortality appeared highest for cases who acquired M. abscessus subsp. abscessus (31% mortality) or had extrapulmonary infections (43% mortality). In this large case-control study, prolonged post-transplant ventilator duration was associated with early post-lung transplant MABC acquisition, which in turn was associated with increased hospital-days and mortality. Further studies are needed to determine the best strategies for MABC prevention, surveillance, and management.

Disulfiram, an Anti-alcoholic Drug, Targets Macrophages and Attenuates Acute Rejection in Rat Lung Allografts.

Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75mg/h) monotherapy or co-solvent only (50% hydroxypropyl-β-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.

Long-Term Survival Following Primary Graft Dysfunction Development in Lung Transplantation

IntroductionPrimary graft dysfunction (PGD) is a known risk factor for early mortality following lung transplant (LT). However, the outcomes of patients who achieve long-term survival following index hospitalization are unknown. We aimed to determine the long-term association of PGD grade 3 (PGD3) in patients without in-hospital mortality. MethodsLT recipients were identified from the United Network for Organ Sharing Database. Patients were stratified based on the grade of PGD at 72 h (No PGD, Grade 1/2 or Grade 3). Groups were assessed with comparative statistics. Long-term survival was evaluated using Kaplan–Meier methods and a multivariable shared frailty model including recipient, donor, and transplant characteristics. ResultsThe PGD3 group had significantly increased length of stay, dialysis, and treated rejection post-transplant (P < 0.001). Unadjusted survival analysis revealed a significant difference in long-term survival (P < 0.001) between groups; however, following adjustment, PGD3 was not independently associated with long-term survival (hazard ratio: 0.972; 95% confidence interval: 0.862-1.096). Increased mortality was significantly associated with increased recipient age and treated rejection. Decreased mortality was significantly associated with no donor diabetes, bilateral LT as compared to single LT, transplant in 2015-2016 and 2017-2018, and no post-transplant dialysis. ConclusionsWhile PGD3 remains a challenge post LT, PGD3 at 72 h is not independently associated with decreased long-term survival, while complications such as dialysis and rejection are, in patients who survive index hospitalization. Transplant providers should be aggressive in preventing further complications in recipients with severe PGD to minimize the negative association on long-term survival.

(631) - Invasive Mechanical Ventilation Status at 72 Hours May be a Pragmatic and Valid Early Outcome Associated with Post-Lung Transplant Survival

(631) - Invasive Mechanical Ventilation Status at 72 Hours May be a Pragmatic and Valid Early Outcome Associated with Post-Lung Transplant Survival

(444) - Similar Waitlist and Post-Lung Transplant Outcomes in Pulmonary Arterial Hypertension Patients When Compared with Other Etiologies of End-Stage Lung Disease, a Propensity-Match Analysis

(444) - Similar Waitlist and Post-Lung Transplant Outcomes in Pulmonary Arterial Hypertension Patients When Compared with Other Etiologies of End-Stage Lung Disease, a Propensity-Match Analysis

Impact of Blood Products Transfusion on Patients in the Immediate Post-Lung Transplant Period: A Cohort Study.

BACKGROUND Anemia is common in post-transplant patients. Blood product transfusion is associated with mortality and rejection in solid organ transplants. In lung transplant recipients, transfusion predisposes to primary graft dysfunction (PGD). The adverse effects and associated mortality of perioperative transfusions in lung transplant recipients have not been evaluated. This study examined the effects of perioperative blood transfusions in lung transplant recipients. MATERIAL AND METHODS We conducted a retrospective study of the effects of blood product transfusions in patients who received single- or double-lung transplantation at Houston Methodist Hospital between August 2017 and September 2019. Univariable and multiple logistic regression modeling were used to determine the characteristics associated with single events as well as a composite outcome within 30 days (including mortality, acute myocardial infarction, acute stroke, lower respiratory tract infection, urinary tract infection, surgical site infections, or PGD). RESULTS A total of 232 patients received lung transplants between December 2015 and September 2019 at our center. Univariable analysis revealed an increased risk of PGD (P<0.001), more mechanical ventilation days (P<0.001), more ICU days post-transplant (P<0.001), and greater need for ECMO support (P=0.001) in patients who received blood product transfusions. In univariate analysis, the composite outcome was also more common (P=0.01) in patients who received any transfusion perioperatively. A total of 7 patients died within 30 days from transplant, and they were all in the transfused group. CONCLUSIONS Among lung transplant recipients, PGD, ICU days, need for mechanical ventilation and ECMO support, and total composite events were significantly greater in patients who received blood transfusion perioperatively.

The Association of Post-Lung Transplant Pulmonary Embolism With the Development of Chronic Lung Allograft Dysfunction.

Pulmonary embolism (PE) is a rare yet serious postoperative complication for lung transplant recipients (LTRs). The association between timing and severity of PE and the development of chronic allograft lung dysfunction (CLAD) has not been described. A single-center, retrospective cohort analysis of first LTRs included bilateral or single lung transplants and excluded multiorgan transplants and retransplants. PEs were confirmed by computed tomography angiography or ventilation/perfusion (VQ) scans. Infarctions were confirmed on computed tomography angiography by a trained physician. The PE severity was defined by the Pulmonary Embolism Severity Index (PESI) score, a 30-d post-PE mortality risk calculator, and stratified by low I and II (0-85), intermediate III and IV (85-125), and high V (>125). PE and PESI were analyzed in the outcomes of overall survival, graft failure, and chronic lung allograft dysfunction (CLAD). We identified 57 of 928 patients (6.14%) who had at least 1 PE in the LTR cohort with a median follow-up of 1623 d. In the subset with PE, the median PESI score was 85 (75.8-96.5). Most of the PESI scores (32/56 available) were in the low-risk category. In the CLAD analysis, there were 49 LTRs who had a PE and 16 LTRs (33%) had infarction. When treating PE as time-dependent and adjusting for covariates, PE was significantly associated with death (hazard ratio [HR] 1.8; 95% confidence interval [CI], 1.3-2.5), as well as increased risk of graft failure, defined as retransplant, CLAD, or death (HR 1.8; 95% CI, 1.3-2.5), and CLAD (HR 1.7; 95% CI, 1.2-2.4). Infarction was not associated with CLAD or death. The PESI risk category was not a significant predictor of death or CLAD. PE is associated with decreased survival and increased hazard of developing CLAD. PESI score was not a reliable predictor of CLAD or death in this lung transplant cohort.

Airway pepsinogen A4 identifies lung transplant recipients with microaspiration and predicts chronic lung allograft dysfunction

BackgroundAspiration is a known risk-factor for adverse outcomes post-lung transplantation. Airway bile acids are the gold-standard biomarker of aspiration – however they are released into the duodenum and likely reflect concurrent gastrointestinal dysmotility. Previous studies investigating total airway pepsin have found conflicting results on its relationship with adverse outcomes post-lung transplantation. These studies measured total pepsin and pepsinogen in the airways. Certain pepsinogens are constitutively expressed in the lungs while others, like pepsinogen A4 (PGA4), are not. We sought to evaluate the utility of measuring airway PGA4 as a biomarker of aspiration and predictor of adverse outcomes in lung transplant recipients (LTRs) early post-transplant. MethodsExpression of PGA4 was compared to other pepsinogens in lung tissue. Total pepsin and PGA4 were measured in large airway bronchial washings and compared to pre-existing markers of aspiration. Two independent cohorts of LTRs were used to assess the relationship between airway PGA4 and chronic lung allograft dysfunction (CLAD). Changes to airway PGA4 after anti-reflux surgery was assessed in a third cohort of LTRs. ResultsPGA4 was expressed in healthy human stomach but not lung. Airway PGA4, but not total pepsin, was associated with aspiration. Airway PGA4 was associated with an increased risk of CLAD in two independent cohorts of LTRs. Anti-reflux surgery was associated with reduced airway PGA4. ConclusionsAirway PGA4 is a marker of aspiration that predicts CLAD in LTRs. Measuring PGA4 at surveillance bronchoscopies can help triage high-risk LTRs for anti-reflux surgery.

Feasibility and performance of continuous glucose monitoring in hyperglycemia after lung transplantation.

Post-Transplant Diabetes Mellitus (PTDM) affects 20%-40% of lung transplant recipients within five years, impacting rejection, infection, cardiovascular events, and mortality. Continuous glucose monitoring (CGM) is used in diabetes but not well-studied in PTDM. This study assessed CGM performance in detecting hypoglycemia and hyperglycemia post-lung transplantation, compared to self-monitoring blood glucose. A prospective pilot study included 15 lung transplant patients (mean age 58.6 years; 53.3% men; 73.3% with pre-transplantation diabetes) managing hyperglycemia with insulin. Patients used a blinded CGM and self-monitored glucose for ten days. Data were categorized (% time in range, % high, % very high, % low, % very low) and compared using paired t-tests. CGM showed superior hyperglycemia detection. Mean differences for "% very high", "% high", and "% high and % very high" were 7.12 (95% CI, 1.8-12.4), 11.1 (95% CI, 3.5-18.8), and 18.3 (95% CI: 7.37-29.24), respectively. No significant difference was found for "% low and % very low". All patients reported a positive CGM experience. CGM use post-lung transplantation seems feasible and offers advantages in detecting hyperglycemia and in optimizing glucose management. Study limitations include a small sample size, requiring larger studies to assess glycemic control, hypoglycemia detection, and transplant outcomes.

Evaluating Sinus Microbiology by Transplant Status in Persons With Cystic Fibrosis: A Matched Cohort Study.

Sinus disease is prevalent in persons with cystic fibrosis (PwCF) and may be a reservoir of airway infection in postlung transplant (pTx) patients. The microbial composition of cystic fibrosis sinuses and its associations with chronic rhinosinusitis (CRS) is relatively unexplored. We aimed to examine the sinus and lower airway microbiome and their associations with CRS in PwCF and pTxPwCF. Prospective single-centre study. A total of 31 sex and age (±2 years) matched PwCF and pTxPwCF. Demographic and clinical data along with sinus swabs and sputum were collected. CRS was assessed using Sinonasal Outcome Test-22 (SNOT-22) (patient reported outcome) and Lund-McKay (computed tomography sinus) scores. Samples underwent MiSeq Illumina sequencing of the universal 16S ribosomal RNA gene. A total of 31 PwCF (15 pTxPwCF) were included. Aggregate airways microbiome composition was dominated by Pseudomonas (46%), Haemophilus (14%), Staphylococcus (11%), Streptococcus (10%), and Fusobacterium (6%). α-diversity was significantly lower in post-Tx samples across both sputum and sinus samples (P = .005). β-diversity was significantly different between sputum (P = .004), but not sinus (P = .75) samples by transplant status. While there was a trend in higher β-diversity associated with lower SNOT-22 score at time of first visit, this did not reach significance (P = .05). Sinus and airway microbiomes differed in PwCF and pTxPwCF, but the prevalent organisms remained consistent. Elucidating the relationship of the microbiome with clinical status to better understand when to intervene accordingly is needed to optimize sinus disease management in PwCF.

Resistin Pathway as Novel Mechanism of Post-lung Transplantation Bronchial Stenosis.

Bronchial stenosis remains a significant source of morbidity among lung transplant recipients. Though infection and anastomotic ischemia have been proposed etiologies of the development of bronchial stenosis, the pathophysiologic mechanism has not been well elucidated. In this single-centered prospective study, from January 2013 through September 2015, we prospectively collected bronchoalveolar lavage (BAL) and endobronchial epithelial brushings from the direct anastomotic site of bronchial stenosis of bilateral lung transplant recipients who developed unilateral post-transplant bronchial stenosis. Endobronchial epithelial brushings from the contralateral anastomotic site without bronchial stenosis and BAL from bilateral lung transplant recipients who did not develop post-transplant bronchial stenosis were used as controls. Total RNA was isolated from the endobronchial brushings and real-time polymerase chain reaction reactions were performed. Electrochemiluminescence biomarker assay was used to measure 10 cytokines from the BAL. Out of 60 bilateral lung transplant recipients, 9 were found to have developed bronchial stenosis with 17 samples adequate for analysis. We observed a 1.56 to 70.8 mean-fold increase in human resistin gene expression in the anastomotic bronchial stenosis epithelial cells compared with nonstenotic airways. Furthermore, IL-1β (21.76±10.96pg/mL; control 0.86±0.44pg/mL; P <0.01) and IL-8 levels (990.56±326.60pg/mL; control 20.33±1.17pg/mL; P <0.01) were significantly elevated in the BAL of the lung transplant patients who developed anastomotic bronchial stenosis. Our data suggest that the development of postlung transplantation bronchial stenosis may be in part mediated through the human resistin pathway by IL-1β induced transcription factor nuclear factor-κβ activation and downstream upregulation of IL-8 in alveolar macrophages. Further study is needed in the larger patient cohorts and to determine its potential therapeutic role in the management of post-transplant bronchial stenosis.

Erratic tacrolimus levels at 6 to 12 months post-lung transplant predicts poor outcomes

Erratic tacrolimus levels at 6 to 12 months post-lung transplant predicts poor outcomes

Self-reported engagement in everyday activities following bilateral lung transplantation in paediatric cystic fibrosis: a single centre study

IntroductionFollowing lung transplantation, it is unknown how children/adolescents self-assess their performance in everyday activities, importance of these activities, and whether resumption of everyday activities influences self-reported quality of life. The...