Immediate Postoperative COVID-19 Infection after Lung Transplantation: A Systematic Review and Case Series.

BACKGROUND: With new variants challenging the effectiveness of preventive measures, we are beginning to recognize the reality that COVID-19 will continue to pose an endemic threat. The manifestations of COVID-19 in lung transplant recipients during index admission are poorly understood with very few cases reported in recent lung transplant recipients. Optimal management of immunosuppression and antiviral therapy in recent transplant recipients is challenging. METHODS: We performed a retrospective analysis identifying lung transplant recipients at our institution who contracted COVID-19 in the immediate postoperative period (within index admission). In addition, we performed a systematic review from January 2020 to August 2023 identifying all publications on the PUBMED database regarding COVID-19 infection in lung transplant recipients during index admission. RESULTS: We report four cases of COVID-19 pneumonia in lung transplant recipients in the immediate postoperative period and we describe the clinical course, treatment options, and immunosuppression changes to manage this unique clinical problem. All patients made a full recovery and were eventually discharged home. Within our review of the literature, the most prevalent presenting symptoms were cough, dyspnea, and fatigue. Six (75%) patients decreased or held their antimetabolite. The two most common treatments were monoclonal antibodies (38%) and remdesivir (63%). CONCLUSION: Although previous literature demonstrates that COVID-19 can be deadly in recent lung transplant recipients, rapid treatment with anti-viral therapy/immunotherapy, deescalating immunosuppression, and treatment of respiratory decompensation with Decadron was effective in our patients.

A novel scoring system to predict survival in cirrhotic patients undergoing isolated lung transplantation: The PENS-CEPT score.

Cirrhosis is usually regarded as a contraindication to isolated lung transplantation (ILT). We sought to determine which patients with cirrhosis could safely undergo ILT. Based on a retrospective analysis of patients with cirrhosis who underwent ILT at our center between 2007 and 2020, we developed an exclusionary algorithm (PENS-CEPT: Pittsburgh ExclusioN Score in Cirrhotics Evaluated for Pulmonary Transplant) to help determine which patients can undergo ILT with minimal incurred risk from their underlying liver disease. The score utilizes a combination of readily available clinical data and the presence (or absence) of spontaneous portosystemic shunts on preoperative cross-sectional imaging. Sixteen patients underwent ILT with a diagnosis of cirrhosis: nine with cystic fibrosis. On univariate analysis, only our model was able to predict 1 year survival. Of the nine patients that would have been approved using our model, there was only one short term death. Of the seven patients that would have been rejected by the model, all but one died within the first year with six dying of complications from liver failure. We are proposing a simple score utilizing routine clinical parameters and pre-operative imaging to determine the safety of ILT in cirrhotic patients. Further studies are required to validate this scoring system with the goal of safely increasing the opportunity for cirrhotic patients who would otherwise be rejected for ILT.

Postoperative Acute Kidney Injury and Long-Term Outcomes After Lung Transplantation.

BACKGROUND: This study sought to characterize perioperative risk factors of acute kidney injury (AKI) and report outcomes associated with its development in the immediate postoperative setting after lung transplantation. METHODS: Study investigator performed a retrospective analysis of all adult patients undergoing primary lung transplantation at a single institution from January 1, 2011 to December 31, 2021 AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria after lung transplantation and was stratified on the basis of whether patients required renal replacement therapy (RRT; AKI-no RRT vs AKI-RRT). RESULTS: Of the 754 patients included, 369 (48.9%) any AKI developed in the postoperative period (252 AKI-no RRT vs 117 AKI-RRT). Risk factors for postoperative AKI included higher preoperative creatinine levels (odds ratio [OR], 5.15; P < .001), lower preoperative estimated glomerular filtration rate (OR, 0.99; P < 0.018), delayed chest closure (OR, 2.72; P < .001), and higher volumes of postoperative blood products (OR, 1.09; P < .001) in the multivariable analysis. On univariate analysis, both AKI groups were also associated with higher rates of pneumonia (P < .001), reintubation (P < .001), mortality on index admission (P < 0.001), longer ventilator duration (P < .001), longer intensive care unit length of stay (P < .001), and longer hospital length of stay (P < .001), with the highest rates in the AKI-RRT group. In a multivariable survival analysis, postoperative AKI-no RRT (hazard ratio [HR], 1.50; P = .006) and AKI-RRT (HR, 2.70; P < .001) were associated with significantly worse survival independent of severe grade 3 primary graft dysfunction at 72 hours (HR, 1.45; P = .038). CONCLUSIONS: The development of postoperative AKI was associated with numerous preoperative and intraoperative factors. Postoperative AKI remained significantly associated with poorer posttransplantation survival. Severe cases of AKI necessitating RRT portended the worst survival after lung transplantation.

Waitlist Mortality and Extracorporeal Membrane Oxygenation Bridge to Lung Transplant.

BACKGROUND: Use of extracorporeal membrane oxygenation (ECMO) as bridge to lung transplant has increased. However, little is known about patients placed on ECMO who die while on the waiting list. Using a national lung transplant data set, we investigated variables associated with waitlist mortality of patients bridged to lung transplant. METHODS: All patients supported on ECMO at time of listing were identified using the United Network for Organ Sharing database. Univariable analyses were performed using bias-reduced logistic regression. Cause-specific hazard models were used to determine the effect of variables of interest on hazard of outcomes. RESULTS: From April 2016 to December 2021, 634 patients met inclusion criteria. Of these, 445 (70%) were successfully bridged to transplant, 148 (23%) died on the waitlist, and 41 (6.5%) were removed for other reasons. Univariable analysis found associations between waitlist mortality and blood group, age, body mass index, serum creatinine, lung allocation score, days on waitlist, United Network for Organ Sharing region, and being listed at a lower-volume center. Cause-specific hazard models demonstrated that patients at high-volume centers were 24% more likely to survive to transplant and 44% less likely to die on the waitlist. Among patients who were successfully bridged to transplant, there was no difference in survival between low- and high-volume centers. CONCLUSIONS: ECMO is an appropriate strategy to bridge selected high-risk patients to lung transplant. Of those placed on ECMO with intent to transplant, about one quarter may not survive to transplantation. High-risk patients requiring advanced support strategies may be more likely to survive to transplant when bridged at a high-volume center.

Risk Factors and Outcomes of Postoperative Hepatic Dysfunction After Lung Transplantation.

BACKGROUND: Hepatic dysfunction is a morbid complication of lung transplantation. Little is known about risk factors for postoperative hepatic dysfunction or its impact on survival after lung transplantation. METHODS: This retrospective analysis of 1406 adult lung transplant recipients was performed at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania between January 1, 2007 and December 1, 2019. Patients were excluded for redo lung transplantation, concomitant cardiac surgery, or concurrent solid organ transplantation. Postoperative liver dysfunction was classified as either ischemic liver injury or nonischemic dysfunction (transaminitis, hyperbilirubinemia). RESULTS: Among the 1155 primary lung transplant recipients included, postoperative hepatic dysfunction developed in 96 (8.3%) after lung transplantation. A history of liver disease was the greatest predictor of postoperative hepatic dysfunction (odds ratio, 6.19; CI, 2.13-17.4; P < .001). Patients with postoperative hepatic dysfunction had a greater need for intraoperative blood products (ischemic, 12 U [range, 6-21 U]; nonischemic, 10 U [range, 4-28 U]; vs none, 4 U [range, 1-12 U]; P < .001) and an increased need for postoperative circulatory support (ischemic, 16 [76%]; nonischemic, 25 [33%]; none, 117 [11%]; P < .001). Both ischemic liver injury and nonischemic dysfunction were associated with diminished 1-, 3-, and 5-year term survival (ischemic, 27.5%, 16.5%, and 0%, respectively; nonischemic, 60%, 49.6%, and 46.9%, respectively; none, 87.3%, 72.3%, and 59.5%, respectively; P < .001). CONCLUSIONS: Hepatic dysfunction after lung transplantation is associated with significant morbidity and mortality. A history of liver disease was the best positive predictor for postoperative dysfunction. Additional studies are necessary to identify the best treatment algorithm to avoid hepatic dysfunction more effectively in the postoperative setting after lung transplantation.

Intraoperative Support for Primary Bilateral Lung Transplantation: A Propensity-Matched Analysis.

BACKGROUND: Single-center studies support benefits of venoarterial extracorporeal membrane oxygenation (VA-ECMO) as a method of intraoperative support. Propensity-matched data from a large cohort, however, are currently lacking. Therefore, our goal was to compare outcomes of intraoperative VA-ECMO and cardiopulmonary bypass (CPB) during bilateral lung transplantation (LTx) with a propensity analysis. METHODS: We performed a retrospective analysis of 795 consecutive primary adult LTx patients (June 1, 2011-December 26, 2020) using no intraoperative support (n = 210), VA-ECMO (n = 150), or CPB (n = 197). Exclusion criteria included LTx on venovenous-ECMO, single/redo LTx, ex vivo lung perfusion, and concomitant solid-organ transplantation or cardiac procedure. Propensity analysis was performed comparing patients who underwent intraoperative CPB or VA-ECMO. RESULTS: The propensity CPB group required more blood products at 72 hours (P = .02) and longer intensive care unit length of stay (P < .001) and ventilator dependence days (P < .001). There were no differences in cerebrovascular accident (P = 1), reintubation (P = .4), dialysis (P = .068), in-hospital mortality (P = .33), and 1-year (P = .67) and 3-year (P = .32) survival. The CPB group had a higher incidence of grade 3 primary graft dysfunction at 72 hours (P < .001). Neither support strategy was a predictor of 1- and 3-year mortality in our multivariable model (VA-ECMO, P = .72 and P = .57; CPB, P = .45 and P = .91, respectively). CONCLUSIONS: Intraoperative VA-ECMO during lung transplantation was associated with fewer postoperative blood transfusions, shorter length of mechanical ventilation, and lower incidence of a grade 3 primary graft dysfunction at 72 hours. Although there were some differences in the postoperative course between the VA-ECMO and CPB groups, support type was not associated with differences in survival.

Anatomic Position and Durability of Polytetrafluoroethylene Conduit ≥18 mm: Single-Center Experience.

BACKGROUND: Conduit longevity after right ventricular outflow tract (RVOT) reconstruction is determined by the interaction of different factors. We evaluated the relationship between conduit anatomic position and long-term durability among ≥18 mm polytetrafluoroethylene (PTFE) conduits. METHODS: A single-institution RVOT reconstructions using a PTFE conduit ≥18 mm were identified. Catheter-based interventions or the need for conduit replacement were comparatively assessed between orthotopic vs heterotopic conduit position. Time to the first reintervention, censored by death, was compared between the groups. RESULTS: A total of 102 conduits were implanted in 99 patients, with a median age of 13.2 years (interquartile range [IQR] 8.9-17.8 years), median weight of 47 kg (IQR, 29-67 kg), and body surface area of 1.4 m2 (IQR, 1-1.7 m2). Overall, 50.9% (n = 52) of conduits were placed in an orthotopic position after the Ross procedure in congenital aortic valve abnormalities (80% [n = 36]). Tetrology of Fallot in 39% (n = 18), followed by truncus arteriosus with 33% (n = 15), were the most common in the heterotopic position. Trileaflet configuration was similar (67% vs 69%; P = .32) between the groups. Survival free from reintervention was 91% (95% CI, 79-97) and 88% (95% CI, 71-95) in the orthotopic and the heterotopic group, respectively, at 5 years, without differences in the Kaplan Meier curves (log-rank >.05). CONCLUSIONS: RVOT reconstruction with PTFE conduits ≥ 8 mm showed >90% conduit survival free from replacement in our cohort at 5 years. The anatomic position of the PTFE conduit does not seem to impact intermediate durability.

The Use of Extracorporeal Support to Rescue Patients With Acute Respiratory Distress Syndrome Following Thoracic Surgery.

Postoperative acute respiratory distress syndrome (ARDS) following a general thoracic procedure is associated with high morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) offers an alternate means of cardiopulmonary support in the setting of refractory respiratory failure. We report indications and outcomes patients who after complex general thoracic surgery developed ARDS requiring ECMO support. We performed a retrospective analysis of all patients requiring venovenous (VV) ECMO support in the postoperative period following a general thoracic surgical procedure from January 2011 to December 2019. Exclusion criteria include those who underwent a cardiac procedure, venoarterial (VA) ECMO, cardiothoracic transplantation, or required ECMO only for intraoperative support. Forty instances of postoperative VV ECMO were utilized in patients who underwent a surgery with the thoracic surgical service. Lung procedures were the most common index operations performed (45%) followed by esophageal procedures (40%). Mean time to ECMO initiation from the index operation was 5.45 days with a range of 0 days to 1.3 months. Median length of ECMO support was 9.41 days with a range of 12 hours to 33 days. Patients were cannulated in an elective (70%) or emergent (30%) fashion. ECMO-related complications included a major bleeding event in seven patients. Thirty day survival was 62.5% for the entire cohort and 52.5% of patients were discharged from the hospital and 80.95% of these patients were still alive 90 days after discharge. ECMO is a viable means of cardiopulmonary support that can provide a survival advantage for patients who experience severe refractory respiratory failure following a complex general thoracic surgery.

Induction Strategies in Lung Transplantation: Alemtuzumab vs. Basiliximab a Single-Center Experience.

Background: Induction therapy is used in about 80% of lung transplant centers and is increasing globally. Currently, there are no standards or guidelines for the use of induction therapy. At our institution, we have two induction strategies, basiliximab, and alemtuzumab. The goal of this manuscript is to share our experience and practice since this is an area of controversy. Methods: We retrospectively reviewed 807 lung transplants performed at our institution between 2011 and 2020. Indications for the use of the basiliximab protocol were as follows: patients over the age of 70 years, history of cancer, hepatitis C virus or human immunodeficiency virus infection history, and cytomegalovirus or Epstein-Barr virus (donor positive/ recipient negative). In the absence of these clinical factors, the alemtuzumab protocol was used. Results: 453 patients underwent alemtuzumab induction and 354 patients underwent basiliximab. There were significant differences in delayed chest closure (24.7% alemtuzumab vs 31.4% basiliximab, p = 0.037), grade 3 primary graft dysfunction observed within 72 hours (19.9% alemtuzumab vs 29.9% basiliximab, p = 0.002), postoperative hepatic dysfunction (8.8% alemtuzumab vs 14.7% basiliximab, p = 0.009), acute cellular rejection in first year (39.1% alemtuzumab vs 53.4% basiliximab, p < 0.001). The overall survival rate of the patients with alemtuzumab induction was significantly higher than those of the patients with basiliximab induction (5 years survival rate: 64.1% alemtuzumab vs 52.3%, basiliximab, p < 0.001). Multivariate Cox regression analysis confirmed lower 5-year survival for basiliximab induction (HR = 1.41, p = 0.02), recipient cytomegalovirus positive (HR = 1.49, p = 0.01), postoperative hepatic dysfunction (HR = 2.20, p < 0.001), and acute kidney injury requiring renal replacement therapy (HR = 2.27, p < 0.001). Conclusions: In this single center retrospective review, there was a significant difference in survival rates between induction strategies. This outcome may be attributable to differences in recipient characteristics between the groups. However, the Alemtuzumab group experienced less episodes of acute cellular rejection within the first year.

Outcomes following lung re-transplantation in patients with cystic fibrosis.

PURPOSE: We examined cystic fibrosis (CF) patients and compared their clinical status at the time of primary versus double lung re-transplantation (re-DLTx) in order to better understand lung retransplant practice patterns. METHODS: We performed a retrospective analysis of the UNOS Database identifying CF patients ≥18 years old undergoing re-DLTx (5/4/2005 and 12/4/2020). Baseline and clinical variables at the primary and re-DLTx were compared utilizing the paired student t-test. Graft survival was defined as time from surgery to retransplant and analyzed using Kaplan-Meier estimates. RESULTS: 277 CF patients who underwent re-DLTx experienced a significantly worse 5-year survival when compared to the primary DLTx cohort (47.9% vs 58.8%, p = 0.00012). The following differences were observed comparing CF re-DLTx group to their primary DLTx: higher LAS score at the time of listing (50.66 vs 42.15, p < 0.001) and transplant (62.19 vs 48.20, p < 0.001), and increase LAS from the time of listing to transplant (+12.22 vs +7.23, p = 0.002). While serum albumin and total bilirubin were similar, CF patients had a higher creatinine (1.05 vs 0.74, p < 0.001), dialysis (4.4% vs 0.6%, p < 0.001), ECMO bridge to transplant rates (7.6% vs 4.0%, p < 0.001), and higher oxygen requirements (5.95 vs 3.93, p < 0.001) at the time of listing for a re-DLTx. CONCLUSION: Compared to their initial transplant, CF patients experience significant clinical decline in renal, cardiac, and pulmonary function at the time of lung retransplantation. This may indicate that an earlier evaluation and rehabilitation process may be necessary to identify patients earlier for lung retransplantation prior significant clinical decline.

A review of liver dysfunction in the lung transplant patient.

Liver dysfunction is an increasingly common finding in patients evaluated for lung transplantation. New or worsening dysfunction in the perioperative period, defined by presence of clinical ascites/encephalopathy, high model for end-stage liver disease (MELD) score, and/or independent diagnostic criteria, is associated with high short- and long-term mortality. Therefore, a thorough liver function assessment is necessary prior to listing for lung transplant. Unfortunately, identification and intraoperative monitoring remain the only options for prevention of disease progression with isolated lung transplantation. Combined lung and liver transplantation may provide an option for definitive long-term management in selecting patients with known liver disease at high risk for postoperative progression. However, experience with the combined operation is extremely limited and indications for combined lung and liver transplant remain unclear. Herein, we present a comprehensive literature review of patients with liver dysfunction undergoing lung transplantation with and without concurrent liver transplant in an effort to illuminate the risks, benefits, and clinical judgement surrounding decision to pursue combined lung-liver transplantation (CLLT). We also argue description of liver function is currently a weakness of the current lung allocation scoring system. Additional algorithms incorporating liver function may aid in risk stratification and decision to pursue combined transplantation.

The Transcriptional Regulator Id2 Is Critical for Adipose-Resident Regulatory T Cell Differentiation, Survival, and Function.

Adipose regulatory T cells (aTregs) have emerged as critical cells for the control of local and systemic inflammation. In this study, we show a distinctive role for the transcriptional regulator Id2 in the differentiation, survival, and function of aTregs in mice. Id2 was highly expressed in aTregs compared with high Id3 expression in lymphoid regulatory T cells (Tregs). Treg-specific deletion of Id2 resulted in a substantial decrease in aTregs, whereas Tregs in the spleen and lymph nodes were unaffected. Additionally, loss of Id2 resulted in decreased expression of aTreg-associated markers, including ST2, CCR2, KLRG1, and GATA3. Gene expression analysis revealed that Id2 expression was essential for the survival of aTregs, and loss of Id2 increased cell death in aTregs due to increased Fas expression. Id2-mediated aTreg depletion resulted in increased systemic inflammation, increased inflammatory macrophages and CD8+ effector T cells, and loss of glucose tolerance under standard diet conditions. Thus, we reveal an unexpected and novel function for Id2 in mediating differentiation, survival, and function of aTregs that when lost result in increased metabolic perturbation.

The Lysophosphatidylcholine Transporter MFSD2A Is Essential for CD8+ Memory T Cell Maintenance and Secondary Response to Infection.

Access to nutrients is critical for an effective T cell immune response to infection. Although transporters for sugars and amino acids have previously been described in the context of the CD8+ T cell immune response, the active transport of exogenous fatty acids has remained enigmatic. In this study, we discovered that the sodium-dependent lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (MFSD2A) is upregulated on activated CD8+ T cells and is required for memory T cell maintenance. MFSD2A deficiency in mice resulted in decreased import of LPC esterified to long chain fatty acids into activated CD8+ T cells, and MFSD2A-deficient cells are at a competitive disadvantage resulting in reduced memory T cell formation and maintenance and reduced response to secondary infection. Mechanistically, import of LPCs was required to maintain T cell homeostatic turnover, which when lost resulted in a decreased memory T cell pool and thus a reduced secondary response to repeat infection.

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes.

OBJECTIVE: Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. APPROACH AND RESULTS: We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. CONCLUSIONS: These data indicate a previously unrecognized role for TERT in neointima formation through epigenetic regulation of proliferative gene expression in SMC.