Resolvin D1 prevents injurious neutrophil swarming in transplanted lungs.

Neutrophils are the primary cell type involved in lung ischemia-reperfusion injury (IRI), which remains a frequent and morbid complication after organ transplantation. Endogenous lipid mediators that become activated during acute inflammation-resolution have gained increasing recognition for their protective role(s) in promoting the restoration of homeostasis, but their influence on early immune responses following transplantation remains to be uncovered. Resolvin D1, 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (RvD1), is a potent stereoselective mediator that exhibits proresolving and anti-inflammatory actions in the setting of tissue injury. Here, using metabololipidomics, we demonstrate that endogenous proresolving mediators including RvD1 are increased in human and murine lung grafts immediately following transplantation. In mouse grafts, we observe lipid mediator class switching early after reperfusion. We use intravital two-photon microscopy to reveal that RvD1 treatment significantly limits early neutrophil infiltration and swarming, thereby ameliorating early graft dysfunction in transplanted syngeneic lungs subjected to severe IRI. Through integrated analysis of single-cell RNA sequencing data of donor and recipient immune cells from lung grafts, we identify transcriptomic changes induced by RvD1. These results support a role for RvD1 as a potent modality for preventing early neutrophil-mediated tissue damage after lung IRI that may be therapeutic in the clinics.

Smoking exposure-induced bronchus-associated lymphoid tissue in donor lungs does not prevent tolerance induction after transplantation.

The presence of bronchus-associated lymphoid tissue (BALT) in donor lungs has been suggested to accelerate graft rejection after lung transplantation. Although chronic smoke exposure can induce BALT formation, the impact of donor cigarette use on alloimmune responses after lung transplantation is not well understood. Here, we show that smoking-induced BALT in mouse donor lungs contains Foxp3+ T cells and undergoes dynamic restructuring after transplantation, including recruitment of recipient-derived leukocytes to areas of pre-existing lymphoid follicles and replacement of graft-resident donor cells. Our findings from mouse and human lung transplant data support the notion that a donor's smoking history does not predispose to acute cellular rejection or prevent the establishment of allograft acceptance with comparable outcomes to nonsmoking donors. Thus, our work indicates that BALT in donor lungs is plastic in nature and may have important implications for modulating proinflammatory or tolerogenic immune responses following transplantation.

Role of tertiary lymphoid organs in the regulation of immune responses in the periphery.

Tertiary lymphoid organs (TLOs) are collections of immune cells resembling secondary lymphoid organs (SLOs) that form in peripheral, non-lymphoid tissues in response to local chronic inflammation. While their formation mimics embryologic lymphoid organogenesis, TLOs form after birth at ectopic sites in response to local inflammation resulting in their ability to mount diverse immune responses. The structure of TLOs can vary from clusters of B and T lymphocytes to highly organized structures with B and T lymphocyte compartments, germinal centers, and lymphatic vessels (LVs) and high endothelial venules (HEVs), allowing them to generate robust immune responses at sites of tissue injury. Although our understanding of the formation and function of these structures has improved greatly over the last 30 years, their role as mediators of protective or pathologic immune responses in certain chronic inflammatory diseases remains enigmatic and may differ based on the local tissue microenvironment in which they form. In this review, we highlight the role of TLOs in the regulation of immune responses in chronic infection, chronic inflammatory and autoimmune diseases, cancer, and solid organ transplantation.

Different-team procurements: A potential solution for the unintended consequences of change in lung allocation policy.

The new lung allocation policy has led to an increase in distant donors and consequently enhanced logistical burden of procuring organs. Though early single-center studies noted similar outcomes between same-team transplantation (ST, procuring team from transplanting center) and different-team transplantation (DT, procuring team from different center), the efficacy of DT in the contemporary era remains unclear. In this study, we evaluated the trend of DT, rate of transplanting both donor lungs, 1-year graft survival, and risk of Grade 3 primary graft dysfunction (PGD) using the Scientific Registry of Transplant Recipient (SRTR) database from 2006 to 2018. A total of 21619 patients (DT 2085, 9.7%) with 19837 donors were included. Utilization of DT decreased from 15.9% in 2006 to 8.5% in 2018. Proportions of two-lung donors were similar between the groups, and DT had similar 1-year graft survival as ST for both double (DT, HR 1.108, 95% CI 0.894-1.374) and single lung transplants (DT, HR 1.094, 95% CI 0.931-1.286). Risk of Grade 3 PGD was also similar between ST and DT. Given our results, expanding DT may be a feasible option for improving lung procurement efficiency in the current era, particularly in light of the COVID-19 pandemic.

Tolerance, immunosuppression, and immune modulation: impacts on lung allograft survival.

PURPOSE OF REVIEW: Immune responses following lung transplantation continue to result in high rates of allograft failure and rejection, and current immunosuppression does not address the unique immunologic properties of the lung. Here, we review recent studies on lung allograft tolerance and alloimmunity and discuss implications for immunosuppression. RECENT FINDINGS: Processes governing tolerance and alloimmunity in lung allografts differ from other solid organs. Recent studies have suggested that allorecognition is regulated at the level of the lung graft. Furthermore, certain cell populations essential for lung allograft tolerance may facilitate rejection in other organs. Induction of lung allograft tolerance is associated with the formation of tertiary lymphoid organs, which are enriched in regulatory T cells and play an important role in preventing rejection. SUMMARY: Recent discoveries regarding alloactivation and the regulation of tolerance following lung transplantation have introduced exciting potential avenues for the development of lung-specific immunosuppression.

B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling.

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.

Utilizing computed tomography volumetry for size matching prior to lung transplantation: a case series.

Background: Appropriate size matching between donor and recipient is critical for successful pulmonary transplantation. Although surrogate measurements such as height and gender are often utilized to approximate predicted lung volume, these methods provide only a gross estimation with wide variability and poor predictive value. Case Description: A single center exploratory study was conducted in which four patients underwent lung transplantation (LT) with pre-operative computed tomography (CT) volumetry obtained in both the donor and recipient to facilitate decision making regarding organ size and suitability. In four cases in which CT volumetry was used, the lung volumes calculated using surrogate measurements significantly overestimated both donor and recipient lung volumes quantified by CT volumetric analysis. All recipients underwent successful LT without necessary graft downsizing. Conclusions: This is an initial report of prospectively utilizing CT volumetry as an adjunct to decision-making regarding suitability of donor lungs. In these cases, CT volumetry facilitated the confident acceptance of donor lungs that were initially predicted to be oversized based on other clinical measures.

Mouse Heterotopic Cervical Cardiac Transplantation Utilizing Vascular Cuffs.

Murine models of cardiac transplantation are frequently utilized to study ischemia-reperfusion injury, innate and adaptive immune responses after transplantation, and the impact of immunomodulatory therapies on graft rejection. Heterotopic cervical heart transplantation in mice was first described in 1991 using sutured anastomoses and subsequently modified to include cuff techniques. This modification allowed for improved success rates, and since then, there have been multiple reports that have proposed further technical improvements. However, translation into more widespread utilization remains limited due to the technical difficulty associated with graft anastomoses, which requires precision to achieve adequate length and caliber of the cuffs to avoid vascular anastomotic twisting or excessive tension, which can result in damage to the graft. The present protocol describes a modified technique for performing heterotopic cervical cardiac transplantation in mice which involves cuff placement on the recipient's common carotid artery and the donor's pulmonary artery in alignment with the direction of the blood flow.

Updated Views on Neutrophil Responses in Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury is an inevitable event during organ transplantation and represents a primary risk factor for the development of early graft dysfunction in lung, heart, liver, and kidney transplant recipients. Recent studies have implicated recipient neutrophils as key mediators of this process and also have found that early innate immune responses after transplantation can ultimately augment adaptive alloimmunity and affect late graft outcomes. Here, we discuss signaling pathways involved in neutrophil recruitment and activation after ischemia-mediated graft injury in solid organ transplantation with an emphasis on lung allografts, which have been the focus of recent studies. These findings suggest novel therapeutic interventions that target ischemia-reperfusion injury-mediated graft dysfunction in transplant recipients.

Transplantation of Donor Lung With Partial Anomalous Pulmonary Venous Return Using a Carrel Patch.

Partial anomalous pulmonary venous return is a rare congenital aberrancy that involves oxygen-rich pulmonary venous drainage into the right atrium instead of into the systemic circulation. This report describes a case of isolated partial anomalous pulmonary venous return of the right upper lobe in a donor lung. Successful transplantation was performed with a Carrel patch technique for left atrial cuff reconstruction using a segment of donor vena cava. This report of partial anomalous pulmonary venous return in a right donor lung describes this reconstructive approach to restore physiologic venous drainage.

Acute Interstitial Pneumonia (Hamman-Rich Syndrome) in Lung Transplantation: A Case Series.

BACKGROUND: Acute interstitial pneumonia (AIP), also known as Hamman-Rich syndrome, is a rare and rapidly progressive idiopathic interstitial lung disease with a high mortality rate. Treatment is limited to supportive care and empirical high-dose steroids; however, outcomes are generally poor. There are few reports of lung transplantation (LTx) in patients with AIP. METHODS: We retrospectively identified patients with AIP among those who underwent LTx at our center between January 2008 and December 2020. RESULTS: During the study period, 4 patients with AIP underwent bilateral LTx: 3 men and 1 woman, between 30 and 57 years of age. The lung allocation score ranged between 71 and 89. Of the 4 patients, 2 needed extracorporeal membrane oxygenation and mechanical ventilation (MV) and 1 needed MV preoperatively. Time of onset to transplant ranged from 1 to 3 months. None of the patients had primary graft dysfunction after LTx; 2 had acute cellular rejection and 1 had chronic lung allograft dysfunction. The 4 patients are alive with survival ranging between 1 and 12 years after LTx. CONCLUSION: AIP should be considered in patients with acute respiratory failure without a clear etiology. Our study showed that LTx led to good outcomes and should be considered as a treatment option in appropriate candidates.

Bleeding and thrombotic complications associated with anticoagulation prior to lung transplantation: a case series.

Background: Scarce data is available on therapeutic anticoagulation (AC) in patients undergoing pulmonary transplantation. We describe our institutional experience with AC-induced coagulopathy in recipients at the time of transplantation and evaluate its impact on posttransplant outcomes. Methods: Records of adult patients on therapeutic AC at the time of lung transplantation from January 2014 to July 2021 were reviewed. Administration of preoperative pharmacologic reversal was assessed, with adequate reversal defined as international normalized ratio (INR) ≤1.5. We evaluated the incidence of major bleeding complications [delayed sternal closure, reoperation due to bleeding, chest tube output ≥1,500 cc, ≥4 units of packed red blood cells, ≥4 units of platelets, or ≥5 units of fresh frozen plasma (FFP)], major thrombotic complications [venous thromboembolism (VTE) or other major thrombosis on imaging], and inpatient mortality. Results: Of 602 lung transplant recipients, 10 patients taking preoperative warfarin were included in the study. While most patients received pharmacologic reversal preoperatively (n=9, 90%), successful reversal was rarely achieved (n=3, 30%). Inadequate INR reversal was associated with major bleeding events (n=6, 60%). Major thrombotic complications were more frequent (n=7, 70%) than bleeding events. Notably, all fatalities within the cohort (n=2, 20%) were associated with thrombotic, but not bleeding, complications. Conclusions: This is the first known report on the incidence and impact of AC-induced coagulopathy in patients undergoing lung transplantation. Major thrombotic events are frequent and associated with high mortality. Routine surveillance and treatment may be warranted.

Emergent Lung Resection for Massive Hemoptysis From Bronchial Malformation.

Bronchial arteriovenous malformations are usually asymptomatic findings noted on imaging but may present with massive hemoptysis after endobronchial rupture. Initial treatment usually involves transcatheter embolization with surgery reserved for refractory cases. Here, we present a patient with large-volume hemoptysis after bronchial arteriovenous malformation rupture. Attempted endovascular management was unsuccessful owing to unfavorable anatomy and hemodynamic instability, necessitating emergent use of extracorporeal membrane oxygenation followed by right bilobectomy.

Advanced considerations in organ donors.

The rising need for lung transplantation over recent years has not paralleled the availability of suitable lung allografts. The number of lung transplantations performed each year in the United States remains limited by an inadequate supply of suitable donors as well as low donor utilization rates. While several methods have been proposed for increasing the donor pool, there is considerable disparity between acceptance and utilization of these practices among transplant centers. In this review article, we explore various approaches for enhancing donor selection and expanding the donor pool. We discuss the use of "extended criteria" donors including high risk groups such as drug overdose donors, and we examine the role of techniques in donor assessment and selection such as the use of computed tomography for accurate size matching. We review topics in donor management such as the establishment of specialized donor care facilities and the implementation of lung-focused resuscitation protocols, and we discuss advancements in donor procurement such as the utilization of local procurement teams. We also review barriers to donation, such as variability in organ procurement organization (OPO) consent practices, as well as patient-specific factors such as religious or cultural beliefs. Addressing these aspects of donor evaluation, management, and accessibility is essential in maximizing the number of lungs available for transplantation within the existing donor pool.

Innate immunity in lung transplantation.

Innate immune pathways early after pulmonary transplantation have been shown to cause primary graft dysfunction (PGD) and also predispose to late graft failure. Recent studies in animal models have elucidated critical mechanisms governing such innate immune responses. Here, we discuss pathways of inflammatory cell death, triggers for sterile and infectious inflammation, and signaling cascades that mediate lung injury early after transplantation. These studies highlight potential avenues for lung-specific therapies early following lung transplantation to dampen innate immune responses and improve outcomes.

Hemoglobin A1c as a marker to stratify diabetes risk following pancreaticoduodenectomy.

BACKGROUND: Pancreatic cancer has been shown to cause diabetes mellitus, and diabetes mellitus has been shown to be a risk factor for pancreatic cancer. The effect of pancreaticoduodenectomy on risk for development of diabetes mellitus is unclear. This study used hemoglobin A1c to determine the incidence of diabetes mellitus development following pancreaticoduodenectomy based on preoperative risk of diabetes mellitus. METHODS: Retrospective review of patients undergoing pancreaticoduodenectomy was performed with comparison of preoperative diabetes mellitus status and hemoglobin A1c with development of diabetes mellitus postoperatively. Risk ratios were calculated to determine the risk for diabetes mellitus development. RESULTS: Among 90 patients who met inclusion criteria, 26.7% developed new-onset or worsening diabetes mellitus following pancreaticoduodenectomy. Of those with hemoglobin A1c ≤ 5.6%, only 7.7% of patients developed diabetes mellitus. Patients at risk for diabetes mellitus preoperatively had 4.0 times greater risk for development of diabetes mellitus following pancreaticoduodenectomy. CONCLUSION: Hemoglobin A1c levels should be used to identify patients at risk for new-onset or worsening diabetes mellitus following pancreaticoduodenectomy.

Association of the Patient Protection and Affordable Care Act With Insurance Coverage for Head and Neck Cancer in the SEER Database.

Importance: Patients with head and neck squamous cell cancer (HNSCC) are often uninsured or underinsured at the time of their diagnosis. This access to care has been shown to influence treatment decisions and survival outcomes. Objective: To examine the association of the Patient Protection and Affordable Care Act (ACA) health care legislation with rates of insurance coverage and access to care among patients with HNSCC. Design, Setting, and Participants: Prospectively gathered data from the Surveillance, Epidemiology, and End Results (SEER) database were used to examine rates of insurance coverage and access to care among 89 038 patients with newly diagnosed HNSCC from January 2007 to December 2014. Rates of insurance were compared between states that elected to expand Medicaid coverage in 2014 and states that opted out of the expansion. Statistical analysis was performed from January 1, 2007, to December 31, 2014. Main Outcomes and Measures: Rates of insurance coverage and disease-specific and overall survival. Results: Among 89 038 patients newly diagnosed with HNSCC (29 384 women and 59 654 men; mean [SD] age, 59.8 [7.6] years), there was an increase after implementation of the ACA in the percentage of patients enrolled in Medicaid (16.2% after vs 14.8% before; difference, 1.4%; 95% CI, 1.1%-1.7%) and private insurance (80.7% after vs 78.9% before; difference, 1.8%; 95% CI, 1.2%-2.4%). In addition, there was a large decrease in the rate of uninsured patients after implementation of the ACA (3.0% after vs 6.2% before; difference, 3.2%; 95% CI, 2.9%-3.5%). This decrease in the rate of uninsured patients and the associated increases in Medicaid and private insurance coverage were only different in the states that adopted the Medicaid expansion in 2014. No survival data are available after implementation of the ACA, but prior to that point, from 2007 to 2013, uninsured patients had reduced 5-year overall survival (48.5% vs 62.5%; difference, 14.0%; 95% CI, 12.8%-15.2%) and 5-year disease-specific survival compared with insured patients (56.6% vs 72.2%; difference, 15.6%; 95% CI, 14.0%-17.2%). Conclusions and Relevance: Access to health care for patients with HNSCC was improved after implementation of the ACA, with an increase in rates of both Medicaid and private insurance and a 2-fold decrease in the rate of uninsured patients. These outcomes were demonstrated only in states that adopted the Medicaid expansion in 2014. Uninsured patients had poorer survival outcomes.

Association of Celecoxib Use With Decreased Opioid Requirements After Head and Neck Cancer Surgery With Free Tissue Reconstruction.

Importance: Head and neck cancer (HNC) surgery with free tissue reconstruction is associated with considerable postoperative pain. Opioids are typically used but can have adverse effects, including respiratory depression and high rates of dependence and addiction. Safe alternative analgesics that minimize opioid requirements are beneficial in HNC surgery. Objective: To investigate the association of celecoxib use with opioid requirements in the postoperative setting after HNC surgery with free tissue reconstruction. Design, Setting, and Participants: A retrospective, matched-cohort study of 147 patients who had undergone HNC surgery with free tissue reconstruction between June 2015 and Sept 2017 in an academic cancer hospital. Patients were separated into groups based on whether celecoxib had been used perioperatively or not. These groups were then matched by stage and site resulting in 102 included participants (51 celecoxib, 51 control). Main Outcomes and Measures: Oral, intravenous (IV), and total morphine equivalents used in the postoperative setting per patient per day. Results: There were 51 patients in the celecoxib cohort (19 women and 32 men) and 51 patients in the control cohort (20 women and 31 men) who met inclusion criteria after clinicopathologic data were matched. The mean age of the celecoxib and control cohorts was 61.6 years and 66.1 years, respectively. Treatment with celecoxib in the postoperative setting was associated with decreased mean use of opioids in oral (mean difference, 9.9 mg/d; 95% CI, -1.2 to 21.1), IV (mean difference, 3.9 mg/d; 95% CI, 1.0-6.8), and total (mean difference, 14 mg/d; 95% CI, 2.6-25.4) amount of morphine equivalents per day. When patients were matched to surgical procedure, the effect was more significant. Patients who underwent composite oral resection and received celecoxib had decreased opioid use in oral (mean difference, 25 mg/d; 95% CI, 12.5-25.4), IV (mean difference, 3.4 mg/d; 95% CI, 1.5-5.5), and total (mean difference, 28.4 mg/d; 95% CI, 15.7-41.5) amounts compared with those in the control group. There was no significant difference in complication rates between the 2 cohorts. Conclusions and Relevance: Use of celecoxib after head and neck cancer surgery and reconstruction with free tissue transfer was associated with a decrease in oral, IV, and total opioid requirements without increasing surgical or flap-related complications.