Predicting Primary Graft Dysfunction in Lung Transplantation: Machine Learning-Guided Biomarker Discovery.

BACKGROUND ­: There is an urgent need to better understand the pathophysiology of primary graft dysfunction (PGD) so that point-of-care methods can be developed to predict those at risk. Here we utilize a multiplex multivariable approach to define cytokine, chemokines, and growth factors in patient-matched biospecimens from multiple biological sites to identify factors predictive of PGD. METHODS ­: Biospecimens were collected from patients undergoing bilateral LTx from three distinct sites: donor lung perfusate, post-transplant bronchoalveolar lavage (BAL) fluid (2h), and plasma (2h and 24h). A 71-multiplex panel was performed on each biospecimen. Cross-validated logistic regression (LR) and random forest (RF) machine learning models were used to determine whether analytes in each site or from combination of sites, with or without clinical data, could discriminate between PGD grade 0 (n = 9) and 3 (n = 8). RESULTS ­: Using optimal AUROC, BAL fluid at 2h was the most predictive of PGD (LR, 0.825; RF, 0.919), followed by multi-timepoint plasma (LR, 0.841; RF, 0.653), then perfusate (LR, 0.565; RF, 0.448). Combined clinical, BAL, and plasma data yielded strongest performance (LR, 1.000; RF, 1.000). Using a LASSO of the predictors obtained using LR, we selected IL-1RA, BCA-1, and Fractalkine, as most predictive of severe PGD. CONCLUSIONS ­: BAL samples collected 2h post-transplant were the strongest predictors of severe PGD. Our machine learning approach not only identified novel cytokines not previously associated with PGD, but identified analytes that could be used as a point-of-care cytokine panel aimed at identifying those at risk for developing severe PGD.

ProtekDuo Cannula for Pre-, Intra-, and Postoperative Lung Transplantation Management.

ABSTRACT: We present a 61-year-old patient with pulmonary hypertension, acute respiratory failure, and acute severe right ventricular (RV) dysfunction. Preoperatively, a ProtekDuo® was inserted for extracorporeal membrane oxygenation (ECMO) and RV protection with venopulmonary (VP) ECMO in (dl) V-P ECMO configuration. Intraoperatively, it provided venous drainage for venoarterial (VA) ECMO in (dl) VP-/AO configuration for bilateral orthotopic lung transplantation (BOLT). Postoperatively, the patient remained on (dl) V-P ECMO for RV support and was decannulated with mild RV dysfunction after 5 days. This is the first description of the ProtekDuo® used in (dl) V-P to (dl) VP-/AO to (dl) V-P configuration for the entire perioperative period of BOLT.

Participation in Non-small Cell Lung Cancer Clinical Trials in the United States by Race/Ethnicity.

INTRODUCTION: Despite efforts by Cancer Centers and community organizations to increase diversity in clinical trials, significant racial/ethnic disparities remain. Given the high mortality rates in non-small cell lung cancer (NSCLC), it is important to increase diversity in NSCLC trials, ensuring all patients benefit from advances in new treatment modalities. MATERIALS AND METHODS: We evaluated the distribution of racial/ethnic minority enrollment in NSCLC clinical trials using data from ClinicalTrials.gov. We extracted trial characteristics, including start year, study phase, tumor stage, sample size, sponsor, geographic region, and masking. The number of participants by race/ethnicity was obtained from ClinicalTrials.gov or linked publications. Using annual NSCLC incidence data from SEER*Stat for each racial/ethnic group from 2010 to 2019, we applied a 2-sample test for equality of proportions with continuity correction to assess differences between incidence and trial participation. RESULTS: A total of 147 unique studies were included in the final analysis. Of the 28,540 participants, 79.6% were White, with 3% Black, 10.4% Asian or Pacific Islander and 3.4% Hispanic/Latino. Most participants were enrolled in phase III trials (63.8%), industry-sponsored (93.9%), and open-label (67.7%). Black patients were more commonly enrolled in academic sponsored trials and less commonly enrolled in masked (i.e., blinded) studies. When comparing trial participation to annual incidence data, we observed underrepresentation among Black participants (Difference: -7.9%) and Hispanic/Latino participants (Difference: -3.2%). CONCLUSION: Persistent underrepresentation exists in NSCLC clinical trials among Black and Hispanic/Latino patients. We urge further investigation of these findings through well-designed clinical trials among diverse patient populations.

Veno-arterial extracorporeal membrane oxygenation as bridge for fluid resuscitation in a patient with acute respiratory failure and circulatory shock two years post lung transplantation.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) continues to evolve and is recognized as an important adjunct as a bridge to recovery or a bridge to transplant. We wanted to share our experience of using veno-arterial (VA) ECMO as an adjunct to lung recovery and an aide for fluid resuscitation. CASE DESCRIPTION: We present the case of a 77-year-old man with a history of previous single lung transplant who had acute respiratory decompensation and cardiovascular collapse secondary to CMV pneumonia and septic shock. He was cannulated for VA ECMO, treated for CMV pneumonia and resuscitated with 5 L of albumin 5% and antibiotics, within 12 hours of cannulation. He required two days of VA ECMO and was ultimately decannulated and discharged to a rehabilitation facility on hospital day 73. CONCLUSION: This case emphasizes the challenging clinical scenario of fluid resuscitation in a lung transplant patient. With adequate patient selection, a multidisciplinary team and the use of VA ECMO, success can be achieved.

Extended perioperative use of the ProtekDuo cannula for drainage in central venopulmonary-aortic ECMO for bilateral orthotopic lung transplantation.

We present the case of a 24-year-old female who was supported with ProtekDuo cannula with variations of venopulmonary (VP) extracorporeal membrane oxygenation. The patient was cannulated for acute respiratory distress syndrome and she underwent bilateral orthotopic lung transplantation. This is the first report of the ProtekDuo cannula as a drainage cannula in central (dl)VP-/AO ECMO for 5 days.

Paediatric donor lung preservation using Paragonix BAROguard.

Paediatric lung transplantation is a lifesaving option in selected patients with end-stage lung disease. Favourable long-term outcomes are limited by impaired mucus clearance, increased risk of infection resulting from immunosuppression, and chronic lung allograft dysfunction. Organ preservation techniques play an important role in the quality of donated organs. Barotrauma to donated lungs may arise from a combination of excessive recruitment manoeuvres and altitude change during air transportation. The Paragonix BAROguard Donor Lung Preservation System is an FDA-approved advanced organ recovery system that maintains continuous airway pressure of 15 cm of water during transportation of the donated lung(s) to the recipient. The Paragonix LUNGguard monitors temperature during transportation of donor lung(s), while the new BAROguard monitors both temperature and pressure during transportation of donor lung(s). In this publication, we present technical aspects of advanced preservation of paediatric donor lungs using the Paragonix BAROguard Donor Lung Preservation System.

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of ischemia/reperfusion injury after lung transplant.

Lung transplantation (LTx) outcomes are impeded by ischemia/reperfusion injury (IRI) and subsequent chronic lung allograft dysfunction (CLAD). We examined the undefined role of receptor Mer tyrosine kinase (MerTK) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis to facilitate resolution of lung IRI. Single-cell RNA sequencing of lung tissue and bronchoalveolar lavage (BAL) from patients after LTx were analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with BALB/c (WT), Cebpb-/- (MDSC-deficient), Mertk-/-, or MerTK-cleavage-resistant mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of patients with CLAD was observed compared with healthy individuals. In the murine IRI model, a significant increase in M-MDSCs, MerTK expression, and efferocytosis and attenuation of lung dysfunction was observed in WT mice during injury resolution that was absent in Cebpb-/- and Mertk-/- mice. Adoptive transfer of M-MDSCs in Cebpb-/- mice significantly attenuated lung dysfunction and inflammation. Additionally, in a murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can substantially contribute to the resolution of post-LTx IRI.

Conversion technique from venovenous to venopulmonary ECMO support.

We present the cannulation technique for venopulmonary extracorporeal membrane oxygenation using the ProtekDuo dual-lumen cannula in a patient who, after a bilateral orthotopic lung transplant and coronavirus disease 2019 infection, was converted from a multisite venovenous extracorporeal membrane oxygenation configuration, using the same vessel.

Venovenous ECMO for Acute Chronic Heart Failure after Bilateral Lung Transplantation.

ABSTRACT: Venovenous (VV) ECMO is rarely used during decompensated circulatory states. Although VA ECMO is the routine option, VV ECMO may be an option in selected patients. We present a case of pulmonary edema due to acute heart failure in a patient 4- and 12-year post-lung transplantation who received VV ECMO. Using a thoughtful cannulation strategy, VV ECMO, and aggressive ultrafiltration, the patient was successfully decannulated, extubated, and discharged from the hospital. In cardiogenic pulmonary edema, VV ECMO represents an additional, and likely under-utilized tool, especially in patients who are at high risk for ventilator-associated lung injury. Cannula location and size should be given additional consideration to potentially transition to V-AV ECMO configuration if necessary.

Outcome of Veno-Pulmonary Extracorporeal Life Support in Lung Transplantation Using ProtekDuo Cannula: A Systematic Review and Description of Configurations.

Background: Refractory end-stage pulmonary failure may benefit from extracorporeal life support (ECLS) as a bridge to lung transplantation. Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) has been recommended for patients who have failed conventional medical therapy and mechanical ventilation. Veno-arterial (VA) ECMO may be used in patients with acute right ventricular (RV) failure, haemodynamic instability, or refractory respiratory failure. Peripheral percutaneous approaches, either dual-site single-lumen cannulation for veno-pulmonary (VP) ECMO or single-site dual-lumen (dl)VP ECMO, using the ProtekDuo right ventricular assist device (RVAD) cannula, has made this configuration a desirable option as a bridge to transplantation. These configurations support the right ventricle, prevent recirculation by placing the tricuspid and pulmonary valve between the drainage and return cannulas, provide the direct introduction of oxygenated blood into the pulmonary artery, and have been shown to decrease the incidence of acute kidney injury (AKI), requiring continuous renal replacement therapy (CRRT) in certain disease states. This promotes haemodynamic stability, potential sedation-weaning trials, extubation, mobilisation, and pre-transplant rehabilitation. Methods: A web-based literature search in PubMed and EMBASE was undertaken based on a combination of keywords. The PICOS and PRISMA approaches were used. Results: Four case series were identified out of 323 articles, with a total of 34 patients placed on VP ECMO as a bridge to lung transplantation. All relevant data are reviewed and integrated into the Discussion. Conclusions: Despite the limited available evidence, the use of ProtekDuo has become very promising for the management of end-stage lung disease as a bridge to lung transplantation.

Concurrent veno-pulmonary extracorporeal membrane oxygenation cannulation with ProtekDuo parallel to an in situ veno-pulmonary single-lumen cannula.

This technical report describes the successful transition from dual lumen, single site veno-venous extracorporeal membrane oxygenation ((dl)V-V ECMO) to single lumen, dual site veno-pulmonary (V-P) ECMO, and subsequently to dual lumen, single site (dl)V-P ECMO involving temporary placement of two cannulas in the main pulmonary artery. No complications were observed during these transitions. This technique could address concerns related to cannula exchanges in VP ECMO. However, caution is warranted and constant monitoring of cannula position using real-time imaging is required when using this technique due to the risk profile.

Double lung en bloc procurement and back table separation of lungs.

Donor organ recovery techniques have improved with novel preservation solutions, implementation of advanced preservation systems and machine perfusion. However, surgical techniques for organ procurement have not changed. In this video tutorial, we have outlined key steps in double lung en bloc organ recovery, including introduction of pulmonoplegia, pulmonectomy en bloc and separation of the two single-lung blocks.

Novel Use of Ivabradine for Persistent Sinus Tachycardia in a Patient on Extracorporeal Life Support With Right Ventricular Dysfunction.

Persistent sinus tachycardia (pST) has been associated with adverse cardiovascular events in critically ill patients. Pharmacological control of heart rate with negative inotropic agents has proven to be safe but could be potentially dangerous in patients with concomitant right ventricular (RV) dysfunction. Ivabradine, a medication devoid of negative inotropy, could be a potentially safe solution for this patient population when adequate heart rate control is desired. A 17-year-old male with a history of vaping developed acute respiratory distress syndrome (ARDS) and RV dysfunction, requiring extra corporal life support (ECLS). He suffered from pST. Given his RV dysfunction, a beta-blocker was avoided, and ivabradine was used safely with improvement of his pST. This case demonstrates the efficacy of ivabradine to reduce heart rate and avoid the use of beta-blockers for patients with RV dysfunction, which could be detrimental. Ivabradine was shown to lower the heart rate without altering hemodynamic parameters.

Bilateral orthotopic lung transplant via a clamshell thoracosternotomy from a donor with extended cold static lung preservation.

In this video tutorial, we present a comprehensive step-by-step operative technique for a bilateral orthotopic lung transplant using a bilateral transverse thoracosternotomy in a patient with idiopathic pulmonary fibrosis lung disease. The donor lungs were exposed to extended cold static ischaemic storage at 10° C for the semi-elective operation.

Dual lumen venopulmonary extracorporeal membrane oxygenation cannulation technique using the ProtekDuo.

In this video tutorial, we present the cannulation technique for venopulmonary extracorporeal membrane oxygenation using the ProtekDuo dual-lumen cannula in a patient with acute respiratory distress syndrome.

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant injury.

Rationale: Patients with end stage lung diseases require lung transplantation (LTx) that can be impeded by ischemia-reperfusion injury (IRI) leading to subsequent chronic lung allograft dysfunction (CLAD) and inadequate outcomes. Objectives: We examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis (phagocytosis of apoptotic cells) to facilitate resolution of lung IRI. Methods: Single-cell RNA sequencing of lung tissue and BAL from post-LTx patients was analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), cebpb -/- (MDSC-deficient), Mertk -/- or MerTK-CR (cleavage resistant) mice. Lung function, IRI (inflammatory cytokine and myeloperoxidase expression, immunohistology for neutrophil infiltration), and flow cytometry of lung tissue for efferocytosis of apoptotic neutrophils were assessed in mice. Measurements and Main Results: A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients compared to healthy subjects was observed. In the murine IRI model, significant increase in M-MDSCs, MerTK expression and efferocytosis was observed in WT mice during resolution phase that was absent in cebpb -/- Land Mertk -/- mice. Adoptive transfer of M-MDSCs in cebpb -/- mice significantly attenuated lung dysfunction, and inflammation leading to resolution of IRI. Additionally, in a preclinical murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Conclusions: Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can significantly contribute to the resolution of post-LTx IRI.

Thoracoliths in Pleural Space Mimicking Lung Cancer: A Case Report.

Pulmonary nodules often present a diagnostic challenge due to their diverse etiology, ranging from benign to malignant conditions. We discuss the diagnostic journey of a 71-year-old female patient with a history of kidney stones, who was incidentally found to have a pleural-based pulmonary nodule during a CT urogram. Subsequent imaging showed nodule growth, prompting further investigations, including a PET/CT scan and CT-guided biopsy, which yielded inconclusive results. A multidisciplinary approach recommended surgical resection, revealing three mobile calcified-like nodules within the pleural space, later identified as hyalinized nodules. The absence of malignancy was reassuring. These benign, mobile pleural bodies, known as thoracoliths, are challenging to differentiate from pulmonary nodules. This case underscores the importance of considering rare benign entities in pulmonary nodule differentials and highlights the need for a multidisciplinary approach, surgical intervention, and open-mindedness in complex diagnostic scenarios.

Intralobar pulmonary sequestration presenting as recurrent left lower lobe pneumonia.

This case discusses the diagnosis and management of pulmonary sequestration. Typically discovered incidentally on imaging, it can be a cause of recurrent pulmonary infections causing severe morbidity to the patient. Surgical management is indicated when found to prevent the complications of recurrent infections, including pulmonary necrosis, abscess, or fistula formation.