Use of bivalirudin after initial heparin management among adult patients on long-term venovenous extracorporeal support as a bridge to lung transplant: A case series.

A growing body of evidence supports the use of bivalirudin as an alternative to unfractionated heparin (UFH) for the prevention of thrombotic events in patients on venovenous (VV) extracorporeal membrane oxygenation (ECMO). However, data in patients bridged to lung transplantation are limited. In this case series, we describe the outcomes of six patients who were transitioned from UFH to bivalirudin during their course of VV ECMO support as a bridge to lung transplantation. All six patients were on VV ECMO support until transplant, with a median duration of 73 days. Bivalirudin demonstrated a shorter time to first therapeutic activated thromboplastin time (aPTT) level. Additionally, time in therapeutic range was longer while patients were receiving bivalirudin compared to UFH (median 92.9% vs. 74.6%). However, major bleeding and thrombotic events occurred while patients were receiving either anticoagulant. Based on our experience, bivalirudin appears to be a viable option for anticoagulation in VV ECMO patients bridged to lung transplantation. Larger studies evaluating the optimal anticoagulation strategy in patients bridged to transplant are needed.

A Pilot Randomized Controlled Trial of De Novo Belatacept-based Immunosuppression After Lung Transplantation.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. The development of donor-specific antibodies (DSA) is a recognized risk factor for CLAD. Based on experience in kidney transplantation, we hypothesized that belatacept, a selective T-cell costimulatory blocker, would reduce the incidence of DSA after lung transplantation, which may ameliorate the risk of CLAD. METHODS: We conducted a pilot randomized controlled trial (RCT) at 2 sites to assess the feasibility and inform the design of a large-scale RCT. All participants were treated with rabbit antithymocyte globulin for induction immunosuppression. Participants in the control arm were treated with tacrolimus, mycophenolate mofetil, and prednisone, and participants in the belatacept arm were treated with tacrolimus, belatacept, and prednisone through day 89 after transplant then converted to belatacept, mycophenolate mofetil, and prednisone for the remainder of year 1. RESULTS: After randomizing 27 participants, 3 in the belatacept arm died compared with none in the control arm. As a result, we stopped enrollment and treatment with belatacept, and all participants were treated with standard-of-care immunosuppression. Overall, 6 participants in the belatacept arm died compared with none in the control arm (log rank P = 0.008). We did not observe any differences in the incidence of DSA, acute cellular rejection, antibody-mediated rejection, CLAD, or infections between the 2 groups. CONCLUSIONS: We conclude that the investigational regimen used in this pilot RCT is associated with increased mortality after lung transplantation.

Progress in Combined Liver-lung Transplantation at a Single Center.

Combined liver-lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung-liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods: A single-center, retrospective review of the medical records of 19 adult lung-liver transplant recipients was conducted, comparing early recipients (2009-2014) with a recent cohort (2015-2021). Patients were also compared with the center's single lung or liver transplant recipients. Results: Recent lung-liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung-liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung-liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions: The severity of illness in lung-liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.

Brief Report: Rapid Clinical Recovery From Critical Coronavirus Disease 2019 With Respiratory Failure in a Pregnant Patient Treated With IV Vasoactive Intestinal Peptide.

BACKGROUND: Aviptadil, a synthetic form of human vasoactive intestinal peptide, has entered clinical trials to treat critical coronavirus disease 2019 pneumonia with respiratory failure. Vasoactive intestinal peptide protects the lung against a broad array of injuries by binding to the vasoactive intestinal peptide receptor 1 receptor of alveolar type II cells, the cells that severe acute respiratory syndrome coronavirus 2 binds to. As the role of Aviptadil in treating pregnant patients with critical coronavirus disease 2019 pneumonia is unknown, the authors report successful treatment in such a patient who is ineligible for phase 3 trials of Aviptadil. CASE SUMMARY: Under an open-label Food and Drug Administration-approved Expanded Access Protocol NCT04453839, a 32-year-old female patient Gravida 6 Para 4 at 27-week gestation, body mass index 42.5 kg/m2, admitted to the ICU of a quaternary care hospital with critical coronavirus disease 2019 was treated in January 2021 and followed for 4 months post-ICU admission. Standard of care included remdesivir, methylprednisolone, enoxaparin, and inhaled epoprostenol. In addition, the patient received three successive 12-hour IV infusions of Aviptadil at 50/100/150 pmol/kg/hr escalating doses, per randomized clinical trial NCT04311697. Human subjects' protection was overseen by the Institutional Review Board of the Houston Methodist Hospital. The patient was enrolled in the treatment and was given informed consent approved by the Food and Drug Administration and the Institutional Review Board. Data on the patient was incorporated based on her consent for de-identified data to be used in research given at the time of hospital admission in a manner approved by the Institutional Review Board (PRO00025607). Baseline inflammatory markers, arterial blood gases, radiologic imaging, oxygen requirements, Pao2/Fio2, continuous fetal monitoring at baseline, throughout the patient's treatment with the investigational drug, and throughout the patient's hospital course. CONCLUSION: The rapid clinical improvement seen in this patient treated with IV vasoactive intestinal peptide is consistent with the theory that vasoactive intestinal peptide protects the alveolar type II cell, ameliorates cytokine storm, and improves oxygenation in acute lung injury. This specific role of vasoactive intestinal peptide in the lung may be vital to combating the lethal effects of severe acute respiratory syndrome coronavirus 2 infection. In addition, the role of vasoactive intestinal peptide in the human maternal-fetal interface suggests that vasoactive intestinal peptide is a safe treatment of severe coronavirus disease 2019 respiratory failure during pregnancy.

ProtekDuo as a bridge to lung transplant and heart-lung transplant.

Recent advances in technology have led to significantly greater use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation with better outcomes. The novel ProtekDuo veno-venous ECMO (CardiacAssist, Inc.) has gained significance as it facilitates effective decompression of the right heart in patients with acute decompensation, while also providing consistent and effective gas exchange by eliminating recirculation. Here, we report two cases of effectively using ProtekDuo veno-venous ECMO: one case as a bridge to lung transplantation and another case as a bridge to heart-lung transplantation.

The Houston Methodist Lung Transplant Risk Model: A Validated Tool for Pretransplant Risk Assessment.

BACKGROUND: Lung transplantation is the gold standard for a carefully selected patient population with end-stage lung disease. This study sought to create a risk stratification model using only preoperative recipient data to predict 1-year postoperative mortality during the pretransplant assessment. METHODS: Data of lung transplant recipients at Houston Methodist Hospital in Houston, Texas from January 2009 to December 2014 were extracted from the United Network for Organ Sharing (UNOS) database. Patients were randomly divided into development and validation cohorts. Cox proportional-hazards models were conducted. Variables associated with 1-year mortality after transplantation were assigned weights on the basis of the beta coefficients, and risk scores were derived. Patients were stratified into low-, medium- and high-risk categories. The model was validated using the validation data set and data from other US transplant centers in the UNOS database. RESULTS: The study randomized 633 lung recipients from Houston Methodist Hospital into development (n = 317 patients) and validation cohorts (n = 316). The 1-year survival after transplantation was significantly different among risk groups: 95% (low risk), 84% (medium risk), and 72% (high risk) (P < .001), with a C-statistic of 0.74. Patient survival in the validation cohort was also significantly different among risk groups (85%, 77%, and 65%, respectively; P < .001). Validation of the model with the UNOS data set included 9920 patients and found 1-year survival to be 91%, 86%, and 82%, respectively (P < .001). CONCLUSIONS: Using only recipient data collected at the time of the prelisting evaluation, this simple scoring system was found to have good discrimination power and could be a practical tool in the assessment and selection of potential lung transplant recipients.

Association of methacholine challenge test with diagnosis of chronic lung allograft dysfunction in lung transplant patients.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a complication of lung transplantation. We sought to determine whether bronchial hyperresponsiveness detected by the methacholine challenge test (MCT) at 3 months after lung transplant (LT) predicts the development of CLAD. METHODS: We performed a retrospective cohort study of 140 LT patients between 1/2008 and 6/2014 who underwent MCT at 3 months after LT. Pearson's chi-squared test and Kruskal-Wallis test were used to compare categorical and continuous variables, respectively. Cox proportional hazards modeling was used to evaluate the association between CLAD and MCT. RESULTS: Methacholine challenge test+ was associated with the development of overall CLAD (adjusted hazards ratio [aHR]: 3.47; 95% confidence interval [95% CI]: 1.71, 7.03; P = 0.001) and CLAD within 3 years (aHR: 4.98; 95%CI: 1.84, 13.48; P = 0.002). Subgroup analysis showed that MCT (+) is associated with overall CLAD in single lung transplant (SLT) (aHR: 8.18; 95% CI: 2.22, 30.09; P = 0.002), double lung transplant (DLT) (aHR: 3.27; 95% CI: 1.22, 8.78; P = 0.02) and CLAD within 3 years in DLT patients (aHR: 6.76; 95% CI: 1.71, 26.74; P = 0.01). CONCLUSION: Methacholine challenge test+ at 3 months after LT is associated with the development of overall CLAD. Positive MCT could predict the development of early CLAD within 3 years in DLT patients.

A rare case of pulmonary cement embolism in a lung transplant patient.

Pulmonary cement embolism (PCE) is a complication of percutaneous vertebral augmentation techniques. PCE in lung transplant patient population has not been reported. We report a case 57-year-old male patient with double lung transplant secondary to idiopathic pulmonary fibrosis presented with shortness of breath after vertebroplasty. CTA chest showed thin dense opacities within the bilateral pulmonary arteries consistent with pulmonary cement embolism. The patient was treated with therapeutic enoxaparin and remained stable at one year follow up.

Use of Extracorporeal Membrane Oxygenation in Postpartum Management of a Patient with Pulmonary Arterial Hypertension.

Current guidelines do not recommend pregnancy in patients with pulmonary arterial hypertension (PAH). This is due to the associated high mortality, which both dissuades PAH patients from becoming pregnant and encourages termination of pregnancy due to high maternal mortality risk. As a result, there is a lack of data and, consequently, there are only general guidelines available for management of pregnancy in PAH patients. Additionally, novel therapeutic strategies such as extracorporeal membrane oxygenation (ECMO), although used in the management of nonpregnant PAH patients as a bridge to lung transplantation, have not been used to treat cardiopulmonary collapse in pregnant PAH patients. In an attempt to bridge this paucity of data, we report the successful use of ECMO in resuscitation and management of a pregnant PAH patient who experienced cardiopulmonary collapse following a caesarian section.

Long-Term Survival in Bilateral Lung Transplantation for Scleroderma-Related Lung Disease.

BACKGROUND: Lung disease is the leading cause of morbidity and death in scleroderma patients, but scleroderma is often considered a contraindication to lung transplantation because of concerns for worse outcomes. We evaluated whether 5-year survival in scleroderma patients after lung transplantation differed from other patients with restrictive lung disease. METHODS: This was a single-center, retrospective cohort study of all patients undergoing bilateral lung transplantation for scleroderma-related pulmonary disease between January 2006 and December 2014. This cohort was compared with patients undergoing bilateral lung transplantation for nonscleroderma group D restrictive disease. Primary outcomes reported were 1-year and 5-year survival. Diagnoses were identified by United Network of Organ Sharing listing and were confirmed by clinical examination and prelisting workup. RESULTS: We compared 26 patients who underwent BLT for scleroderma and 155 patients who underwent BLT for group D restrictive disease. Overall, the nonscleroderma cohort was younger, with lower lung allocation score but no difference in functional status. Donor characteristics were not different between the cohorts. Survival at 1 year was not different (73.1% vs 80.0%, p = 0.323). Long-term survival at 5 years was also not significantly different (65.4% vs 66.5%, p = 0.608). Multivariate Cox proportional hazards analysis found no differences in survival between scleroderma and nonscleroderma group D restrictive disease (hazard ratio, 2.19; p = 0.122). CONCLUSIONS: Despite being at high risk for extrapulmonary complications, patients undergoing bilateral lung transplantation for scleroderma have similar 1-year and 5-year survival as those with restrictive lung disease. Transplantation is a reasonable treatment option for a carefully selected population of candidates.

Distinct roles for LFA-1 affinity regulation during T-cell adhesion, diapedesis, and interstitial migration in lymph nodes.

During the course of homing to lymph nodes (LNs), T cells undergo a multistep adhesion cascade that culminates in a lymphocyte function-associated antigen 1 (LFA-1)-dependent firm adhesion to the luminal surface of high endothelial venules (HEVs). The importance of LFA-1 affinity regulation in supporting T-cell arrest on HEVs has been well established, however, its importance in the postadhesion phase, which involves intraluminal crawling and diapedesis to the extravascular space, remains elusive. Here we have shown that LFA-1 affinity needs to be appropriately regulated to support these essential steps in the homing cascade. Genetically engineered T cells that were unable to properly down-regulate LFA-1 affinity underwent enhanced, chemokine-independent arrest in HEVs but showed perturbed intravascular crawling to transmigration sites and compromised diapedesis across HEVs. By contrast, the extravascular migration of T cells was insensitive to the affinity-enhancing LFA-1 mutation. These results highlight the requirement for balanced LFA-1 affinity regulation in intravascular and transvascular, but not extravascular, T-cell migration in LNs.

Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets.

Resolvin E1 (RvE1) is an omega-3 eicosapentaenoic acid (EPA)-derived lipid mediator generated during resolution of inflammation and in human vasculature via leukocyte-endothelial cell interactions. RvE1 possesses anti-inflammatory and proresolving actions. Here, we report that RvE1 in human whole blood rapidly regulates leukocyte expression of adhesion molecules. RvE1 in the 10- to 100-nM range stimulated L-selectin shedding, while reducing CD18 expression in both neutrophils and monocytes. When added to whole blood, RvE1 did not stimulate reactive oxygen species by either neutrophils or monocytes, nor did it directly stimulate cytokine/chemokine production in heparinized blood. Intravital microscopy (IVM) demonstrated that RvE1 rapidly reduced leukocyte rolling (approximately 40%) in venules of mice. In human platelet-rich plasma (PRP), RvE1 selectively blocked both ADP-stimulated and thromboxane receptor agonist U46619-stimulated platelet aggregation in a concentration-dependent manner. In contrast, Delta 6,14-trans-RvE1 isomer was inactive. RvE1 did not block collagen-stimulated aggregation, and regulation of ADP-induced platelet aggregation was not further enhanced with aspirin treatment. These results indicate RvE1 is a potent modulator of leukocytes as well as selective platelet responses in blood and PRP, respectively. Moreover, the results demonstrate novel agonist-specific antiplatelet actions of RvE1 that are potent and may underlie some of the beneficial actions of EPA in humans.