Worth a Double Take? An In-Depth Review of Lung Retransplantation.

Provided advancements in Lung Transplantation (LT) survival, the efficacy of Lung Retransplantation (LRT) has often been debated. Decades of retrospective analyses on thousands of LRT cases provide insight enabling predictive patient criteria for retransplantation. This review used the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. The PubMed search engine was utilized for articles relating to LRT published through August 2023, and a systematic review was performed using Covidence software version 2.0 (Veritas Health Innovation, Australia). Careful patient selection is vital for successful LRT, and the benefit leans in favor of those in optimal health following their initial transplant. However, the lack of a standardized approach remains apparent. Through an in-depth review, we will address considerations such as chronic lung allograft dysfunction, timing to LRT, surgical and perioperative complexity, and critical ethical concerns that guide the current practice as it relates to this subset of patients for whom LRT is the only therapeutic option available.

The Evaluation and Management of Coronary Artery Disease in the Lung Transplant Patient.

Lung transplantation can greatly improve quality of life and extend survival in those with end-stage lung disease. In order to derive the maximal benefit from such a procedure, patients must be carefully selected and be otherwise healthy enough to survive a high-risk surgery and sometimes prolonged immunosuppressive therapy following surgery. Patients therefore must be critically assessed prior to being listed for transplantation with close attention paid towards assessment of cardiovascular health and operative risk. One of the biggest dictators of this is coronary artery disease. In this review article, we discuss the assessment and management of coronary artery disease in the potential lung transplant candidate.

Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

Genome-wide DNA methylation profiling of peripheral blood reveals an epigenetic signature associated with severe COVID-19.

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID-19) in humans. Although most patients with COVID-19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi-organ failure, and death. RNA viruses such as SARS-CoV-2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS-CoV-2 infection pathology. Here, we examined genome-wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally-ill, critical COVID-19 patients with confirmed SARS-CoV-2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID-19 HIV coinfected individuals. Cell-type deconvolution analyses confirmed lymphopenia in severe COVID-19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID-19 characterized by hypermethylation of IFN-related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single-cell transcriptional studies of severe COVID-19. Epigenetic clock analyses revealed severe COVID-19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID-19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS-CoV-2.

CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14.

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic. Emerging results indicate a dysregulated immune response. Given the role of CCR5 in immune cell migration and inflammation, we investigated the impact of CCR5 blockade via the CCR5-specific antibody leronlimab on clinical, immunological, and virological parameters in severe COVID-19 patients. METHODS: In March 2020, 10 terminally ill, critical COVID-19 patients received two doses of leronlimab via individual emergency use indication. We analyzed changes in clinical presentation, immune cell populations, inflammation, as well as SARS-CoV-2 plasma viremia before and 14 days after treatment. RESULTS: Over the 14-day study period, six patients survived, two were extubated, and one discharged. We observed complete CCR5 receptor occupancy in all donors by day 7. Compared with the baseline, we observed a concomitant statistically significant reduction in plasma IL-6, restoration of the CD4/CD8 ratio, and resolution of SARS-CoV2 plasma viremia (pVL). Furthermore, the increase in the CD8 percentage was inversely correlated with the reduction in pVL (r = -0.77, p = 0.0013). CONCLUSIONS: Our study design precludes clinical efficacy inferences but the results implicate CCR5 as a therapeutic target for COVID-19 and they form the basis for ongoing randomized clinical trials.

Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-19. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.

Non-respiratory complaints are main reasons for disturbed sleep post lung transplant.

BACKGROUND: Poor sleep is prevalent in lung transplant recipients and affects quality of life negatively. To improve quality of sleep, it's important to identify the causes of poor sleep. We conducted a survey to identify the reasons for poor sleep quality in the recipients. METHODS: We surveyed lung transplant recipients (2003-2010) at Baylor College of Medicine/The Methodist Hospital lung transplant center. We used a compilation of questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), Berlin Questionnaire, Epworth Sleepiness Scale (ESS) and Short Form 36 (SF36). Descriptive analysis was performed on the responses. RESULTS: Of the 167 participants, 54 responded (32.3%) with mean age 60.6 years (SD 9.8), 48% male, and a mean post-transplant body mass index (BMI) of 27 (SD 4.7). The responders reported a long mean sleep latency of 33.2 min (SD 32.5), poor sleep quality (74% with PSQI score > 5), excessive daytime sleepiness (ESS > 9 in 29%), poor physical QOL with SF36 mean score of 41.3 (SD 9.4), and high risk for OSA (48.2%). About 30% and 72% reported sleep initiation and maintenance insomnia, respectively. The poor sleep quality was due to "getup to go to bathroom" (85%), "cough or snore loudly" (33%), "have pain" (27.8%), and "feel too cold" (27.8%). Furthermore, 5% reported "Can't breathe comfortably" as reason for poor sleep. CONCLUSIONS: The recipients reported poor sleep and quality of life. The non-respiratory complaints were important factors for poor sleep. Attention to these factors may help to outline better management strategies to improve sleep in lung transplant recipients.

Bridging to lung transplantation with double-lumen venovenous extracorporeal membrane oxygenation.

BACKGROUND: Double-lumen venovenous extracorporeal membrane oxygenation may be used as a bridge to lung transplantation. Predictors of outcome with this strategy have not been well described. METHODS: All patients with irreversible lung disease who developed acute pulmonary failure and required double-lumen venovenous extracorporeal membrane oxygenation as a bridge to decision or lung transplant at our institution were included in this study. Survival of the extracorporeal membrane oxygenation patients was compared with listed patients who did not require extracorporeal membrane oxygenation with lung allocation score in the highest 10% for the same period. RESULTS: Fifteen patients (46 ± 17 years old) received double-lumen venovenous extracorporeal membrane oxygenation cannula. Mean length of extracorporeal membrane oxygenation support was 18.2 (1-60) days. Of these, seven patients were bridged to lung transplant, six died on extracorporeal membrane oxygenation, and two weaned to recovery. Amount of red blood cell transfusion was significantly higher (3.3 vs 18.5 U, p = 0.003) and lowest oxygen saturation was significantly lower in non-survivors (84.5% vs 66.3%, p = 0.002). Of the seven patients who were already listed for lung transplant at the onset of extracorporeal membrane oxygenation, five were transplanted. Overall survival to hospital discharge was 60%. Survival of patients with lung allocation score in the highest 10% (average lung allocation score 83.4) in the same period was 80%. CONCLUSION: Double-lumen venovenous extracorporeal membrane oxygenation cannula is a feasible option to bridge patients to decision or lung transplantation. Blood transfusion requirement and low oxygen saturation are markers of poor prognosis. Listing status at the time of cannulation and ambulation during extracorporeal membrane oxygenation support may be important indicators of good outcome.

Post-transplant survival in idiopathic pulmonary fibrosis patients concurrently listed for single and double lung transplantation.

BACKGROUND: Lung transplantation is a widely accepted treatment for patients with end-stage lung disease related to idiopathic pulmonary fibrosis (IPF). However, there are conflicting data on whether double lung transplant (DLT) or single lung transplant (SLT) is the superior therapy in these patients. The purpose of this study was to determine whether actuarial post-transplant graft survival among IPF patients concurrently listed for DLT and SLT is greater for recipients undergoing the former or the latter. METHODS: The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant candidates with IPF listed between January 1, 2001 and December 31, 2009 (n = 3,411). The study population included 1,001 (29.3%) lung transplant recipients concurrently listed for DLT and SLT, all ≥18 years of age. The primary outcome measure was actuarial post-transplant graft survival, expressed in years. RESULTS: Among the study population, 433 (43.26%) recipients underwent SLT and 568 (56.74%) recipients underwent DLT. The analysis included 2,722.5 years at risk, with median graft survival of 5.31 years. On univariate (p = 0.317) and multivariate (p = 0.415) regression analyses, there was no difference in graft survival between DLT and SLT. CONCLUSIONS: Among IPF recipients concurrently listed for DLT and SLT, there is no statistical difference in actuarial graft survival between recipients undergoing DLT vs SLT. This analysis suggests that increased use of SLT for IPF patients may increase the availability of organs to other candidates, and thus increase the net benefit of these organs, without measurably compromising outcomes.

Persistent hypoxemia and platypnea-orthodeoxia after left single-lung transplantation: a case report.

INTRODUCTION: Platypnea-orthodeoxia is a relatively uncommon but striking clinical syndrome characterized by dyspnea and deoxygenation accompanying a change to sitting or standing from a recumbent position. Hypoxemia early after lung transplant can have multiple etiologies. We report a rare case of persistent hypoxemia and platypnea-orthodeoxia after left single-lung transplantation, as a result of right-to-left interatrial shunt through a patent foramen ovale, with subsequent resolution of hypoxemia after percutaneous closure of the patent foramen ovale. CASE PRESENTATION: Our 66-year-old Caucasian male patient exhibited a persistent patent foramen ovale. Persistent patent foramen ovale produces an intermittent intra-atrial right-to-left shunt and occurs in approximately 25 % of the general population. Although the majority of people with patent foramen ovale are asymptomatic, it is believed to act as a pathway for chemicals or thrombi that can result in a variety of clinical manifestations, including stroke, migraine headache, decompression sickness, high-altitude pulmonary edema, and platypnea-orthodeoxia syndrome. Percutaneous closure of the patent foramen ovale has been shown to be effective in the case of right-to-left shunting with normal pulmonary arterial pressure, but the indication remains controversial in other situations where pulmonary pressures are not normal. The most common causes of hypoxemia immediately after lung transplant include: graft dysfunction, reperfusion injury, acute thromboembolic disease, and acute rejection. We report a case of reopening of a patent foramen ovale after left single-lung transplantation with normal pulmonary pressure. CONCLUSIONS: Our case demonstrates that an open patent foramen ovale leading to massive right-to-left shunting is a possible complication after lung transplant, with significant morbidity, and that it can be treated successfully using a percutaneously placed occlusion device. Through this case report, we aim to improve pre-transplant procedures by demonstrating that a bubble contrast transesophageal echocardiogram can be performed pre-operatively to detect a patent foramen ovale.

Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.

The feasibility of lung transplantation in HIV-seropositive patients.

RATIONALE: HIV seropositivity has long been considered a contraindication to lung transplantation, primarily because of the potential risks of added immunosuppression. In the past decade, however, experience with kidney and liver transplantation in the setting of HIV infection, with achievement of satisfactory outcomes, has grown considerably. This promising development has created a need to reconsider this contraindication to lung transplantation. OBJECTIVES: There is presently limited evidence upon which to base medical decision-making regarding lung transplantation in individuals with HIV infection. In our present study, we wished to extend the existing literature by reporting the outcomes of three individuals with HIV infection who underwent lung transplantation at two centers. METHODS: We compiled data for a case series of three HIV-infected subjects undergoing lung transplantation at two centers. MEASUREMENTS AND MAIN RESULTS: We reviewed medical records to investigate the effects of lung transplantation on the course of HIV infection, the development of HIV-related opportunistic infections or malignancies, the occurrence of lung transplant and HIV drug interactions, and the extent of acute rejection. Subject 1, who underwent transplantation for HIV-associated pulmonary arterial hypertension, experienced recalcitrant acute rejection requiring a lymphocyte-depleting agent with subsequent rapid development of bronchiolitis obliterans syndrome. Subjects 2 and 3, who underwent transplantation for idiopathic pulmonary fibrosis, experienced mild acute rejection but remain free from chronic rejection at 4 and 2 years after transplant, respectively. CONCLUSIONS: Lung transplantation may be feasible for carefully selected patients in the setting of controlled HIV infection. On the basis of our experience with three patients, we caution that acute graft rejection may be more common in such patients.

Atrial arrhythmias after lung transplant: underlying mechanisms, risk factors, and prognosis.

BACKGROUND: Atrial arrhythmias (AAs) early after lung transplant are frequent and have a significant impact on morbidity and mortality. However, the pathogenesis of AAs after lung transplant remains incompletely understood. In this study we aimed to determine the prevalence of atrial fibrillation (AF) and other AAs, as well as risk factors, clinical outcomes and possible underlying mechanisms associated with AAs after lung transplant. METHODS: A retrospective analysis was performed on 382 patients who underwent lung transplantation from 2000 to 2010. A 12-lead electrocardiogram (ECG) was obtained and AAs classified as AF and other AAs (atrial flutter [AFL] and supraventricular tachycardia [SVT]). Multivariate logistic regression analysis was performed to determine predictors, and Kaplan-Meier survival curves were constructed. RESULTS: The incidence of AAs was 25%; 17.8% developed AF and 7.6% other AAs (AFL/SVT). The major indication for transplant was idiopathic pulmonary fibrosis (IPF, 35%). Significant predictors of AF were as follows: age; IPF; left atrial enlargement; diastolic dysfunction; and history of coronary artery disease (CAD). Risk factors for other AAs (AFL/SVT) were: age; right ventricle dysfunction; right ventricular enlargement; and elevated right atrial pressure (RAP). One-year mortality was higher in the arrhythmia group (21.5% arrhythmia vs 15.7% no-arrhythmia group; p < 0.05). In addition, patients treated with anti-arrhythmic medications had higher mortality (p < 0.05). CONCLUSIONS: AAs are common after lung transplantation. Risk factors for developing either AF or other AAs (AFL/SVT) are different. The development of early AAs post-transplant is associated with prolonged post-operative stay and increased mortality. A rate-control strategy should be used as first-line therapy and anti-arrhythmic agents reserved for those patients who do not respond to the initial treatment.

Combined lung and liver transplantation: analysis of a single-center experience.

Patients with end-stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung-liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single-center CLLT series. Eight consecutive CLLT performed during 2009-2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 ± 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n = 3), idiopathic pulmonary fibrosis (n = 2), α1-antitrypsin deficiency (AATD) (n = 1) and pulmonary hypertension (n = 2). Liver indications were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic (n = 1), and cardiac/congestive (n = 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0-89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20-58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1-year. Median length of stay was 25 days (7-181). Complications requiring operative intervention included bile duct ischemia (n = 1) and bile leak (n = 1), ischemia of the bronchial anastomosis (n = 1), and necrotizing pancreatitis with duodenal perforation (n = 1). This series reflects a large single-center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50.

Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.