Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.

Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.

https://www.mdpi.com/1422-0067/21/21/8081/pdf

Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets.

Chronic obstructive pulmonary disease (COPD), the frequently fatal pathology of the respiratory tract, accounts for half a billion cases globally. COPD manifests via chronic inflammatory response to irritants, frequently to tobacco smoke. The progression of COPD from early onset to advanced disease leads to the loss of the alveolar wall, pulmonary hypertension, and fibrosis of the respiratory epithelium. Here, we focus on the epidemiology, progression, and biomarkers of COPD with a particular connection to lung cancer. Dissecting the cellular and molecular players in the progression of the disease, we aim to shed light on the role of smoking, which is responsible for the disease, or at least for the more severe symptoms and worse patient outcomes. We summarize the inflammatory conditions, as well as the role of EMT and fibroblasts in establishing a cancer-prone microenvironment, i.e., the soil for 'COPD-derived' lung cancer. We highlight that the major health problem of COPD can be alleviated via smoking cessation, early diagnosis, and abandonment of the usage of biomass fuels on a global basis.

Chronic Obstructive Pulmonary Disease: Epidemiology, Biomarkers, and Paving the Way to Lung Cancer

The advancing science of transplantation has led to more transplants and longer survival. As a result, primary care physicians are more involved in the care of transplant recipients. Immunosuppressive therapy has significantly decreased rates of transplant rejection but accounts for more than 50% of transplant-related deaths, often due to infections and other risks related to long-term use. Cardiovascular disease is the leading cause of non-transplant-related mortality. Aggressive risk factor management is recommended for transplant recipients, including a blood pressure goal of less than 130/80 mm Hg and statin therapy in kidney, liver, and heart recipients. Fertility typically increases posttransplant, and female transplant recipients should avoid pregnancy for one year after surgery. The best contraceptive choice is usually an intrauterine device. Because of the increased risk of infection, patients should be tested for graft dysfunction or infection if suspicion arises. Testing should be coordinated with the transplant center. Malignancies are a common cause of death in transplant recipients, requiring careful attention to screening recommendations and informed discussions with patients. Family physicians should maintain an ongoing relationship with the transplant team to discuss medication changes and the risk of infection or graft rejection.

Primary Care of the Solid Organ Transplant Recipient.

Background: Acute respiratory distress syndrome (ARDS) is a severe and often fatal disease. The causes that lead to ARDS are multiple and include inhalation of salt water, smoke particles, or as a result of damage caused by respiratory viruses. ARDS can also arise due to systemic complications such as blood transfusions, sepsis, or pancreatitis. Unfortunately, despite a high mortality rate of 40%, there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies. Aim of review: A complication of ARDS is the development of pulmonary hypertension (PH); however, the mechanisms that lead to PH in ARDS are not fully understood. In this review, we summarize the known mechanisms that promote PH in ARDS. Key scientific concepts of review: (1) Provide an overview of acute respiratory distress syndrome; (2) delineate the mechanisms that contribute to the development of PH in ARDS; (3) address the implications of PH in the setting of coronavirus disease 2019 (COVID-19).

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Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS)

Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a highly fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that adenosine and its receptor, ADORA2B, are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases and increased hyaluronan, a glycosaminoglycan which contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and hyaluronan synthases (HAS). Next using a unique model of experimental lung injury that replicates features of CPFE, namely airspace enlargement, PH and fibrotic deposition, we investigated whether 4MU, a hyaluronan synthase inhibitor, was able to inhibit features of CPFE. Increased protein levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We have generated pre-clinical data demonstrating the capacity of 4MU, a FDA-approved drug, to attenuate features of CPFE in an experimental model of chronic lung injury.

Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema.

Background With the increase of primary lung transplantation across major centers worldwide, over the last several years the need of lung retransplant (ReTX) is likely to increase. Therefore, characterization of ReTX patients is prudent and necessary. Our study aimed to investigate and characterize the covariates and outcomes associated with lung ReTX survival in a single large U.S. transplant center. Methods Demographic, clinical diagnoses, and comorbidities were analyzed. Kaplan-Meier statistics were used to calculate and predict survival for 30 days and up to 3 years. Cox proportional modeling was used to determine the variables associated with mortality. Results Of included 684 lung transplants performed at the Houston Methodist Hospital between January 2009 and December 2015, 49 were lung ReTX. Median age of primary lung transplant (non-ReTX) and ReTx recipients was 62 and 49 years, respectively. Chronic graft rejection in the form of restrictive chronic lung allograft dysfunction and bronchiolitis obliterans syndrome was the main indications for ReTX. Compared with non-ReTX patients, ReTX patients had higher median lung allocation score (46.2 vs 37.0, respectively) and higher mortality after 6 months posttransplant. ReTX, older age, female sex, hospitalization 15 days or longer, estimated glomerular filtration rate less than 60, 6-minute walk distance less than 400 ft, and donor/recipient height ratio less than 1 were significantly associated with decreased 1-year patient and graft survival. Chronic graft rejection was still the major cause of death in the long-term follow-up recipients. Conclusions Our findings suggested that lung ReTX recipients have poor long-term survival outcomes. Lung ReTX should only be offered to carefully selected patients.

Retransplantation Outcomes at a Large Lung Transplantation Program.

Background: Acute respiratory distress syndrome (ARDS) is a clinical presentation of acute lung injury (ALI) with often fatal lung complication. Adenosine, a nucleoside generated following cellular stress provides protective effects in acute injury. The levels of extracellular adenosine can be depleted by equilibrative nucleoside transporters (ENTs). ENT inhibition by pharmaceutical agent dipyridamole promotes extracellular adenosine accumulation and is protective in ARDS. However, the therapeutic potential of dipyridamole in acute lung injury has not yet been evaluated. Methods: Adenosine acts on three adenosine receptors, the adenosine A1 (Adora1), A2a (Adora2a), the A2b (Adora2b) or the adenosine A3 (Adora 3) receptor. Accumulation of adenosine is usually required to stimulate the low-affinity Adora2b receptor. In order to investigate the effect of adenosine accumulation and the contribution of epithelial-specific ENT2 or adora2b expression in experimental ALI, dipyridamole, and epithelial specific ENT2 or Adora2b deficient mice were utilized. MLE12 cells were used to probe downstream Adora2b signaling. Adenosine receptors, transporters, and targets were determined in ARDS lungs. Results: ENT2 is mainly expressed in alveolar epithelial cells and is negatively regulated by hypoxia following tissue injury. Enhancing adenosine levels with ENT1/ENT2 inhibitor dipyridamole at a time when bleomycin-induced ALI was present, reduced further injury. Mice pretreated with the ADORA2B agonist BAY 60-6583 were protected from bleomycin-induced ALI by reducing vascular leakage (558.6 ± 50.4 vs. 379.9 ± 70.4, p < 0.05), total bronchoalveolar lavage fluid cell numbers (17.9 ± 1.8 to 13.4 ± 1.4 e4, p < 0.05), and neutrophil infiltration (6.42 ± 0.25 vs. 3.94 ± 0.29, p < 0.05). While mice lacking Adora2b in AECs were no longer protected by dipyridamole. We also identified occludin and focal adhesion kinase as downstream targets of ADORA2B, thus providing a novel mechanism for adenosine-mediated barrier protection. Similarly, we also observed similar enhanced ADORA2B (3.33 ± 0.67 to 16.12 ± 5.89, p < 0.05) and decreased occludin (81.2 ± 0.3 to 13.3 ± 0.4, p < 0.05) levels in human Acute respiratory distress syndrome lungs. Conclusion: We have highlighted a role of dipyridamole and adenosine signaling in preventing or treating ALI and identified Ent2 and Adora2b as key mediators in important for the resolution of ALI.

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Enhancing Extracellular Adenosine Levels Restores Barrier Function in Acute Lung Injury Through Expression of Focal Adhesion Proteins.

(DFT) testing the patient’s ICD was unsuccessful in multiple configurations and an azygous coil was placed. His DFT was at the maximum output of his device (41 J), which was achieved after 7 inductions of VF. Six months later, he received 5 ICD shocks before presenting to an outside hospital. Interrogation of his ICD showed sustained VF, which was untreated because the device had exhausted therapy (Figure 1). He was transferred 200 miles to our center. He failed to convert despite 5 additional attempts with various ICD coil and polarity configurations. A biphasic 200-J external shock also failed (Zoll Defibrillator, Chelmsford, MA). Two sets of pads were placed, attached to 2 external defibrillators. One set of pads was placed in an anterior–posterior arrangement, and the other to the right of the sternum and over the apex. The buttons were pushed simultaneously by one person, delivering a total energy of 400 J. He successfully converted to a ventricular paced rhythm. Over the ensuing months, he presented twice with VF unresponsive to ICD shocks. The first time he was defibrillated with a 200-J external shock. The second time he again required simultaneous defibrillation with 2 sets of pads. He subsequently underwent ablation of triggering premature ventricular complexes, and has been free of VF since that time. Treatment of VF in LVAD patients presents unique opportunities in light of the hemodynamic support provided by the LVAD. Dual defibrillation is a safe, effective treatment for refractory atrial fibrillation. However, stacked shocks have not been examined in ventricular rhythms. To achieve a 400-J external shock, 2 defibrillators and 2 sets of pads must be used simultaneously. Perhaps for this reason, dual defibrillation has not been examined in unstable patients with ventricular arrhythmias who fail 200-J defibrillation. It is possible that nearly simultaneous, rather than truly simultaneous, shocks were delivered. However, if this had occurred, the length of the shock waveform would have resulted in overlapping waves and caused an additive effect similar to our goal. Although the small number of patients with LVADs limits the ability to rigorously study the double defibrillation approach to refractory VF, it should certainly be attempted if other means fail.

Dewei Ren

Papers

Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema.

Retransplantation Outcomes at a Large Lung Transplantation Program.

Enhancing Extracellular Adenosine Levels Restores Barrier Function in Acute Lung Injury Through Expression of Focal Adhesion Proteins.

Lung procurement from a donor with a long-term left ventricular assist device.

Extending Cold Ischemic Time Using LUNGguard: A Single Center Experience in Time Shifting