Survival After Lung Transplantation for Chronic Hypersensitivity Pneumonitis: Results From a Large International Cohort Study

Repeated exposure to antigens via inhalation is the primary cause of hypersensitivity pneumonitis, a form of interstitial pneumonia. The chronic form of hypersensitivity pneumonitis leads to progressive loss of respiratory function; lung transplantation is the only therapeutic option for chronically ill patients. The ESTS Lung Transplantation Working Group conducted a retrospective multicentred cohort study to increase the body of knowledge available on this rare indication for lung transplantation. Data were collected for every patient who underwent lung transplant for hypersensitivity pneumonitis in participating centres between December 1996 and October 2019. Primary outcome was overall survival; secondary outcome was freedom from chronic lung allograft dysfunction. A total of 114 patients were enrolled from 9 centres. Almost 90% of patients were diagnosed with hypersensitivity pneumonitis before transplantation, yet the antigen responsible for the infection was identified in only 25% of cases. Eighty per cent of the recipients received induction therapy. Survival at 1, 3, and 5 years was 85%, 75%, and 70%, respectively. 85% of the patients who survived 90 days after transplantation were free from chronic lung allograft dysfunction after 3 years. The given study presents a large cohort of HP patients who underwent lung transplants. Overall survival rate is higher in transplanted hypersensitivity pneumonitis patients than in those suffering from any other interstitial lung diseases. Hypersensitivity pneumonitis patients are good candidates for lung transplantation

Reconsidered surgical aortic valve replacement after declined transcatheter valve implantation

Background: outcomes for high surgical risk patients who declined transcatheter aortic valve implantation (TAVI) and then reconsidered for conventional aortic valve replacement (rSAVR) for severe calcific aortic stenosis are not well known. Methods: this single-centre, case–control study (rSAVR vs Conservative group) retrospectively analysed patients for rSAVR (2009–2019). Multivariable logistic regression was used to identify independent predictors of composite of neurological sequelae/renal failure/deep sternal wound infection/re-exploration and death. Survival was compared using Kaplan–Meier curves and log-rank test. A Cox proportional hazards model was used to determine predictors of survival. Results: TAVI was denied in 519/1095 patients, 114(10.4%) had rSAVR (cases) and 405 (37%) were managed conservatively (controls). Mean age for rSAVR was 80 years (IQR: 73.5–85 years). The commonest reason for declining TAVI was prohibitive high risk due to multiple comorbidities. Among rSAVR, hospital mortality was 2.2% and stroke was 4.4%. Median follow-up was conservative; 14.4 months versus rSAVR; 34.8 months. Five-year survival was conservative; 12.6% versus rSAVR; and 59.5% (overall conservative; 38.0% vs. rSAVR; 60.5%, p &lt; 0.001). rSAVR was protective (hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.26, 0.51, p &lt; 0.001) and high comorbidities had high hazard (HR: 1.57, 95% CI: 1.19, 2.07, p = 0.001). rSAVR had fewer hospital readmission episodes (Conservative; 13.6/patient-year vs. rSAVR; 6.9/patient-year, p = 0.002). Conclusions: rSAVR may be considered in high surgical risk elderly patients who have been declined TAVI in centres with low operative mortality. rSAVR may be superior to conservative management in carefully selected patients.</p

Inducible lung epithelial resistance requires multisource reactive oxygen species generation to protect against bacterial infections.

Pneumonia remains a global health threat, in part due to expanding categories of susceptible individuals and increasing prevalence of antibiotic resistant pathogens. However, therapeutic stimulation of the lungs' mucosal defenses by inhaled exposure to a synergistic combination of Toll-like receptor (TLR) agonists known as Pam2-ODN promotes mouse survival of pneumonia caused by a wide array of pathogens. This inducible resistance to pneumonia relies on intact lung epithelial TLR signaling, and inducible protection against viral pathogens has recently been shown to require increased production of epithelial reactive oxygen species (ROS) from multiple epithelial ROS generators. To determine whether similar mechanisms contribute to inducible antibacterial responses, the current work investigates the role of ROS in therapeutically-stimulated protection against Pseudomonas aerugnosa challenges. Inhaled Pam2-ODN treatment one day before infection prevented hemorrhagic lung cytotoxicity and mouse death in a manner that correlated with reduction in bacterial burden. The bacterial killing effect of Pam2-ODN was recapitulated in isolated mouse and human lung epithelial cells, and the protection correlated with inducible epithelial generation of ROS. Scavenging or targeted blockade of ROS production from either dual oxidase or mitochondrial sources resulted in near complete loss of Pam2-ODN-induced bacterial killing, whereas deficiency of induced antimicrobial peptides had little effect. These findings support a central role for multisource epithelial ROS in inducible resistance against a bacterial pathogen and provide mechanistic insights into means to protect vulnerable patients against lethal infections

Aspiration of Conjugated Bile Acids Predicts Adverse Lung Transplant Outcomes and Correlates with Airway Lipid and Cytokine Dysregulation.

Introduction: Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD). Reflux aspirate can contain bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes. Methods: Bronchial washings (BW) were prospectively collected from lung transplant recipients and subsequently assayed by liquid chromatography-mass spectrometry for 13 BA and 25 lipid families. Patients were monitored for CLAD, rejection, inflammation and airway infections. Results: Detectable BA were present in 45/50 patients (90%) at 3 months after transplant. Elevated BA and predominance of conjugated species were independent predictors of CLAD (hazard ratio 7.9; 95% confidence interval 2.7-23.6; p &lt; 0.001 and 7.3; 2.4-22; p &lt; 0.001, respectively) and mortality (hazard ratio 4.4; 1.5-12.7; p = 0.007 and 4.8; 1.4-15.8; p = 0.01, respectively). High BA associated with increased positive bacterial cultures (60% vs 25%, p = 0.02). Primary conjugated species independently correlated with the rate of bacterial cultures during the first-year post-transplant (Beta coefficient: 0.77; 0.28-1.26; p = 0.003) and changes in airway lipidome and cytokines. Conclusions: Higher BA levels and predominance of conjugated BA are independent predictors of chronic lung allograft dysfunction, mortality and bacterial infections. Primary conjugated BA are related to distinct changes in airway lipidome and inflammatory cytokines. This elucidates novel evidence into the mechanism following BA aspiration and proposes novel markers for prediction of adverse post-transplant outcomes

Extracorporeal life support as a bridge to pulmonary retransplantation: prognostic factors for survival in a multicentre cohort analysis

OBJECTIVES: Pulmonary retransplant (ReTx) is considered a controversial procedure. Despite literature reporting outcomes following ReTx, limited data exist in recipients bridged to their ReTx on extracorporeal life support (ECLS). The goal of this study was to investigate the outcomes of recipients bridged to a first-time ReTx by ECLS. METHODS: We performed a retrospective multicentre cohort analysis from 10 centres in Europe, Asia and North America. The primary outcome was overall survival. Risk factors were analysed using Cox regression models. RESULTS: ECLS as a bridge to a first-time ReTx was performed in 50 recipients (ECLS-ReTx). During the study period, 210 recipients underwent a first-time ReTx without bridging on ECLS (regular-ReTx) and 4959 recipients had a primary pulmonary transplant (index-Tx). The overall 1-year (55%) and 5-year (29%) survival was significantly worse for the ECLS-ReTx group.Compared to the index-Tx group, the mortality risk was significantly higher after ECLS-ReTx [hazard ratio 2.76 (95% confidence interval 1.94-3.91); P < 0.001] and regular-ReTx [hazard ratio 1.65 (95% confidence interval 1.36-2); P < 0.001].In multivariable analysis, recipient age ≥35 years, time interval <1 year from index-Tx, primary graft dysfunction as transplant indication, venoarterial-extracorporeal membrane oxygenation and Zurich donor score ≥4 points were significant risk factors for mortality in ECLS-ReTx recipients. CONCLUSIONS: Recipients for ECLS-ReTx should be carefully selected. Risk factors, such as recipient age, intertransplant interval, primary graft dysfunction as transplant indication and type of ECLS should be kept in mind before bridging these patients on ECLS to ReTx

Extracorporeal life support as a bridge to pulmonary retransplantation: prognostic factors for survival in a multicentre cohort analysis

 : Objectives: Pulmonary retransplant (ReTx) is considered a controversial procedure. Despite literature reporting outcomes following ReTx, limited data exist in recipients bridged to their ReTx on extracorporeal life support (ECLS). The goal of this study was to investigate the outcomes of recipients bridged to a first-time ReTx by ECLS. Methods: We performed a retrospective multicentre cohort analysis from 10 centres in Europe, Asia and North America. The primary outcome was overall survival. Risk factors were analysed using Cox regression models. Results: ECLS as a bridge to a first-time ReTx was performed in 50 recipients (ECLS-ReTx). During the study period, 210 recipients underwent a first-time ReTx without bridging on ECLS (regular-ReTx) and 4959 recipients had a primary pulmonary transplant (index-Tx). The overall 1-year (55%) and 5-year (29%) survival was significantly worse for the ECLS-ReTx group.Compared to the index-Tx group, the mortality risk was significantly higher after ECLS-ReTx [hazard ratio 2.76 (95% confidence interval 1.94-3.91); P < 0.001] and regular-ReTx [hazard ratio 1.65 (95% confidence interval 1.36-2); P < 0.001].In multivariable analysis, recipient age ≥35 years, time interval <1 year from index-Tx, primary graft dysfunction as transplant indication, venoarterial-extracorporeal membrane oxygenation and Zurich donor score ≥4 points were significant risk factors for mortality in ECLS-ReTx recipients. Conclusions: Recipients for ECLS-ReTx should be carefully selected. Risk factors, such as recipient age, intertransplant interval, primary graft dysfunction as transplant indication and type of ECLS should be kept in mind before bridging these patients on ECLS to ReTx

Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections

Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.Viruses are the most commonly identified causes of pneumonia and inflict unacceptable morbidity, despite currently available therapies. While lung epithelial cells are principal targets of respiratory viruses, they have also been recently shown to contribute importantly to therapeutically inducible antimicrobial responses. This work finds that lung cells can be stimulated to protect themselves against viral challenges, even in the absence of leukocytes, both reducing viral burden and improving survival. Further, it was found that the protection occurs via unexpected induction of reactive oxygen species (ROS) from spatially segregated sources without reliance on type I interferon signaling. Coordinated multisource ROS generation has not previously been described against viruses, nor has ROS generation been reported for epithelial cells against any pathogen. Thus, these findings extend the potential clinical applications for the strategy of inducible resistance to protect vulnerable people against viral infections and also provide new insights into the capacity of lung cells to protect against infections via novel ROS-dependent mechanisms

Rare indications for a lung transplant. A European Society of Thoracic Surgeons survey

OBJECTIVES: The European Society of Thoracic Surgeons Lung Transplantation Working Group promoted a survey to evaluate overall survival in a large cohort of patients receiving lung transplants for rare pulmonary diseases. METHODS: We conducted a retrospective multicentre study. The primary end point was overall survival; secondary end points were survival of patients with the most common diagnoses in the context of rare pulmonary diseases and chronic lung allograft dysfunction (CLAD)-free survival. Finally, we analysed risk factors for overall survival and CLAD-free survival. RESULTS: Clinical records of 674 patients were extracted and collected from 13 lung transplant centres; diagnoses included 46 rare pulmonary diseases. Patients were followed for a median of 3.1 years. The median survival after a lung transplant was 8.5 years. The median CLAD-free survival was 8 years. The multivariable analysis for mortality identified CLAD as a strong negative predictor [hazard ratio (HR) 6.73)], whereas induction therapy was a protective factor (HR 0.68). The multivariable analysis for CLAD occurrence identified induction therapy as a protective factor (HR 0.51). When we stratified patients by CLAD occurrence in a Kaplan-Meier plot, the survival curves diverged significantly (log-rank test: P < 0.001). Patients with rare diseases who received transplants had chronic rejection rates similar to those of the general population who received transplants. CONCLUSIONS: We observed that overall survival and CLAD-free survival were excellent. We support the practice of allocating lungs to patients with rare pulmonary diseases because a lung transplant is both effective and ethically acceptable.status: publishe

Usefulness of Early Treatment With Melatonin to Reduce Infarct Size in Patients With ST-Segment Elevation Myocardial Infarction Receiving Percutaneous Coronary Intervention (From the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty Trial)

Melatonin, an endogenously produced hormone, might potentially limit the ischemia reperfusion injury and improve the efficacy of mechanical reperfusion with primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI). This study was aimed to evaluate whether the treatment effect of melatonin therapy in patients with STEMI is influenced by the time to administration. We performed a post hoc analysis of the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty trial (NCT00640094), which randomized STEMI patients to melatonin (intravenous and intracoronary bolus) or placebo during pPCI. Randomized patients were divided into tertiles according to symptoms onset to balloon time: first tertile (136 ± 23 minutes), second tertile (196 ± 19 minutes), and third tertile (249 ± 41 minutes). Magnetic resonance imaging was performed within 1 week after pPCI. A total of 146 patients presenting with STEMI within 360 minutes of chest pain onset were randomly allocated to intravenous and intracoronary melatonin or placebo during pPCI. In the first tertile, the infarct size was significantly smaller in the melatonin-treated subjects compared with placebo (14.6 ± 14.2 vs 24.9 ± 9.0%; p = 0.003). Contrariwise, treatment with melatonin was associated with a larger infarct size in the group of patients included in the third tertile (20.5 ± 8.7% vs 11.2 ± 5.2%; p = 0.001), resulting in a significant interaction (p = 0.001). In conclusion, the administration of melatonin in patients with STEMI who presented early after symptom onset was associated with a significant reduction in the infarct size after pPCI