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BackgroundAcute exacerbations of interstitial lung diseases (AE-ILD) have a high mortality rate with no effective medical therapies. Lung transplantation is a potentially life-saving option for patients with AE-ILD, but its role is not well established. The aim of this study is to determine if this therapy during AE-ILD significantly affects post-transplant outcomes in comparison to those transplanted with stable disease.MethodsWe conducted a retrospective study of consecutive patients with AE-ILD admitted to our institution from 2015 to 2018. The comparison group included patients with stable ILD listed for lung transplant during the same period. The primary end-points were in-hospital mortality for patients admitted with AE-ILD and 1-year survival for the transplanted patients.ResultsOf 53 patients admitted for AE-ILD, 28 were treated with medical therapy alone and 25 underwent transplantation. All patients with AE-ILD who underwent transplantation survived to hospital discharge, whereas only 43% of the AE-ILD medically treated did. During the same period, 67 patients with stable ILD underwent transplantation. Survival at 1 year for the transplanted patients was not different for the AE-ILD group versus stable ILD group (96% vs 92.5%). The rates of primary graft dysfunction, post-transplant hospital length-of-stay and acute cellular rejection were similar between the groups.ConclusionPatients with ILD transplanted during AE-ILD had no meaningful difference in overall survival, rate of primary graft dysfunction or acute rejection compared with those transplanted with stable disease. Our results suggest that lung transplantation can be considered as a therapeutic option for selected patients with AE-ILD.

Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1−/−recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/ characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.

End-stage lung disease and advanced cardiac conditions are frequently seen together and represent a clinical dilemma. Even though both issues may be amenable to surgical management, combining lung transplant with surgical valve repair is rarely done and theoretically associated with increased morbidity and mortality risks, especially in elderly patients. Here, we describe 2 patients presenting with end-stage lung disease and significant aortic stenosis who were successfully bridged to lung transplant via transcatheter aortic valve replacement. Patient 1 was a 66-year-old man who underwent a double lung transplant 56 days after transcatheter aortic valve replacement. Patient 2 was a 70-year-old man who underwent a single right lung transplant 103 days after transcatheter aortic valve replacement. Both patients had uneventful postoperative courses and are alive at the 1-year time point with excellent performance status. This report suggests that transcatheter aortic valve replacement may favorably impact lung transplant candidacy for patients with end-stage lung disease in the setting of severe aortic stenosis, likely representing a better alternative to concomitant aortic valve replacement and lung transplant in elderly patients.

The lung is a naturally tolerogenic organ. Lung regulatory T cells (T-regs) control lung mucosal tolerance. Here, we identified a lung IFNAR1hiTNFR2+ conventional DC2 (iR2D2) population that induces T-regs in the lung at steady state. Using conditional knockout mice, adoptive cell transfer, receptor blocking antibodies, and TNFR2 agonist, we showed that iR2D2 is a lung microenvironment-adapted dendritic cell population whose residence depends on the constitutive TNFR2 signaling. IFNβ-IFNAR1 signaling in iR2D2 is necessary and sufficient for T-regs induction in the lung. The Epcam+CD45- epithelial cells are the sole lung IFNβ producer at the steady state. Surprisingly, iR2D2 is plastic. In a house dust mite model of asthma, iR2D2 generates lung TH2 responses. Last, healthy human lungs have a phenotypically similar tolerogenic iR2D2 population, which became pathogenic in lung disease patients. Our findings elucidate lung epithelial cells IFNβ-iR2D2-T-regs axis in controlling lung mucosal tolerance and provide new strategies for therapeutic interventions.

Asthma is a common inflammatory lung disease with no known cure. Previously, we uncovered a lung TNFR2+ conventional DC2 subset (cDC2s) that induces regulatory T cells (Tregs) maintaining lung tolerance at steady state but promotes TH2 response during house dust mite (HDM)-induced asthma. Lung IFNβ is essential for TNFR2+ cDC2s-mediated lung tolerance. Here, we showed that exogenous IFNβ reprogrammed TH2-promoting pathogenic TNFR2+ cDC2s back to tolerogenic DCs, alleviating eosinophilic asthma and preventing asthma exacerbation. Mechanistically, inhaled IFNβ, not IFNα, activated ERK2 signaling in pathogenic lung TNFR2+ cDC2s, leading to enhanced fatty acid oxidation (FAO) and lung Treg induction. Last, human IFNβ reprogrammed pathogenic human lung TNFR2+ cDC2s from patients with emphysema ex vivo. Thus, we identified an IFNβ-specific ERK2-FAO pathway that might be harnessed for DC therapy.

A large proportion of controlled donation after circulatory death (cDCD) donor lungs are declined because cardiac arrest does not occur within a suitable time after the withdrawal of life-sustaining therapy. Improved strategies to preserve lungs after asystole may allow the recovery team to arrive after death actually occurs and enable the recovery of lungs from more cDCD donors. The aim of this study was to determine the effect of donor positioning on the quality of lung preservation after cardiac arrest in a cDCD model. Cardiac arrest was induced by withdrawal of ventilation under anesthesia in pigs. After asystole, animals were divided into 2 groups based on body positioning (supine or prone). All animals were subjected to 3 hours of warm ischemia. After the observation period, donor lungs were explanted and preserved at 4°C for 6 hours, followed by 6 hours of physiologic and biological lung assessment under normothermic ex vivo lung perfusion. Donor lungs from the prone group displayed significantly greater quality as reflected by better function during ex vivo lung perfusion, less edema formation, less cell death, and decreased inflammation compared with the supine group. A simple maneuver of donor prone positioning after cardiac arrest significantly improves lung graft preservation and function.

Background Lung transplantation for patients with end-stage lung disease continues to grow worldwide. Increasing demand for this therapy generates significant waitlist mortality, indicating that alternative sources of donor lungs, such as older donors, are needed. The effect of the donor–recipient age relationship on outcomes remains unclear. Methods A retrospective review of the United Network for Organ Sharing Standard Transplant Analysis and Research database was performed for adult lung recipients from 2005 to 2015. Variables examined included donor age, recipient age, listing diagnosis, episodes of acute cellular rejection in the first year, and survival. Both donors and recipients were stratified according to age ranges. Survival was compared with the log-rank test. Propensity score matching was done stratifying donors younger than 60 years versus older than 60 years for the recipient population of 60 to 69 years. Results From May 2005 to February 2015, 15,844 patients underwent lung transplantation. Unadjusted comparisons of donor-to-recipient age showed that older donor age appeared to be more relevant for recipients 60 to 69 years old (p = 0.002). Nevertheless, when propensity matching was done based on relevant covariates for recipients in this age range by donors younger or older than 60 years, there were no differences in survival. Conclusions Our results suggest that even though donor and recipient age may be important in lung transplantation, the interplay between donor and recipient age alone is not an independent determinant of survival. Careful selection of lungs from donors older than 60 years old should be exercised, taking into consideration the totality of donor demographics and risk factors rather than dismissing lungs based on advanced age alone.

Availability of organs is a limiting factor for lung transplantation, leading to substantial mortality rates on the wait list. Use of organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), would increase organ donation, but these organs are generally not offered for transplantation due to a high risk of transmission. Here, we develop a method for treatment of HCV-infected human donor lungs that prevents HCV transmission. Physical viral clearance in combination with germicidal light-based therapies during normothermic ex-vivo Lung Perfusion (EVLP), a method for assessment and treatment of injured donor lungs, inactivates HCV virus in a short period of time. Such treatment is shown to be safe using a large animal EVLP-to-lung transplantation model. This strategy of treating viral infection in a donor organ during preservation could significantly increase the availability of organs for transplantation and encourages further clinical development., Organs from donors with transmissible viral infections, such as hepatitis C virus (HCV), are not offered for transplantation due to a high risk of transmission. Here, Galasso et al. develop a method for treatment of HCV-infected human donor lungs that is safe and prevents HCV transmission in the pig model.

Summary Background Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications. Methods We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres—including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes—were collected by Northwestern University (Chicago, IL, USA) and analysed. Findings Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41–51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19. Interpretation The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients. Funding National Institutes of Health. Video Abstract Early outcomes after lung transplantation for severe COVID-19

Highlights • Radiographic assessment of spinal cord involvement is essential. • Histology is necessary to establish etiology, prognosis, and treatment plan. • Large tumors may require posterolateral thoracotomy and piecemeal resection. • Preoperative angiography may identify arteries shared by the tumor and spinal cord. • Preoperative angioembolization may reduce tumor vascularity and operative blood loss., Introduction: Posterior mediastinal masses present unique diagnostic and therapeutic challenges, particularly when large highly vascularized tumors extend toward or emanate from the spinal cord. The rare nature of these tumors precludes the development of standardized management algorithms, underscoring the importance of case reports. Presentation of case: A 57 year old female presented with exertional dyspnea and right chest pressure. Chest radiography followed by computed tomography (CT) scan demonstrated a 13 cm posterior mediastinal mass involving the T7 vertebral body. CT-guided percutaneous biopsy confirmed benign schwannoma. During open exploration, the tumor bled easily with contact. Angiography with intercostal arterial embolization decreased tumor vascularity while preserving spinal cord perfusion. Subsequent piecemeal resection facilitated exposure of the tumor base and complete resection. Postoperative recovery was uneventful. Discussion: Neurogenic tumors are most commonly located in the posterior mediastinum. When untreated, schwannomas continue to grow, and will inevitably cause compressive symptoms if given sufficient time. Therefore, resection is recommended. This may be performed thoracoscopically in select patients with small tumors, avoiding the morbidity of a thoracotomy incision. Conclusion: Large posterior mediastinal schwannomas require posterolateral thoracotomy and resection. Preoperative angiography helps identify arteries shared by the tumor and the spinal cord, and embolization may reduce tumor vascularity and operative blood loss thereby permitting safer resection.

Purpose Breathing and swallowing are basic survival functions that share a common anatomical conduit for the passage of air and food and are governed by shared neural networks and reciprocal peripheral musculature. Individuals with end-stage respiratory disease who are awaiting lung transplantation (LT) are therefore at high risk for dysphagia. Although dysphagia has been reported in high rates in post-operative LT patients, it is currently unclear if dysphagia is a pre-existing condition or rather a complication of surgical and intubation procedures performed. We therefore aimed to compare radiographic swallowing profiles in LT patients before and after LT. Methods A retrospective review of consecutive patients undergoing LT from 2017 and 2020 at a single academic institution was performed. Pre- and post-operative videofluoroscopic swallow study (VFSS) reports were identified and the validated Penetration Aspiration Scale (PAS) was retrieved. Frequencies, independent t-tests and Chi-Square analyses were conducted. Results 166 patients had viable pre- and post-operative VFSS reports that were included. Pre-Operative Dysphagia Status : 83% (PAS ≤2, n=137) demonstrated safe swallowing, 10% (PAS 3-5, n=17) exhibited penetration into the upper airway, and 7% (PAS ≥ 6, n=12) exhibited tracheal aspiration. Aspiration profiles, in rank order, included an ineffective cough response to remove aspirate in 50% (PAS 7, n=6), expulsion of tracheal aspirate 33% (PAS 6, n=4), while 17% demonstrated silent aspiration (PAS 8, n=2). No associations were noted for pre-operative dysphagia and gender, age, BMI, or race (p>0.05). Post-Operative Dysphagia Status: 20% (n=33) demonstrated safe swallowing, 41% (n=68) penetration, while 39% (n=65) exhibited tracheal aspiration. Swallowing safety distribution profiles differed across pre- versus post-operative profile (p=0.02). Conclusion Frequency of unsafe swallowing increased by 4.7 times across pre- and post-operative time points. Further, an ∼six-fold increase in radiographically confirmed tracheal aspiration was observed. Thus, a high rate of incident dysphagia cases was observed, highlighting the need for close post-operative monitoring and identification of contributing risk factors to optimize procedures, patient care and outcomes.

Purpose Belatacept reduces calcineurin inhibitor (CNI) nephrotoxicity in kidney transplant recipients. However, its use in lung transplantation is extremely limited and it remains unclear whether it can provide a safe and effective renal sparing immunosuppression in patients with chronic kidney disease. Methods This is a prospective cohort study of patients who were started on Belatacept with lower CNI goals post lung transplantation at our institution between 2018 and 2020. Institutional IRB approval was obtained. Patients aged 18 years or older were included and multiorgan recipients were excluded. Continuous data was reported as median and categorical data as proportions. Paired data analyses that include Wilcoxan signed rank test and McNemar's test were performed. Results 85 patients satisfied the inclusion and exclusion criteria. Median time to initiation of Belatacept after transplantation was 293 days, interquartile range (IQR) (148-611). The cohort was followed for a median of 311 days IQR (182-465). 28 patients (33%) stopped the infusion with the majority due to infectious complications. There was a median of 1ml increase in GFR (p=0.68). The FEV1 increased a median of 40ml during the same duration (p=0.0034). Conclusion In this large cohort, Belatacept provided an effective renal sparing immunosuppression. There was no decline in graft function with stabilization of GFR. There was a tendency towards a higher rate of opportunistic infections and cancers; however, this did not achieve statistical significance.

Purpose Due to donor/recipient size matching challenges, lung transplant candidates height may pose a significant disadvantage for receiving a transplant, resulting in longer wait times and increased waitlist mortality. We hypothesize that a proactive approach focused on donor lung size reduction improves access to transplantation with equivalent post-operative outcomes. Methods We retrospectively reviewed our experience with transplant candidates listed from Jan 2010 to May 2019. Since January 2016, our program considers surgical downsizing of donor lungs via non-anatomical reduction or lobar transplantation whenever LAS prioritization recommends matching to a shorter stature candidate and downsizing is anatomically feasible. We compared this cohort of patients (recent era) to those from our early era in which size reduction was not proactively performed (Jan 2010- Dec 2015). We excluded pediatric, redo and multiorgan transplants. Our primary endpoint was waitlist mortality or removal due to clinical deterioration. Secondary endpoints were time to transplant and post-operative outcomes. Results We included 410 patients with 226 in the early era and 184 in the recent era. Age (mean 54.46 vs 57.87) and LAS (mean 44.73 vs 44.18) were comparable between both groups. Donor characteristics were similar between periods. The number of patients with surgically downsized grafts was significantly higher in the current period compared to the early period (n=62; 34.4% vs n=20; 8.9%; p Conclusion Removal of size restrictions through proactive surgical downsizing improved access to transplantation. Despite more technically demanding, this change in practice has not impacted postoperative outcomes. The significant decreases in waitlist mortality and wait times suggest that this approach is able to address a significant disparity in our field.

Objectives: To determine the dose-limiting toxicity of oxaliplatin chemotherapy delivered by in vivo lung perfusion (IVLP). To allow assessment of subacute toxicities, we aimed to develop a 72-hour porcine IVLP survival model. Methods: In total, 12 Yorkshire male pigs were used. Left lung IVLP was performed for 3 hours. At 72 hours postoperatively, computed tomography imaging of the lungs was performed before the pigs were killed. Lung physiology, airway dynamics, gross appearance, and histology were assessed before and during IVLP, at reperfusion, and when the pigs were euthanized. An accelerated titration dose-escalation study design was employed whereby oxaliplatin doses were sequentially doubled provided no clinically significant toxicity was observed, defined as an arterial partial pressure of oxygen to fraction of inspired oxygen ratio

BACKGROUND The application of mesenchymal stromal cell (MSC)–based therapy during ex vivo lung perfusion (EVLP) could repair injured donor lungs before transplantation. The aim of this study was to determine the efficacy of MSC therapy performed during EVLP on ischemia-reperfusion injury using a pig lung transplant model. METHODS Following 24 hours of cold storage, pig lungs were randomly assigned to 2 groups (n = 6 each), the control group without MSC vs the MSC group, where 5 × 106 cells/kg MSCs were delivered through the pulmonary artery during EVLP. After 12 hours of EVLP, followed by a 1-hour second cold preservation period, the left lung was transplanted and reperfused for 4 hours. RESULTS EVLP perfusate hepatocyte growth factor (HGF) level at 12 hours was significantly elevated in the MSC group compared with the control and was associated with a significant decrease in cell death markers, cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells, in the MSC group. The MSC group showed significantly lower interleukin (IL)-18 and interferon gamma levels and a significantly higher IL-4 level in lung tissue at 12 hours of EVLP than the control group. After transplantation, the MSC group showed a significant increase in lung tissue HGF level compared with the control group, associated with a significantly reduced lung tissue wet-to-dry weight ratio. Lung tissue tumor necrosis factor-α level and pathological acute lung injury score were significantly lower in the MSC group than the control group. CONCLUSIONS The administration of MSCs ameliorated ischemic injury in donor lungs during EVLP and attenuated the subsequent ischemia-reperfusion injury after transplantation.

Lung dendritic cells and regulatory T cells control lung mucosal tolerance. Here, we identified a lung-resident IDO-1+TNFR2+ conventional DC2 (iR2D2) subset that induces antigen-specific regulatory T cells in the lung. iR2D2 is a microenvironment specialized DC subset whose existence depends on its constitutive TNFR2-pRelB-IDO-1 signaling. The iR2D2 intrinsic IFNAR-TGFβ1 signaling is necessary and sufficient for regulatory T cells induction in vivo. Surprisingly, iR2D2 is plastic. In a house dust mite (HDM) model of asthma, iR2D2 generates lung Th2 responses. Remarkably, intranasally administration of IFNβ reprogramed HDM-induced Th2-promoting iR2D2 back to generate regulatory T cells, reversed lung inflammation and protected mice from subsequent asthma exacerbation. Healthy human lung has a phenotypically similar tolerogenic iR2D2, which became IL-4+ in emphysema patients. Finally, IFNβ successfully reprogramed human emphysema iR2D2 ex vivo. These findings elucidate a fundamental mechanism controlling lung tolerance and a strategy to restore lung tolerance in inflammatory lung diseases.

Purpose Sensitized lung transplant (LTx) candidates have longer waiting times, decreased likelihood of transplant, and increased risk of death while on waitlist. To mitigate this and to increase the access to donor pool, for sensitized candidates, we modified and implemented The Toronto perioperative strategy to treat DSA-positive recipients with positive virtual crossmatch (VCM) donor offers. We hypothesize that such perioperative desensitization strategy can be safely implemented with acceptable outcomes and help decrease the waitlist mortality. Methods We performed a retrospective chart review of sensitized candidates who underwent LTx between June 2017 - June 2020 and required perioperative desensitization. We collected the baseline demographics and post-transplant variables. The protocol was implemented if the calculated panel reactive antibody (cPRA) was > 30 % and had positive VCM. Desensitization protocol included preoperative plasma exchange (PLEX) with 1.5 volume, intra operative basiliximab induction, followed by five sessions of PLEX, intravenous immunoglobulin (IvIg, 1 gm / kg) and Anti Thymocyte globulin (dose 3 mg/kg for VCM positive vs 5 mg/kg for positive actual crossmatch (ACM)). We used tacrolimus (12 - 15 ng/ml), mycophenolate and prednisone for maintenance immunosuppression. Results 25 patients required desensitization. 76% (n=19) of them are females. Median LAS score is 41.3 (IQR 33.87-60.33). Median wait time was 28.9 days (IQR 12.6-65). All patients underwent bilateral lung transplantation. ACM was positive in 24% of patients (n=6). 76% (n=19) completed the protocol. Incidence of Primary graft dysfunction at any time point was 12% (n=3). Acute cellular rejection >= grade 2 was 8% (n=2). 8% (n=2) had chronic lung allograft dysfunction. Overall survival of this cohort is 96% with a median follow up of 17 months (IQR 5 - 25.5). Conclusion Perioperative desensitization can be safely implemented with acceptable outcomes in sensitized LTx candidates. On comparison of our SRTR data, before and after desensitization implementation, we noted a decline in the waitlist mortality (11.4% to 7.6%) and 50th percentile median wait times (8.5 months to 1.3 months).

Purpose Although lung transplantation (LT) remains the definitive therapy for end-stage respiratory disease, limited long-term survival rates highlight the need for improved post-transplant care. Given the high risk for postoperative dysphagia, we aimed to determine the prevalence, risk factors and associated outcomes of dysphagia in postoperative LT patients. Methods A retrospective review of consecutive adult patients undergoing LT and postoperative videofluoroscopic evaluation of swallowing (VFSS) at our institution between 11/2017 and 6/2020 was conducted. Relevant outcomes were extracted from electronic medical records (EPIC) and entered into a central database (REDCap). VFSS notes were examined and Penetration Aspiration Scale (PAS) scores extracted. Descriptives, t-tests, one-way ANOVA's, chi-squares and odds ratios were derived in SPSS. Results 205 LT recipients met inclusion criteria and were included. Mean age was 58.63 years and 50.7% were male. Postoperatively, 18% demonstrated safe swallowing (n=37), 39% demonstrated laryngeal penetration (n=79), and 43% demonstrated tracheal aspiration (n=89). Aspiration response profiles included: 50% no cough response (n=41), 31.7% ejection of aspirate material (n=26), and 18.3% ineffective cough response (n=15). Postoperative aspiration in LT patients was associated with: 1) peri-transplant venous-venous extracorporeal membrane oxygenation (OR: 2.0, X2 =3.7, p=.05); 2) cardiopulmonary bypass (n=40; OR: 2.3, X2=5.7, p=.02); 3) ≥ 3 intubations (OR: 7.5, X2 =5.2, p=.02); 4) tracheostomy (OR: 4.8, X2 =8.3, p=.004); and 4) longer intubation duration (70 vs. 44 hours, p=.002). LT patients who aspirated waited an average of 240 hours longer to resume a regular diet (p=0.004) and demonstrated a 2.4 and 2.0 higher odds of pneumonia and discharge to a acute rehab, respectively. One-year mortality rate was 2.9% (n=6), with 100% of deaths classified as unsafe swallowers. Conclusion Dysphagia was highly prevalent and associated with inferior patient outcomes. The observation that ∼70% of aspirators could not clear tracheal aspirate may explain, in part, the increased odds for development of pneumonia. Mortality data suggest that presence of dysphagia may impact survival and should be further examined in ongoing prospective studies.

Purpose The COVID-19 pandemic has infected millions of people across the world and caused several thousands of deaths. Given advances in extracorporeal life support technology, ECMO for COVID-19 acute respiratory distress syndrome (ARDS) has proven to be successful in sustaining life, however, has left a significant number of patients fully depended on devices and incapable of being weaned. Lung transplantation, as a well-established therapy for end-stage lung disease, has been considered for some patients with COVID-19 ARDS in the absence of lung recovery and the presence of findings suggestive of end-stage lung disease. Methods This is an International collaborative effort to assess the role of lung transplantation in COVID-19 ARDS. There is worldwide representation with centers from US (3), Europe (2) and Asia (1). Patients with COVID-19 ARDS supported on ECMO and/or mechanical ventilation who were deemed unweanable and developed features of end-stage lung disease were evaluated for lung transplantation. We followed ISHLT conventional recipient selection criteria recommendations and a 2 negative COVID-19 PCRs from bronchoalveaolar lavage or viral culture depending on medical urgency. Endpoints We will present demographics, intraoperative challenges, primary graft dysfunction, postoperative complications, survival and functional outcomes of patients with COVID-19 ARDS who underwent lung transplantation. Additionally, referral patterns, reasons for listing denial and waitlist outcomes will be presented. So far, this collaborative group has transplanted 17 patients. There have been no deaths on the waitlist, there was one post-transplant mortality at day 61. Ten patients have been discharged from the hospital and are doing well. Six patients are recovering well however less than 30 days post-transplantation and remain admitted.

Lung transplantation using RNA+ hepatitis C (HCV+) donors to seronegative recipients is not currently performed due to the very high risk of transmission. Previous reports have shown poor survival when this practice was applied. The emergence of new direct-acting antiviral drugs (DAA) suggests a high chance of sustained virologic response in immunocompetent patients. We report here successful transplantation of lungs from HCV+ donor to HCV- recipient. The recipient was an HCV- patient with chronic lung allograft dysfunction. Viral transmission occurred early posttransplant but excellent clinical outcomes were observed including elimination of HCV after 12 weeks of treatment using DAAs.

Purpose Gastroparesis (GP) is prevalent after lung transplant (Ltx) (50-68%). GP has been associated with symptoms and delayed absorption of medications. Of particular concern after Ltx, GP can predispose to gastroesophageal reflux disease considered the main culprit for chronic allograft dysfunction. Therefore, early diagnosis and treatment is recommended in Ltx patients. Pharmacologic intervention for GP is not efficacious to improve gastric emptying and can induce potential serious side effects. Transcutaneous electric stimulation (TES) has been proposed to improve motility in various gastrointestinal motility disorders Methods We tested the hypothesis that TES may improve gastric emptying in Ltx patients. A 4-hour solid-phase gastric emptying study was done for worsening lung function before and after TES. Surveillance gastric emptying study (GEE) was done 2-12 weeks after TES. Five patients (4 female, age 48 ± 8), interval post-transplant (1-10 years), underwent TES as rescue therapy for moderate to severe GP (gastric retention >25% at 4 hours) that failed standard pharmacologic and dietary interventions. TES was delivered in continuous square wave, pulse rate 120 Hz, pulse width 220 µs, and pulse intensity to the maximum tolerated level without pain or muscle twitching. Two cutaneous electrodes were placed between T6 and T10 spinal levels (gastric autonomic segment) over the spine. Patients were instructed to use TES for 30 min after meals and for 30 min at bedtime Results Following TES, the percentage of gastric retention at 4 hours improved in the majority of patients (42 median, 25-73 min-max before TES; 20 median 7-43 min-max) after TES, p=0.01; figure 1). Three patients reported GP symptoms. Only one patient reported no significant improvement in the severity of symptoms Conclusion TES appears to modulate symptom perception and significantly improves gastric emptying in Ltx patients with moderate to severe gastroparesis

Purpose 1) Determine the incidence of postoperative swallowing impairment in patients undergoing lung transplantation, 2) identify potential demographic or surgical dysphagia risk factors, and 3) examine associated outcomes with aspiration. Methods A retrospective chart review was conducted in 122 consecutive individuals undergoing lung transplantation (LT) and a routine postoperative modified barium swallowing (MBS) exam. Demographic and health-related outcome data were extracted and MBS films assessed using the validated Penetration Aspiration Scale (PAS) by an expert rater. Results Dysphagia Incidence: 27.3% of LT patients demonstrated safe swallowing (PAS:1-2), 43.8% had laryngeal penetration during swallowing (PAS:3-5), while tracheal aspiration occurred in 28.7% (n=35) of patients (PAS:6-8). Thus, 72.5% (n=87) of LT patients demonstrated unsafe swallowing. Of the aspirators, 51% demonstrated no cough response to tracheal aspirate. Risk Factors: Body Mass Index (BMI) was significantly lower in aspirators versus non-aspirators (p=0.03) with a negative correlation noted between PAS score and BMI (r=-0.23, p=0.01). A linear by linear association for prevalence of aspiration by weight class was also noted (p=0.04). No relationships were noted for age, race, gender, or operative time with aspiration status (p>0.05). Outcomes Associated with Dysphagia: Compared to non-aspirators, LT patients who aspirated waited 138 hours longer to resume an oral diet (249 vs. 111, p=0.05), spent 192 hours longer in the intensive care unit (359 vs. 167, p Conclusion Dysphagia is highly prevalent in LT patients and associated with significant morbidity. These data highlight the need for close monitoring of the LT patient and further suggest a key role for implementation of instrumental assessment techniques for accurate and timely detection of dysphagia.

Purpose Postoperative pain for bilateral lung transplant patients is often poorly controlled and may negatively impact recovery. Intercostal cryoanalgesia (IC-CRYO) may provide an additional modality to pain control. We hypothesize that IC-CRYO may enhance recovery compared to traditional opiate based analgesia (OBA) and thoracic paravertebral catheter (TPVC) analgesia. Methods Consecutive patients from January 2015 to May 2019 receiving a double lung transplant were included in this retrospective review. Pediatric age, single lung and redo lung transplants were excluded. TPCV group received 4 bilateral catheters at T4 and T8 levels postoperatively in the intensive care unit. IC-CRYO was performed intraoperatively by the surgeon from intercostal nerves 3-7 bilaterally. Results A total of 66 patients received IC-CRYO, 51 patients received OBA, and 89 received TPVC. The IC-CRYO group was significantly older (59 vs 52; p = 0.01) and had higher BMI (25.8 vs 24.2; p = 0.05) compared to OBA. Both the restrictive lung disease patients (62% IC-CRYO, 46% TPVC and 47% OBA) and the lung allocation scores (52 IC-CRYO, 47 TPVC and 51 OBA) were higher in IC-CRYO. There were no differences in time on the ventilator, ICU or hospital length of stay. There was a trend to lesser need for tracheostomy in IC-CRYO compared to OBA (5% vs 16%; p = value 0.06). IC-CRYO showed a significant decrease in post operative pneumonia compared to OBA (3% vs 22%; p = 0.03) and to TPVC (3% vs 17%; p = 0.03). There were no complications related to TPVC or IC-CRYO. Conclusion The present data suggest IC-CRYO and TPVC are effective as adjuncts to pain control for patients undergoing bilateral lung transplant. The data suggest IC-CRYO is strongly associated with functional improvements in patient recovery from bilateral lung transplant when compared with TPVC and OBA for postoperative pain control.

Background The goal of lung cancer surgery is a complete tumor resection (R0 resection) with clear margins. 4% to 5% of resections have microscopic residual disease associated with worse prognosis. Definitive management is resection of residual tumor, which may not be tolerated by many patients, and definitive management is not well studied in these patients. We treated patients with stage I cancer and bronchial mucosal residual disease (MRD) with bronchoscopic photodynamic therapy (PDT). Methods All patients who underwent definitive surgery for early-stage lung cancer were reviewed. Patients with R1 resection, stage I disease with MRD and or carcinoma in situ along the stump site were treated with bronchoscopic PDT. Patient characteristics, histology, type and site of surgery, pattern of recurrence, recurrence status, adverse events, and survival data were evaluated. Results Eleven patients with bronchial mucosal R1 resection were treated with PDT along the stump site. The median age was 67. Three patients had carcinoma in situ and 8 had MRD. One patient (9%) had local recurrence 1 year after PDT treatment and was treated with radiation. Four patients (36%) had no evidence of recurrence to date after a median follow-up of 4 years and the other 6 patients had evidence of regional (16%) or distant (39%) recurrence. The local control rate was 91%. One patient developed pneumonia and other had photosensitivity reaction. Conclusion Bronchoscopic PDT is safe and effective in selected group of patients with non-small cell lung cancer who have MRD along the stump site.

Purpose Despite a donor shortage, transplantation of lungs from donors identified as Public Health Service (PHS) Increased Risk Donors (IRDs) remains controversial, representing a potential bridge to this supply gap. While these donors are seronegative for HIV , Hepatitis B, and Hepatitis C, they have factors that place them at increased risk. Prior work has shown that the use of IRDs for lung transplantation does not result in worse survival; however, an updated definition of IRD from the PHS in 2013 has led to greater percentages of IRD classification. Methods The UNOS Standard Transplant Analysis and Research database was queried for adult lung transplantations performed between June 2013 through March 2017. Kaplan-Meier analysis compared survival of recipients receiving IRD lungs versus non-IRD lungs. A multivariate logistic regression model was then constructed to control for donor and recipient factors significant on univariate analysis . Results In the examined period, 7254 lung transplantations were performed, 1471 (20.3%) of which were from IRD, a more than two-fold increase from the years prior to the definition change (Table). IRD and non-IRD cohorts differed significantly in terms of donor age, gender, race, and cause of death, as well as recipient gender and diagnosis. Unadjusted 1-year and 3-year survival was 87.6% and 67.8% for the IRD cohort vs. 88.5% and 70.1% for the non-IRD cohort (Figure, log-rank p=0.0268). When controlling for other donor and recipient factors, IRD status was not an independent predictor of mortality (OR 1.055, 95% CI 0.91-1.22; p=0.47). Conclusion Since 2013, the relative percentage of IRD has increased dramatically, relating to the inclusion of Hepatitis C in the definition. Despite several important differences between cohorts, IRD status itself does not confer a mortality disadvantage and in the era of treatability and cure in most instances for Hepatitis C, the practice of avoiding these donors is outdated.

Introduction PDT is a safe procedure with most post procedural complications reported as minor. We report a case of severe acute stridor and trachea-bronchial airway obstruction with mucosal sloughing and fibrous plugs resulting in respiratory failure within three hours following PDT. To our knowledge this is the first reported case where stridor and acute respiratory failure resulted within hours following PDT treatment. Case Report A 65 year old female with previous right pneumonectomy presented with followup bronchoscopy confirming reoccurrence of carcinoma proximal and distal to the anastomosis. A standard photofrin (Porfimer sodium) was administered at 2mg/kg body weight 48 hours prior to her PDT treatment. Three hours following the procedure, patient become acutely stridurous and was subsequently intubated. Bedside bronchoscopy was performed through the endotracheal tube. During the bronchoscopy thick tracheal plugs were retrieved and slough adjacent to the treatment site was noticed which was debrided. Patient underwent 7 bronchoscopies with debridement before she was discharged. Conclusion Airway obstruction (with NSCLA) is an indication as well as complication (with mucosal debris) of PDT. FDA has advised bronchoscopy at 48-72 hours post procedure, however early intervention with bronchoscopy and debridement should be considered to relieve tracheal bronchial airway obstruction and removal of accessory debris and mucosal slough.

Purpose Alpha-1 antitrypsin (AAT) is a significant anti-protease, anti-inflammatory, and immune-regulating protein, which favors organ tolerance after transplantation. Genetic testing for diagnosis of AAT deficiency (AATD) in lung transplant candidates with COPD, and post-transplant replacement of AAT in patients with AATD varies widely among transplants centers. The objective of this survey was to assess the practices of international lung transplant (LTx) centers, pertaining to the testing for, and replacement of, AAT in patients with AATD. Methods We developed a web-based survey to investigate the testing and replacement of AAT in patients with AATD undergoing LTx. The survey was distributed to international LTx centers via the ISHLT Connect platform. Results Respondents consisted of 49 LTx specialists from 10 countries (74% North America, 24% Europe, and 2% Australia). Centers performing >40 transplants per year (considered high-volume) comprised 52% of the respondents. Among all LTx centers, 57% reported screening all patients with COPD for AATD. Screening rates were equal between North America and Europe (58%). Low-volume LTx centers screened for AATD at a much higher rate, compared to high-volume LTx centers (78% vs. 36%). Only 25% of LTx centers provided AAT replacement prior to, or following LTx in patients with known AATD. North America LTx centers replaced AAT (31%) more frequently than European LTx centers (9%). As with screening rates, more low-volume LTx centers provided AAT (35%), compared to high volume centers (16%). One-third of LTx centers reported that, at their respective centers, diagnosis of AATD was an exclusionary criteria for double LTx. Conclusion This is the first systematic survey of LTx centers’ approaches to AATD, with specific attention on testing and post-LTx replacement of AAT. Standards of practice vary widely among lung transplant centers. Low-volume LTx centers screened for AATD, and replaced AAT after LTx in patients with AATD, more frequently than high-volume centers.

Purpose Symptomatic Hyperammonemia syndrome after Lung Transplantation (HSLT) is a fatal complication with a mortality rate exceeding 75%. The current management of HSLT consists of a multimodality approach that includes intravenous administration of an ammonia scavenger (Ammonul), with an estimated cost of $93,000 per day. Although the enteral formulation of an alternative ammonia scavenger (Buphenyl) costs far less, at $4,823 per day, its efficacy has not been established for treatment of HSLT. This study evaluated the efficacy of a multimodal approach to management of symptomatic HSLT using Buphenyl as a replacement for Ammonul (Table 1). Methods This was a retrospective chart review analysis of patients who underwent lung transplantation at UFHealth Shands Hospital, from May 01, 2016 till September 30, 2018. Results There were 129 lung transplants performed at UFHealth Shands Hospital during the study period. Six patients developed symptomatic HSLT and required treatment during this timeframe (Table 2). Fifty-percent developed severe neurological symptoms with hemodynamic instability and signs of multi-organ failure. The other 50% presented with altered mental status with no other systemic symptoms. One patient was treated with the Ammonul formula, and the remaining five patients were treated with the Buphenyl formula. All 6 patients were successfully treated with no reoccurrence of HSLT. Examination of etiological work-ups for HSLT, including urea cycle disorders, liver dysfunction, or infectious causes of HSLT were unrevealing. Conclusion The use of Buphenyl, as an alternative to Ammonul, is safe, efficacious, and cost-effective. Early diagnosis and implementation of a multi-modal approach are crucial for successful management of HSLT.

The production of K0, Λ and {Mathematical expression} particles is studied in the E665 muon-nucleon experiment at Fermilab. The average multiplicities and squared transverse momenta are measured as a function of xF and W2. Most features of the data can be well described by the Lund model. Within this model, the data on the K0/π± ratios and on the average K0 multiplicity in the forward region favor a strangeness suppression factor s/u in the fragmentation process near 0.20. Clear evidence for QCD effects is seen in the average squared transverse momentum of K0 and Λ particles. © 1994 Springer-Verlag.

Results on density integrals Fq(Q2) and correlation integrals Kq(Q2) are presented for the first time in muon-nucleon scattering at ∼ 490 GeV, using data from the E665 experiment at the Tevatron of Fermilab. A clear rise of the Fq integrals with decreasing size of the phase-space cells (“intermittency”) is observed for pairs and triplets of negative hadrons whereas the effect is much weaker for mixed charge combinations. From these findings it is concluded that the observed intermittency signal is mainly caused by Bose-Einstein interference. Furthermore, no energy (W) dependence of F2(Q2) is observed within the W range of the E665 experiment. Finally, the third-order correlation integrals K3(Q2) are found to be significantly different from zero which implies the presence of genuine three-particle correlations in muon-nucleon interactions.

In this paper the spectrometer constructed by the E665 Collaboration is described. The spectrometer was built during the period 1982–87 and the first data were taken during the 1987–88 Fixed Target run of the Fermi National Accelerator Laboratory (FNAL) Tevatron. This is the first of a series of runs in which a comprehensive program of high energy muon scattering experiments will be performed.

The diffractive production of ρ0(770 @#@) mesons in muon-proton interactions is studied in the kinematic region 0.15 GeV2 < Q2 < 20 GeV2 and 20 GeV < ? < 420 GeV. The data were obtained in the Fermilab fixed-target experiment E665 with primary muons of 470 GeV energy. Results are presented on the Q2, x and ? dependence of the cross section, on the shape of the ρ+ρt - mass spectrum, on the slope of the diffraction peak and on the production and decay angular distributions of the ρ0(770). The cross section for diffractive production of ρ0 by virtual photons on protons depends mainly on Q2. At fixed Q2, no significant dependence on x or ? is observed. The extrapolation to Q2 = 0 yields a photoproduction cross section of (10.30 ± 0.33) μb. The slope of the t′ distribution has a value of (7.0 ± 0.2) GeV−2, with a tendency to decrease as Q2 increases. The production and decay angular distributions of the ρ0 depend strongly on Q2 and are consistent with s-channel helicity conservation. The ratio R = σ l /σ t deduced from the decay angular distributions rises strongly with Q2, passing the value of 1 at Q2 ≈ 2 GeV2.

The production of charged hadrons is studied in μXe and μD interactions at 490 GeV beam energy. The data were taken at the Tevatron at Fermilab with the E665 spectrometer, equipped with a streamer chamber as vertex detector. Differences between the μXe and μD data are explained by cascading of hadrons in the Xe nucleus. The average multiplicity of charged hadrons in μXe scattering is compared to previously published pXe scattering data and is found to be strongly reduced. This is traced back to the low number of ‘projectile’ collisions in μXe interactions. From a study of thex Bj dependence of hadron production in μXe scattering, and by considering events with a large rapidity gap, evidence is found for a significant contribution of diffractive scattering, which is enhanced in the kinematic region where shadowing of the cross section is observed. This result supports recent models in which diffractive scattering and nuclear shadowing are closely related.

Background Intravenous plasma administration has been recommended in healthy or sick calves with failure of passive immunity. Hypothesis IV administered plasma‐derived immunoglobulin G (IgG) undergoes increased catabolism as reflected by a rapid decrease in serum IgG concentration with an increase in fecal IgG concentrations within 48 h. Animals Thirty newborn Jersey calves. Fifteen were fed colostrum (CL group) and 15 were given bovine plasma IV (PL group). Materials and Methods Randomized clinical trial. Calves in the CL group were fed 3 L of colostrum once, by oroesophageal tubing. Calves in the PL group were given plasma IV at a dosage of 34 mL/kg. Serum and fecal samples were collected at 0 h, 6 h, 12 h, 48 h, 5 d, and 7 d. Serum and fecal IgG concentrations were determined by radial immunodiffusion. Results Calves in the CL group maintained serum IgG concentrations consistent with adequate transfer of immunity (≥1,000 mg/dL) throughout the study period. Calves in the PL group achieved median IgG concentrations of ≥1,000 mg/dL at 6 h but the concentrations were .05). Conclusions and Clinical Importance Catabolism of plasma derived IgG occurs rapidly during the first 12 h after transfusion. Fecal excretion did not explain the fate of the plasma derived IgG.

Using data from the Fermilab fixed target experiment E665, general properties of forward produced charged hadrons in μp interactions at a primary muon energy of 470 GeV are investigated. The normalized inclusive single-particle distributions for Feynman-x D(xF) and for the transverse momentum D(pt2, xF) are measured as a function of W and Q2. The dependence of the average transverse momentum squared 〈pt2〉 on xF, W and Q2 is studied. The increasing contribution from diffractive production as Q2 decreases leads to a reduction of the average charged hadron multiplicities at low (positive) xF and an enhancement at large xF, for Q2 ≲ 10 GeV2. It also reduces 〈pt2〉 for Q2 ≲ 5 GeV2 and 0.4 ≲ xF < 1.0. © Springer-Verlag 1997.

We have measured the energy levels and purely rotational autoionization rates of 25 different triplet Rydberg states of the ${\mathrm{H}}_{2}$ molecule with quantum numbers n=14--29, L=3, v=0, and R=2--4. Electron impact excites the ground-state molecules in a beam to the metastable c(2p)${\mathrm{}}^{3}$ ${\mathrm{\ensuremath{\Pi}}}_{\mathrm{u}}$ states. Two-color laser excitation from two counterpropagating single-mode cw dye laser beams excites the metastable molecules through an intermediate (3d)${\mathrm{}}^{3}$ \ensuremath{\Sigma} or (3d)${\mathrm{}}^{3}$ \ensuremath{\Pi} state to the triplet nf Rydberg states. The linewidths of the transitions to the Rydberg states give the autoionization rates, which vary widely and agree satisfactorily with the quadrupole-moment-polarizability long-range Coulomb interaction model. The laser transitions have been measured to 0.002 ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}1}$ . We use these measurements, the model, and an extrapolation of the Rydberg series to derive the ionization potential of the metastable c(2p)${\mathrm{}}^{3}$ ${\mathrm{\ensuremath{\Pi}}}_{\mathrm{u}}$ v=0 states with an accuracy of 0.020 ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}1}$ and the energy difference between the singlet ground state and the triplet metastable c(2p)${\mathrm{}}^{3}$ ${\mathrm{\ensuremath{\Pi}}}_{\mathrm{u}}$ states with an accuracy of 0.025 ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}1}$ . This allows the whole singlet and triplet manifolds of ${\mathrm{H}}_{2}$ to be linked together with higher accuracy: our correction to Dieke's ${\mathrm{H}}_{2}$ triplet term values is -149.704(25) ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}1}$ .