Post-lung transplant outcomes of connective tissue disease-related interstitial lung diseases compared with idiopathic interstitial pneumonia: a single-center experience in Japan.

OBJECTIVES: The aim of this study was to investigate the outcomes of lung transplantation for connective tissue disease-related interstitial lung disease (CTD-ILD) conducted at our institution, compared with those for idiopathic interstitial pneumonias (IIPs). METHODS: We retrospectively reviewed patients with CTD-ILD and IIPs who underwent lung transplantation at our hospital from July 2015 to October 2023. We compared patients' backgrounds, early complications within 28 days post-transplant (CTCAE grade 3 or higher), postoperative courses, and prognoses between the two groups. RESULTS: The CTD-ILD group (n = 19) and the IIPs group (n = 56) were compared. The CTD-ILD group had significantly higher preoperative use of corticosteroids and antifibrotic agents, mean pulmonary arterial pressure, anti-human leukocyte antigen antibody positivity, and donor age (p < 0.05). In addition, the CTD-ILD group had significantly longer operation times (579.0 vs 442.5 min), longer stays in the intensive care unit (17.0 vs 9.0 days) and hospital (58.0 vs 44.0 days); required more tracheostomies (57.9 vs 25.0%); and experienced more respiratory (52.6 vs 25.0%) and gastrointestinal (42.1 vs 8.9%) complications (p < 0.05). However, there were no significant differences in overall survival, nor chronic lung allograft dysfunction (CLAD)-free survival between the two groups. CONCLUSION: Perioperative complications, notably respiratory and gastrointestinal complications, were prevalent after lung transplantation among CTD-ILD patients. Despite this, long-term survival rates were comparable to those observed in IIP cases.

Survival after surgery for lung cancer among patients with autoimmune diseases.

PURPOSE: While patients with autoimmune diseases (ADs) are at high risk for developing specific malignancies, including lung cancer, ADs may protect against the development of cancer through increased immune cell activity in tumors. This study aimed to investigate whether the presence of ADs affects surgical outcomes and survival after surgery for lung cancer. METHODS: The medical records of 1236 patients who underwent surgery for non-small cell lung cancer between 2007 and 2018 were retrospectively reviewed. Perioperative and long-term outcomes were compared between patients with and without ADs using propensity score matching. RESULTS: Among the included patients, 115 with ADs and 1121 without ADs underwent surgery. Using 1-to-1 propensity score matching, 114 pairs were selected. Although there were no significant differences in the perioperative outcomes of the two groups, the overall and relapse-free survival rates were significantly lower in the group with ADs than in the group without ADs. CONCLUSIONS: Surgery for lung cancer can be performed without increasing the complications in patients with ADs. However, the long-term outcomes were significantly worse in patients with ADs than in those without ADs, suggesting that close follow-up for lung cancer and careful whole-body examination might be needed for patients with ADs.

Baseline lung allograft dysfunction after bilateral deceased-donor lung transplantation: A single-center experience in Japan.

BACKGROUND: Baseline lung allograft dysfunction (BLAD) refers to a condition in which a lung transplant recipient does not achieve normal pulmonary function (i.e., forced expiratory volume in 1 s or forced vital capacity of <80% of predicted values). Although BLAD is reportedly associated with a poor prognosis, the condition has not been examined in Japanese patients. METHODS: In this study, we retrospectively examined 38 Japanese adults who underwent bilateral lung transplantation from 2015 to 2022 in a single center. RESULTS: Twenty-one (55%) patients met the criteria for BLAD. No significant differences were found in recipient or donor factors between the BLAD and non-BLAD groups, but the donor-recipient ratio of the predicted vital capacity was lower in the BLAD group (p = 0.009). The intensive care unit length of stay, ventilator duration, and blood loss during transplant surgery were significantly higher in the BLAD group (p < 0.05). No significant difference was found in survival. The median observation period was significantly shorter in the BLAD than non-BLAD group (744 vs.1192 days, respectively; p = 0.031). The time to reach the normal threshold of pulmonary function after lung transplantation varied among the patients, ranging from 6 months to 4 years. CONCLUSIONS: The characteristics of these Japanese patients with BLAD were similar to those of other patients in previous reports. The effects of the observation period and donor-recipient age discrepancy on BLAD require further exploration.

Alternative venous access sites for dual-lumen extracorporeal membrane oxygenation cannulation.

OBJECTIVES: Dual-lumen cannulas for veno-venous (VV) extracorporeal membrane oxygenation (ECMO) support are typically inserted in the right internal jugular vein (RIJV); however, some scenarios can make this venous route inaccessible. This multicentre case series aims to evaluate if single-site cannulation using an alternative venous access is safe and feasible in patients with an inaccessible RIJV. METHODS: We performed a multi-institutional retrospective analysis including high-volume ECMO centres with substantial experience in dual-lumen cannulation (DLC) (defined as >10 DLC per year). Three centres [Freiburg (Germany), Toronto (Canada) and Vienna (Austria)] agreed to share their data, including baseline characteristics, technical ECMO and cannulation data as well as complications related to ECMO cannulation and outcome. RESULTS: A total of 20 patients received alternative DLC for respiratory failure. Cannula insertion sites included the left internal jugular vein (n = 5), the right (n = 7) or left (n = 3) subclavian vein and the right (n = 4) or left (n = 1) femoral vein. The median cannula size was 26 (19-28) French. The median initial target ECMO flow was 2.9 (1.8-3.1) l/min and corresponded with used cannula size and estimated cardiac output. No procedural complications were reported during cannulation and median ECMO runtime was 15 (9-22) days. Ten patients were successfully bridged to lung transplantation (n = 5) or lung recovery (n = 5). Ten patients died during or after ECMO support. CONCLUSIONS: Alternative venous access sites for single-site dual-lumen catheters are a safe and feasible option to provide veno-venous ECMO support to patients with inaccessible RIJV.

Association between cytomegalovirus viremia and long-term outcomes in lung transplant recipients.

Although cytomegalovirus (CMV) viremia/DNAemia has been associated with reduced survival after lung transplantation, its association with chronic lung allograft dysfunction (CLAD) and its phenotypes is unclear. We hypothesized that, in a modern era of CMV prophylaxis, CMV DNAemia would still remain associated with death, but also represent a risk factor for CLAD and specifically restrictive allograft syndrome (RAS)/mixed phenotype. This was a single-center retrospective cohort study of all consecutive adult, first, bilateral-/single-lung transplants done between 2010-2016, consisting of 668 patients. Risks for death/retransplantation, CLAD, or RAS/mixed, were assessed by adjusted cause-specific Cox proportional-hazards models. CMV viral load (VL) was primarily modeled as a categorical variable: undetectable, detectable to 999, 1000 to 9999, and ≥10 000 IU/mL. In multivariable models, CMV VL was significantly associated with death/retransplantation (≥10 000 IU/mL: HR = 2.65 [1.78-3.94]; P < .01), but was not associated with CLAD, whereas CMV serostatus mismatch was (D+R-: HR = 2.04 [1.30-3.21]; P < .01). CMV VL was not associated with RAS/mixed in univariable analysis. Secondary analyses with a 7-level categorical or 4-level ordinal CMV VL confirmed similar results. In conclusion, CMV DNAemia is a significant risk factor for death/retransplantation, but not for CLAD or RAS/mixed. CMV serostatus mismatch may have an impact on CLAD through a pathway independent of DNAemia.

Pulmonary epithelial markers in phenotypes of chronic lung allograft dysfunction.

BACKGROUND: Airway epithelial injury is thought to be a key event in the pathogenesis of chronic lung allograft dysfunction (CLAD). We investigated whether markers of epithelial activity and injury in bronchoalveolar lavage fluid (BAL) correlate with CLAD diagnosis and major CLAD phenotypes: bronchiolitis obliterans syndrome (BOS) vs restrictive allograft syndrome (RAS)-related phenotypes (including RAS, mixed phenotype, and all other patients with RAS-like opacities). METHODS: CLAD status and phenotypes were retrospectively determined in a cohort of all consecutive adult, first, bilateral lung transplants performed 2010-2015, with available BAL samples. All patients with RAS-related phenotypes were included and 1:1 matched with BOS patients based on the time from transplant to CLAD-onset. Subjects who were CLAD-free for a minimum of 3 years post-transplant were 1:1 matched to CLAD patients and included as controls. Proteins that maintain the barrier function of the airway epithelial mucosa (club cell secretory protein, surfactant protein-D and epithelial mucins: MUC1, MUC5AC, MUC5B, MUC16), as well as epithelial cell death markers (M30&M65 representing epithelial cell apoptosis and overall death, respectively), were measured in BAL obtained within 6-months post CLAD onset using a double-sandwich ELISA or a multiplex bead assay. Protein levels were compared using Mann-Whitney-U-test. Association between protein levels and graft survival was assessed using Cox proportional hazards models, adjusted for CMV serology mismatch status and CLAD phenotype. RESULTS: Fifty-four CLAD (27 BOS, 11 RAS, 7 mixed, 9 others with RAS-like opacities) patients and 23 CLAD-free controls were included. Median BAL levels were significantly higher in patients with CLAD compared to CLAD-free controls for M30 (124.5 vs 88.7 U/L), MUC1 (6.8 vs 3.2 pg/mL), and MUC16 (121.0 vs 30.1 pg/mL). When comparing CLAD phenotypes, M30 was significantly higher in patients with RAS-related phenotypes than BOS (160.9 vs 114.6 U/L). In multivariable models, higher M30 and MUC5B levels were associated with decreased allograft survival after CLAD onset independent of phenotype (p < 0.05 for all). CONCLUSIONS: Airway epithelial mucins and cell death markers are enhanced in the BAL of patients with CLAD and can assist in differentiating between CLAD phenotypes and post-CLAD outcomes. Abnormal airway mucin expression and epithelial cell death may be involved in the pathogenesis of CLAD, and therefore their detection may aid in future selection of targeted therapies.

Evaluation of 10°C as the optimal storage temperature for aspiration-injured donor lungs in a large animal transplant model.

BACKGROUND: Our recent work has challenged 4°C as an optimal lung preservation temperature by showing storage at 10°C to allow for the extension of preservation periods. Despite these findings, the impact of 10°C storage has not been evaluated in the setting of injured donor lungs. METHODS: Aspiration injury was created through bronchoscopic delivery of gastric juice (pH: 1.8). Injured donor lungs (n = 5/group) were then procured and blindly randomized to storage at 4°C (on ice) or at 10°C (in a thermoelectric cooler) for 12 hours. A third group included immediate transplantation. A left lung transplant was performed thereafter followed by 4 hours of graft evaluation. RESULTS: After transplantation, lungs stored at 10°C showed significantly better oxygenation when compared to 4°C group (343 ± 43 mm Hg vs 128 ± 76 mm Hg, p = 0.03). Active metabolism occurred during the 12 hours storage period at 10°C, producing cytoprotective metabolites within the graft. When compared to lungs undergoing immediate transplant, lungs preserved at 10°C tended to have lower peak airway pressures (p = 0.15) and higher dynamic lung compliances (p = 0.09). Circulating cell-free mitochondrial DNA within the recipient plasma was significantly lower for lungs stored at 10°C in comparison to those underwent immediate transplant (p = 0.048), alongside a tendency of lower levels of tissue apoptotic cell death (p = 0.075). CONCLUSIONS: We demonstrate 10°C as a potentially superior storage temperature for injured donor lungs in a pig model when compared to the current clinical standard (4°C) and immediate transplantation. Continuing protective metabolism at 10°C for donor lungs may result in better transplant outcomes.

Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy.

BACKGROUND: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular "recharge", allowing for multi-day lung preservation. METHODS: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. FINDINGS: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. INTERPRETATION: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. FUNDING: This work was supported by the UHN Foundation (Grant#1013612).

Phenotyping CLAD after single lung transplant: Limits and prognostic assessment of the 2019 ISHLT classification system.

BACKGROUND: Phenotyping chronic lung allograft dysfunction (CLAD) in single lung transplant (SLTX) is challenging, due to the native lung contribution to pulmonary function test (PFT). We aimed to assess the applicability and prognostic performance of International Society for Heart and Lung Transplantation (ISHLT) classification in SLTX. METHODS: In this retrospective study of adult, first, SLTX performed 2009-2017, patients with persistent drop in FEV1≥20% were assessed by 2 independent adjudicators to determine CLAD status and phenotype. Interobserver agreement (IOA) was calculated (Cohen's Kappa) for CLAD, phenotype and presence of RAS (resttrictive allograft syndrome)-like opacities (RLO). Association of CLAD phenotypes with time to death or retransplant (ReTx), adjusted for age at SLTX, sex, CMV mismatch and native lung condition, were assessed using Cox proportional hazards models. RESULTS: Of 172 SLTX recipients, 92 experienced a persistent drop in FEV1>20%. Following adjudication, 67 were diagnosed with CLAD. We noted a moderate IOA for CLAD diagnosis (Kappa 0.69) and poor IOA for phenotype adjudication (Kappa 0.52). The final phenotype adjudication was 31 bronchiolitis obliterans syndrome (BOS) (46.3%), 13 RAS (19.4%), 2 mixed (3%), 2 Undefined (3%), and 19 remained Unclassified (28.3%). Using these adjudicated phenotypes, RAS was significantly associated with a higher risk of death/ReTx compared to other groups (HR 2.98, 95%CI [1.39-6.4]). The adjudication of RLO had the best IOA (Kappa 0.73). The presence of RLO was a strong predictor of death or ReTx (HR 2.37, 95%CI [1.2-4.5]), regardless of the final phenotype. CONCLUSIONS: PFT interpretation is challenging in SLTX. A classification essentially relying on imaging, which harbored good IOA, obtained better prognostic performance than a classification using published physiological cut-offs.

Outcomes of lung transplantation from organ donation after medical assistance in dying: First North American experience.

Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n = 33) and end stage organ failure (n = 5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p = .0009). Median ventilation period and 30 day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1 day [1-3] vs 2 days [1-3]; p = .37, deaths 0% [0/33] vs. 2% [11/560], p = .99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Significance of phenotype change after chronic lung allograft dysfunction onset.

Definitions for chronic lung allograft dysfunction (CLAD) phenotypes were recently revised (2019 ISHLT consensus). Post-CLAD onset phenotype transition may occur as a result of change in obstruction, restriction, or RAS-like opacities (RLO). We aimed to assess the prevalence and prognostic implications of these transitions. This was a single-center, retrospective cohort study of bilateral lung transplants performed in 2009-2015. CLAD phenotypes were determined per ISHLT guidelines. CLAD phenotype transition was defined as a sustained change in obstruction, restriction or RLO. We specifically focused on phenotype changes based on RLO emergence. Association of RLO development with time to death or retransplant were assessed using Kaplan-Meier and Cox proportional hazards models. Among 211 patients with CLAD, 47 (22.2%) experienced a phenotype transition. Nineteen patients developed RLO. Development of RLO phenotype after CLAD onset was associated with a shorter time to death/retransplant when considering the entire CLAD patient cohort (HR = 4.00, CI 2.74-5.83, P < 0.001) and also when restricting the analysis to only patients with a Non-RLO phenotype at CLAD onset (HR 9.64, CI 5.52-16.84, P < 0.0001). CLAD phenotype change based on emergence of RAS-like opacities implies a worse outcome. This highlights the clinical importance of imaging follow-up to monitor for phenotype transitions after CLAD onset.

A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide.

Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied. Herein we aim to explore the feasibility and safety of delivering continuous high-dose iNO over an extended period of time using an in vivo animal model. Yorkshire pigs were randomized to one of the following two groups: group 1, standard ventilation; and group 2, standard ventilation + continuous iNO 160 ppm + methylene blue (MB) as intravenous bolus, whenever required, to maintain metHb <6%. Both groups were ventilated continuously for 6 hours, then the animals were weaned from sedation, mechanical ventilation and followed for 3 days. During treatment, and on the third post-operative day, physiologic assessments were performed to monitor lung function and other significative markers were assessed for potential pulmonary or systemic injury. No significant change in lung function, or inflammatory markers were observed during the study period. Both gas exchange function, lung tissue cytokine analysis and histology were similar between treated and control animals. During treatment, levels of metHb were maintained <6% by administration of MB, and NO2 remained <5 ppm. Additionally, considering extrapulmonary effects, no significant changes were observed in biochemistry markers. Our findings showed that high-dose iNO delivered continuously over 6 hours with adjuvant MB is clinically feasible and safe. These findings support the development of investigations of continuous high-dose iNO treatment of respiratory tract infections, including SARS-CoV-2.

Micronodular Thymoma with Lymphoid Stroma: A Case Report.

BACKGROUND: Micronodular thymoma with lymphoid stroma (MNT) is a rare subtype of thymic neoplasms. Therefore, clinical guidelines, histopathological diagnostic criteria, prognostic factors, and therapeutic regimens have not been established. CASE PRESENTATION: A 69-year-old woman was admitted to our hospital because of an abnormal shadow detected by chest radiography. Further imaging revealed an anterior mediastinal tumor measuring 65×28×15 mm. We performed thymectomy for diagnosis and treatment. Histopathological examination revealed spindle cells comprised multiple micronodules separated by abundant interstitial lymphocytes and lymphoid follicles. Immunohistochemical staining showed that the tumor was positive for cell adhesion molecule (CAM), cytokeratin (CK) 5/6, and terminal deoxynucleotidyl transferase. The histopathological diagnosis was MNT and the stage was I by the World Health Organization classification. The patient remained free of recurrence for seven years after surgery. CONCLUSION: When the lesion is completely resected, MNT has a good prognosis. Therefore, MNT is considered to be a borderline tumor with good prognosis and no reports of recurrences, distant metastasis, or tumor-related deaths exist thus far. However, preoperative diagnosis is difficult in most cases. Hence, complete surgical resection is recommended for suspicious mediastinal masses, if feasible, for both accurate diagnosis and to ensure long-term survival.

The role of innate immunity in the long-term outcome of lung transplantation.

Long-term survival after lung transplantation remains suboptimal due to chronic lung allograft dysfunction (CLAD), a progressive scarring process affecting the graft. Although anti-donor alloimmunity is central to the pathogenesis of CLAD, its underlying mechanisms are not fully elucidated and it is neither preventable nor treatable using currently available immunosuppression. Recent evidence has shown that innate immune stimuli are fundamental to the development of CLAD. Here, we examine long-standing assumptions and new concepts linking innate immune activation to late lung allograft fibrosis.

Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a heterogeneous condition. Characterization of CLAD phenotypes is essential to enhance the understanding of pathogenesis and guide new therapies. The study objective was to validate the new International Society for Heart and Lung Transplantation (ISHLT) CLAD classification system and further explore patients who do not fall into the defined CLAD sub-categories. METHODS: We performed a single-center, retrospective cohort study of adult, first, bilateral lung transplants performed from 2010 to 2015. Patients with CLAD were classified on the basis of the 2019 ISHLT consensus document. CLAD phenotypes and other potential predictors of survival after CLAD onset were assessed using Kaplan-Meier and Cox proportional hazards models. RESULTS: Among the 174 subjects with CLAD, 104 (59.8%) had bronchiolitis obliterans syndrome (BOS), 16 (9.2%) restrictive allograft syndrome (RAS), 9 (5.2%) mixed, and 19 (10.9%) undefined phenotype. A total of 26 patients (14.9%) did not match any of these 4 categories and remained unclassified. Allograft survival post-CLAD onset was longer for patients with BOS (median, 500 days) than patients with RAS (median, 372 days) or mixed (median, 328 days). The 45 patients (26.8%) with undefined/unclassified phenotype were combined and recategorized on the basis of the presence or absence of characteristic RAS-like opacities on chest imaging; those with RAS-like opacities had significantly worse allograft survival than patients with BOS (hazard ratio, 2.14; 95% confidence interval, 1.17-3.93; p = 0.014) and similar survival to RAS or mixed phenotype. CONCLUSIONS: The new ISHLT CLAD phenotype classification is informative with regards to post-CLAD outcomes. Chest imaging demonstrating persistent parenchymal or pleural fibrosis may be used for risk-stratification of patients who do not match the major CLAD phenotypes.