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Bronchiolitis obliterans syndrome (BOS) is a chronic complication following lung transplantation that limits the long-term survival. Although the enhancer of zeste homolog 2 (EZH2) is involved in post-transplantation rejection, its involvement in BOS pathogenesis remains unclear. We aimed to investigate the therapeutic potential of EZH2 inhibition in BOS. 3-deazaneplanocin A (DZNep) was administered intraperitoneally to heterotopic tracheal transplant recipient model mice. Tracheal allografts were obtained on days 7, 14, 21, and 28 after transplantation. The obstruction ratios of the DZNep and control groups on days 7, 14, 21, and 28 were 15.1% ± 0.8% vs. 20.4% ± 3.6% (p = 0.996), 16.9% ± 2.1% vs. 67.7% ± 11.5% (p < 0.001), 47.8% ± 7.8% vs. 92.2% ± 5.4% (p < 0.001), and 60.0% ± 9.6% vs. 95.0% ± 2.3% (p < 0.001), respectively. The levels of interleukin (IL)-6 and interferon-γ on day 7 and those of IL-2, tumor necrosis factor, and IL-17A on days 14, 21, and 28 were significantly reduced following DZNep treatment. DZNep significantly decreased the number of infiltrating T-cells on day 14. In conclusion, DZNep-mediated EZH2 inhibition suppressed the inflammatory reactions driven by pro-inflammatory cytokines and T cell infiltration, thereby alleviating BOS symptoms. [ABSTRACT FROM AUTHOR]

Simple Summary: Bronchitis obliterans syndrome (BOS) may occur following lung transplantation (LTx) or hematopoietic cell transplantation (HCT). The primary issue is graft-versus-host disease, complicating diagnosis. Treatment is based on empirical evidence and interdisciplinary knowledge. Recent advances emphasize understanding the etiology, clinical features, and pathobiology of BOS, fostering cross-disciplinary knowledge. Treatment algorithms are based on thorough research and expert clinical insights, with new therapies being explored to enhance survival rates and prevent LTx or re-transplantation. Background: Similar in histological characteristics and clinical manifestations, bronchiolitis obliterans syndrome (BOS) can develop following lung transplantation (LTx) or hematopoietic cell transplantation (HCT). In contrast to lung transplantation, where BOS is restricted to the lung allograft, HCT-related systemic graft-versus-host disease (GVHD) is the root cause of BOS. Because lung function declines following HCT, diagnosis becomes more difficult. Given the lack of proven effective medicines, treatment is based on empirical evidence. Methods: Cross-disciplinary learning is crucial, and novel therapies are under investigation to improve survival and avoid LTx. Recent advances have focused on updating the understanding of the etiology, clinical features, and pathobiology of BOS. It emphasizes the significance of learning from experts in other transplant modalities, promoting cross-disciplinary knowledge. Results: Our treatment algorithms are derived from extensive research and expert clinical input. It is important to ensure that immunosuppression is optimized and that any other conditions or contributing factors are addressed, if possible. Clear treatment algorithms are provided for each condition, drawing from the published literature and consensus clinical opinion. There are several novel therapies currently being investigated, such as aerosolized liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies, and B-cell-directed therapies. Conclusions: We urgently need innovative treatments that can greatly increase survival rates and eliminate the need for LTx or re-transplantation. [ABSTRACT FROM AUTHOR]

The utility of measuring serum periostin levels for predicting the occurrence of bronchiolitis obliterans syndrome (BOS) after lung transplantation remains underexplored. We analyzed differentially expressed genes (DEGs) between initially transplanted lung tissue and lung tissue with BOS from four patients. Periostin levels were assessed in 97 patients who had undergone lung transplantation 1 year post-transplantation and at the onset of BOS. The association between periostin levels and BOS, as well as their correlation with the decline in forced expiratory volume in one second (FEV1), was evaluated. Periostin levels in the BOS group were significantly higher than those in the control group (p < 0.001) and the stable group (p < 0.001). Periostin levels at the onset of BOS were significantly higher than those 1 year post-transplantation in the BOS group (p < 0.001). The serum periostin levels at the time of BOS diagnosis showed a positive correlation with the reduction in FEV1 (%) (r = 0.745, p < 0.001). The increase in the serum periostin levels at the time of BOS diagnosis compared with those 1 year post-transplantation was positively correlated with reduction in FEV1 (%) (r = 0.753, p < 0.001). Thus, serum periostin levels may serve as biomarkers for predicting a decline in lung function in patients with BOS after lung transplantation. [ABSTRACT FROM AUTHOR]

Long-term survival after lung transplantation (LTx) remains limited by chronic lung allograft dysfunction (CLAD), which includes 2 main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types. Peripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, and epithelial and vascular abnormalities. CLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in histologic scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p = 0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes, and airway fibrosis. Immunofluorescence staining demonstrated a trend toward a lower frequency of club cells in CLAD and a higher frequency of apoptotic club cells in BOS samples (p = 0.01). CLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathologic changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD histologic assessments. [ABSTRACT FROM AUTHOR]

Criteria for airflow obstruction (AFO) at one year after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in pulmonary function tests (PFTs) are more stringent than the bronchiolitis obliterans syndrome (BOS) criteria of the National Institutes of Health. This single-center, retrospective cohort study evaluated the clinical impact of the AFO criteria at any time after transplantation. In 132 patients who underwent allo-HSCT from 2006 to 2016, the 2-year cumulative incidence of AFO was 35.0%, and the median time to diagnosis of AFO was 101 days after transplantation (range 35–716 days). Overall chronic graft-versus-host disease (cGVHD) incidence was significantly higher in patients with AFO than in those without AFO (80.4% vs. 47.7%, P < 0.01); notably, 37.0% of patients with AFO developed cGVHD after AFO diagnosis. AFO patients developed BOS with a 5-year cumulative incidence of 49.1% after AFO onset. The 5-year cumulative incidence of non-relapse mortality in the AFO group was higher than that in the non-AFO group (24.7% vs. 7.1%, P < 0.01). These results suggest that closely monitoring PFTs within two years after allo-HSCT, regardless of cGVHD status, is important for early detection of AFO and prevention of progression to BOS. (192words). [ABSTRACT FROM AUTHOR]

Whereas aGVHD has strong inflammatory components, cGVHD displays autoimmune and fibrotic features; incidence and risk factors are similar but not identical; indeed, the aGVHD is the main risk factor for cGVHD. Calcineurin Inhibitors (CNI) with either Methotrexate (MTX) or Mycophenolate (MMF) still represent the standard prophylaxis in HLA-matched allogeneic stem cell transplantation (HSCT); other strategies focused on ATG, Post-Transplant Cyclophosphamide (PTCy), Abatacept and graft manipulation. Despite the high rate, first-line treatment for aGVHD is represented by corticosteroids, and Ruxolitinib is the standard second-line therapy; investigational approaches include Microbiota transplant and the infusion of Mesenchymal stem cells. GVHD is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. It is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. Extracorporeal Photopheresis (ECP) is still an option used for steroid refractoriness or to achieve a steroid-sparing. For Ruxolitinib-refractory cGVHD, Belumosudil and Axatilimab represent the most promising agents. Bronchiolitis obliterans syndrome (BOS) still represents a challenge; among the compounds targeting non-immune effectors, Alvelestat, a Neutrophil elastase inhibitor, seems promising in BOS. Finally, in both aGVHD and cGVHD, the association of biological markers with specific disease manifestations could help refine risk stratification and the availability of reliable biomarkers for specific treatments. [ABSTRACT FROM AUTHOR]

Background: Our aim is to investigate cardiovascular risk factors, chronic graft-versus-host disease (CGvHD), and vitamin D metabolism in very long-term survivors of adult allogeneic stem cell transplantation (alloSCT). Methods: This study is a prospective unicentric, non-interventional trial. The detailed study protocol is available via the WHO Clinical Trial Registry. Results: We were able to include 33 patients with a mean age of 60.5 years (SD 11.1). Acute myeloid leukemia (AML) was the most frequent underlying disease (n = 12; 36.4%). The median survival time was 9.0 years (IQR 8.5–13.0). Relevant cardiovascular risk factors in the study population are the body mass index, cholesterol, LDL cholesterol, and lipoprotein(a). Cardiovascular risk factors have no significant impact on HRQoL. CGvHD of the skin as a limited disease was present in six patients (18.2%), and it has no impact on HRQoL. CGvHD was significantly associated with eosinophilia in peripheral blood (p = 0.003). Three patients (9.1%) had a shortage of calcitriol, and one patient (3.0%) took calcium substitution. The shortage is significantly associated with increased infection rates (p = 0.038). Conclusions: Cardiovascular risk factors and CGvHD need to be closely monitored. Eosinophilia might be a good and convenient monitoring parameter for CGvHD. [ABSTRACT FROM AUTHOR]

Background: Despite the fundamental progress in hematopoietic stem cell transplant, this treatment is also associated with complications. Graft-versus-host disease is a possible complication of HSCT. Bronchiolitis obliterans syndrome (BOS) is the pulmonary form of this syndrome. Due to the high morbidity and mortality rate of BOS, various studies have been conducted in the field of drug therapy for this syndrome, although no standard treatment has yet been proposed. According to the hypotheses about the similarities between BOS and chronic obstructive pulmonary disease, the idea of using tiotropium bromide as a bronchodilator has been proposed. Method/design: A randomized, double-blind, placebo-controlled, and crossover clinical trial is being conducted to evaluate the efficacy of tiotropium in patients with BOS. A total of 20 patients with BOS were randomly assigned (1:1) to receive a once-daily inhaled capsule of either tiotropium bromide (KP-Tiova Rotacaps 18 mcg, Cipla, India) or placebo for 1 month. Patients will receive tiotropium bromide or placebo Revolizer added to usual standard care. Measurements will include spirometry and a 6-min walking test. Ethics/dissemination: This study was approved by the Research Ethics Committees of Imam Khomeini Hospital Complex, Tehran University of Medical Science. Recruitment started in September 2022, with 20 patients randomized. The treatment follow-up of participants with tiotropium is currently ongoing and is due to finish in April 2024. The authors will disseminate the findings in peer-reviewed publications, conferences, and seminar presentations. Trial registration: Iranian Registry of Clinical Trial (IRCT) IRCT20200415047080N3. Registered on 2022–07-12, 1401/04/21. [ABSTRACT FROM AUTHOR]

Background: The development of connective tissue disease‐associated lung diseases (CTD‐LD) occurs in association with specific human leukocyte antigens (HLA). For CTD‐LD patients who require lung transplant, it is unknown whether utilization of donor organs expressing these same HLA impacts posttransplant outcomes. Methods: Using the Scientific Registry of Transplant Recipients, we assessed whether CTD‐LD lung transplant recipients in the United States have worse bronchiolitis obliterans (BOS)‐free survival based on the degree of donor HLA matching. This included overall degree of donor‐recipient HLA matching, donor‐recipient matching at DR loci, and recipient matching with specific donor HLA antigens associated with the development of pulmonary disease in their condition. Results: Among 1413 patients with CTD‐ILD, highly HLA‐matched donor‐recipients did not have worse adjusted survival (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.58–1.51, p = 0.77). Recipients who were fully matched at HLA DR did not have worse survival (HR = 0.82, 95% CI = 0.56–1.19, p = 0.29). Finally, among individual CTD‐LD, including rheumatoid arthritis, systemic sclerosis, the idiopathic inflammatory myopathies, and systemic lupus erythematous, transplant with a donor expressing HLA antigens associated with lung manifestations in these conditions was not associated with worse BOS‐free survival. Conclusions: Among transplant recipients with CTD‐LD, HLA donor‐recipient matching, including at the DR loci, does not result in worse BOS‐free survival. Based on these findings, there is no reason to treat these as unacceptable antigens when considering donor offers for CTD‐LD candidates. [ABSTRACT FROM AUTHOR]

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory syncytial virus (RSV) can cause severe respiratory infections in adults; however, information on associated sequelae is limited. This systematic literature review aimed to identify sequelae in adults within 1 year following RSV-related hospitalization or resolution of acute infection. Methods: Studies were identified from Embase, MEDLINE, LILACS, SciELO, and grey literature. Random-effects meta-analyses using restricted maximum likelihood were used to calculate the proportions and relative risks of sequelae in patients with RSV compared with controls (patients with RSV-negative influenza-like illness, influenza, and parainfluenza) per follow-up period, population, and treatment setting, where possible. Results: Twenty-one relevant studies covering the period from 1990 to 2019 were included. Among the general population, the most frequent clinical sequela was sustained function loss (33.5% [95% CI 27.6–39.9]). Decline in lung function and cardiovascular event or congestive heart failure were also identified. Utilization sequelae were readmission (highest at > 6 months after discharge) and placement in a skilled nursing facility. The only subpopulation with data regarding sequelae was transplant patients. Among lung transplant patients, the most frequently reported clinical sequelae were decline in lung function, followed by graft dysfunction and bronchiolitis obliterans syndrome. Pooled relative risks were calculated for the following sequela with controls (primarily influenza-positive patients): cardiovascular event (general population) and pulmonary impairment (hematogenic-transplant patients) both 1.4 (95% CI 1.0–2.0) and for readmission (general population) 1.2 (95% CI 1.1–1.3). Conclusions: Although less data are available for RSV than for influenza or other lower respiratory tract infections, RSV infection among adults is associated with medically important sequelae, with a prevalence similar to other respiratory pathogens. RSV sequelae should be included in disease burden estimates. [ABSTRACT FROM AUTHOR]

• Prevalence of chronic lung allograft dysfunction (CLAD) in our cohort was 29%. • BMI category at lung transplant (LTx) was not associated with the risk of CLAD. • Post-transplant weight/BMI gain was associated with a greater risk of RAS. Chronic lung allograft dysfunction (CLAD) is a lung transplant complication for which four phenotypes are recognized: Bronchiolitis obliterans syndrome (BOS), Restrictive allograft syndrome (RAS), mixed and undefined phenotypes. Weight gain is common after transplant and may negatively impact lung function. Study objectives were to describe post-transplant weight trajectories of patients who developed (or did not) CLAD phenotypes and examine the associations between BMI at transplant, post-transplant changes in weight and BMI, and the risk of developing these phenotypes. Adults who underwent a bilateral lung transplant between 2000 and 2020 at our institution were categorized as having (or not) one of the four CLAD phenotypes based on the proposed classification system. Demographic, anthropometric, and clinical data were retrospectively collected from medical records and analyzed. Study population included 579 recipients (412 [71.1%] CLAD-free, 81 [14.0%] BOS, 20 [3.5%] RAS, 59 [10.2%] mixed, and 7 [1.2%] undefined phenotype). Weight gains of greater amplitude were seen in recipients with restrictive phenotypes than CLAD-free and BOS patients within the first five years post-transplant. While the BMI category at transplant was not statistically associated with the risk of developing CLAD phenotypes, an increase in weight (Hazard ratio [HR]: 1.04, 95% CI [1.01-1.08]; P =.008) and BMI (HR: 1.13, 95% CI [1.03-1.23]; P =.008) over the post-transplant period was associated with a greater risk of RAS. Post-LTx gain in weight and BMI modestly increased the risk of RAS, adding to the list of unfavorable outcomes associated with weight gain following transplant. [ABSTRACT FROM AUTHOR]

Respiratory complications following allogeneic HSCT can lead to severe morbidity and mortality. Lung transplantation (LT) is a potential treatment for select patients with late-onset non-infectious pulmonary complications post-HSCT. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for monitoring the health of allografts following LT. However, its utility in a multi-genome setting of LT after HSCT has not yet been clinically validated. Here we describe a case of a 75-year-old, male patient who underwent single-lung transplantation for BOS related to chronic GVHD and presented with persistently elevated dd-cfDNA levels. In a surveillance biopsy, the patient was diagnosed with mild acute cellular rejection at three months. The patient's lung function remained stable, and the reported dd-cfDNA levels decreased after the rejection episode but remained elevated above levels that would be considered quiescent for LT alone. In this unique setting, as 3 different genomes contributed to the dd-cfDNA% reported value, valuable insight was obtained by performing further analysis to separate the specific SNPs to identify the contribution of recipient, lung-donor, and HSCTdonor cfDNA. This study highlights the potential utility of dd-cfDNA in the multi-genome setting of lung transplant post-HSCT, nuances that need to be considered while interpreting the results, and its value in monitoring lung rejection. [ABSTRACT FROM AUTHOR]

Background: Due to development of chronic lung allograft dysfunction (CLAD), prognosis for patients undergoing lung transplantation (LTx) is still worse compared to other solid organ transplant recipients. Treatment options for slowing down CLAD progression are scarce with extracorporeal photopheresis (ECP) as an established rescue therapy. The aim of the study was to identify characteristics of responders and non‐responders to ECP treatment, assess their survival, lung function development and by that define the subset of patients who should receive early ECP treatment. Methods: We performed a retrospective study of all LTx patients receiving ECP treatment at the University Hospital Zurich between January 2010 and March 2020. Patients were followed‐up for a maximum period of 5 years. Mortality and lung function development were assessed by CLAD stage and by CLAD subtype before initiation of ECP treatment. Results: Overall, 105 patients received at least one ECP following LTx. A total of 57 patients (61.3%) died within the study period with a median survival of 15 months. Mortality was 57% for patients who started ECP at CLAD1, 39% for CLAD2, 93% for CLAD3, and 90% for CLAD4 (p < 0.001). Survival and lung function development was best in young patients at early CLAD stages 1 and 2. Response to ECP treatment was worst in patients with CLAD‐RAS/mixed subtype (14.3%) and patients with ECP initiation in CLAD stages 3 (7.1%) and 4 (11.1%). Survival was significantly better in a subset of patients with recurrent acute allograft dysfunction and earlier start of ECP treatment (105 vs 15 months). Conclusion: In this retrospective analysis of a large group of CLAD patients treated with ECP after LTx, early initiation of ECP was associated with better long‐term survival. Besides a subset of patients suffering of recurrent allograft dysfunction, especially a subset of patients defined as responders showed an improved response rate and survival, suggesting that ECP should be initiated in early CLAD stages and young patients. ECP might therefore prevent long‐term disease progression even in patients with CLAD refractory to other treatment options and thus prevent or delay re‐transplantation. [ABSTRACT FROM AUTHOR]

Bronchiolitis obliterans syndrome (BOS) is a chronic complication following lung transplantation that limits the long-term survival. Although the enhancer of zeste homolog 2 (EZH2) is involved in post-transplantation rejection, its involvement in BOS pathogenesis remains unclear. We aimed to investigate the therapeutic potential of EZH2 inhibition in BOS. 3-deazaneplanocin A (DZNep) was administered intraperitoneally to heterotopic tracheal transplant recipient model mice. Tracheal allografts were obtained on days 7, 14, 21, and 28 after transplantation. The obstruction ratios of the DZNep and control groups on days 7, 14, 21, and 28 were 15.1% ± 0.8% vs. 20.4% ± 3.6% (p = 0.996), 16.9% ± 2.1% vs. 67.7% ± 11.5% (p < 0.001), 47.8% ± 7.8% vs. 92.2% ± 5.4% (p < 0.001), and 60.0% ± 9.6% vs. 95.0% ± 2.3% (p < 0.001), respectively. The levels of interleukin (IL)-6 and interferon-γ on day 7 and those of IL-2, tumor necrosis factor, and IL-17A on days 14, 21, and 28 were significantly reduced following DZNep treatment. DZNep significantly decreased the number of infiltrating T-cells on day 14. In conclusion, DZNep-mediated EZH2 inhibition suppressed the inflammatory reactions driven by pro-inflammatory cytokines and T cell infiltration, thereby alleviating BOS symptoms.

The article presents case studies of three pediatric patients with steroid-refractory gastrointestinal graft-versus-host disease (GVHD) who were treated with vedolizumab. It discusses the retrospective analysis of these patients who underwent allogeneic hematopoietic cell transplantation and later developed severe gastrointestinal GVHD. It is reported that Vedolizumab, an anti-α4β7 integrin antibody, was administered off-label as a treatment after the failure of first-line therapies.

BACKGROUND: HLA haploid allogeneic hematopoietic stem cell transplantation provides a chance of survival for patients with high-risk hematologic malignancies. In recent years, the research on the transplantation mode and graft selection of haploidentical transplantation is still ongoing. At present, the mixed transplantation model of non-extracorporeal T-cell removal bone marrow and peripheral blood stem cells established by the Hematology Research Center of Peking University is gradually becoming popular in China, but this model requires the collection of donor bone marrow fluid, which increases the pain and risk of the donor. OBJECTIVE: To explore the curative effect of infusion of umbilical cord mesenchymal stem cells replacing donor bone marrow cells in haploidentical peripheral blood hematopoietic stem cell transplantation for malignant hematological diseases. METHODS: Fifty hematological malignancies patients who underwent haploidentical hematopoietic stem cell transplantation from January 2019 to May 2022 were selected and randomly assigned to two study groups at a ratio of 2:3. Among them, 19 patients received umbilical cord mesenchymal stem cell combined with peripheral blood stem cell transplantation, and 31 patients were treated with bone marrow cells combined with peripheral blood stem cells. The study was approved by the Ethics Committee of Henan Provincial People’s Hospital. The recipients of umbilical cord mesenchymal stem cells were first transfused with third-party umbilical cord mesenchymal stem cells (1×106 /kg) on the day of transplantation, followed by peripheral blood hematopoietic stem cells 6 hours later. In the bone marrow group, donor bone marrow cells were transfused +1 day after transplantation and peripheral blood stem cells were transfused +2 days after transplantation. After transplantation, rabbit anti-human thymocyte immunoglobulin, cyclosporine A, mycophenolate mofetil, and a short-course methotrexate were used for graft-versus-host disease prophylaxis for all recipients. RESULTS AND CONCLUSION: No adverse events occurred during the reinfusion of umbilical cord mesenchymal stem cells. There were no significant differences between the mesenchymal stem cell group and the bone marrow group in the engraftment rate [100% (19/19) vs. 96.8%(30/31), P > 0.05], median duration for neutrophil engraftment (14 days vs.15 days, P > 0.05) and median duration for platelet engraftment (20 days vs.19 days, P > 0.05). The incidence of grade IIIV acute graft-versus-host disease in the mesenchymal stem cell group was significantly lower than in the bone marrow group [21.1% (4/19) vs. 58.1% (18/31), P = 0.01]. There were no significant differences between the two groups in the incidence of chronic graft-versus-host disease [21.1% (4/19) vs. 25.8% (8/31), P > 0.05], the relapse rates [15.8% (3/19) vs. 16.1% (5/31), P > 0.05] and the incidence of early cytomegalovirus viremia [42.1% (8/19) vs. 35.5% (11/31), P > 0.05], and the 2-year overall survival rate [68.4% (10/19) vs. 70.9% (16/31), P > 0.05]. It is indicated that umbilical cord mesenchymal stem cells replace donor bone marrow cells in haploidentical peripheral blood stem cell transplantation for malignant hematological diseases, which reduced the incidence of acute graft-versus-host disease after transplantation, did not increase the incidence of chronic graft-versus-host disease, recurrence rate and early cytomegalovirus viremia, and reduced the pain and risk of donor pulp extraction. [ABSTRACT FROM AUTHOR]

Reoperative lung transplantation (LTx) survival has improved over time such that a growing number of patients may present for third-time LTx (L3Tx). To understand the safety of L3Tx, we evaluated perioperative outcomes and 3-year survival after L3Tx at a high-volume US LTx center. This retrospective study included all patients who underwent bilateral L3Tx at our institution. Using an optimal matching technique, a primary LTx (L1Tx) cohort was matched 1:2 and a second-time LTx (L2Tx) cohort 1:1. Recipient, operative, and donor characteristics, perioperative outcomes, and 3-year survival were compared among L1Tx, L2Tx, and L3Tx groups. Eleven L3Tx, 11 L2Tx, and 22 L1Tx recipients were included. Among L3Tx recipients, median age at transplant was 37 years and most (73%) had cystic fibrosis. L3Tx was performed median 6.0 and 10.6 years after L2Tx and L1Tx, respectively. Compared to L1Tx and L2Tx recipients, L3Tx recipients had greater intraoperative transfusion requirements, a higher incidence of postoperative complications, and a higher rate of unplanned reoperation. Rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation at 72 hours, reintubation, and in-hospital mortality were similar among groups. There were no differences in 3-year patient (log-rank p = 0.61) or rejection-free survival (log-rank p = 0.34) after L1Tx, L2Tx, and L3Tx. At our institution, L3Tx was associated with similar perioperative outcomes and 3-year patient survival compared to L1Tx and L2Tx. L3Tx represents the only safe treatment option for patients with allograft failure after L2Tx; however, further investigation is needed to understand the long-term survival and durability of L3Tx. [ABSTRACT FROM AUTHOR]

Objective To evaluate clinical efficacy of lung transplantation for lung chronic graft-versus-host disease (cGVHD) after hematopoietic stem cell transplantation (HSCT). Methods Clinical data of 12 patients undergoing lung transplantation for lung cGVHD were retrospectively analyzed. Preoperative clinical manifestations and involved organs of patients were analyzed. The lung function before and after lung transplantation was compared, and the survival of patients after lung transplantation was analyzed. Results Eleven patients underwent HSCT due to primary hematological malignancies, including 9 cases of leukemia, 1 case of myelodysplastic syndrome, 1 case of lymphoma. And 1 case underwent HSCT for systemic lupus erythematosus. Among 12 cGVHD patients, skin involvement was found in 8 cases, oral cavity involvement in 5 cases, gastrointestinal tract involvement in 4 cases and liver involvement in 3 cases. All 12 patients developed severe respiratory failure caused by cGVHD before lung transplantation, including 9 cases of typeⅡ respiratory failure and 3 cases of type Ⅰ respiratory failure. Two patients underwent right lung transplantation, 2 cases of left lung transplantation and 8 cases of bilateral lung transplantation. The interval from HSCT to lung transplantation was 75 (19-187) months. Upon the date of submission, postoperative follow-up time was 18 (7-74) months. Ten patients survived, 1 died from severe hepatitis at postoperative 22 months, and 1 died from gastrointestinal bleeding at postoperative 6 months. No recurrence of primary diseases was reported in surviving patients. Conclusions Lung transplantation is an efficacious treatment for lung cGVHD after HSCT, which may prolong the survival time and improve the quality of life of the recipients. [ABSTRACT FROM AUTHOR]

Tracheobronchomalacia (TBM) occurs due to the weakening of cartilaginous part of the trachea, resulting in compromised airway function and leading to symptoms such as dyspnea, cough, and inability to clear secretions. Bronchiolitis obliterans syndrome (BOS) is the most prevalent late noninfectious pulmonary complication in patients who underwent allogeneic haematopoietic stem cell transplantation (HSCT). Therefore, patients experiencing progressive dyspnea and chronic cough after allogenic HSCT, with new obstructive pattern on pulmonary function test, are typically diagnosed with post‐transplant BOS. However, it is important to note that TBM can also manifest as an obstructive defect pattern on pulmonary function test. Tracheomalacia has been reported as a rare complication of allogenic stem cell transplantation. We present two patients who developed TBM following allogeneic HSCT and were initially treated for post‐transplant BOS but did not experience symptom improvement. However, after treatment with continuous positive airway pressure, their symptom subsided. [ABSTRACT FROM AUTHOR]

Obejective: To explore the diagnostic and therapeutic effect of ultra-fine bronchoscopic interventional in bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Methods: Retrospective analysis of clinical data of 2 patients with BOS diagnosed 3 months after transplantation were collected, and the characteristics of diagnosis and therapeutics of BOS were analyzed. Results: The time from Allo-HSCT to diagnosed of BOS in 2 patients in our hospital was within 3 months after transplantation, the clinical manifestations were chest tightness and shortness of breath after activity, and mixed ventilation dysfunction in lung function, Under the direct vision of ultra-fine bronchoscopy, the membrane-like hyperplasia of the lumen orifice of the bronchioles of grade 6 and above in the left and right sides could block the lumen was observed, and the occluded airway could be opened by mechanical expansion or freezing with biopsy forceps, no examination-related complications occurred during and after the operation, the symptoms of the patients were significantly improved compared with the previous ones after treatment, One patient was followed up and the original occluded bronchiole lumen was continuously open after treatment under bronchoscopy. Conclusion: Ultra-fine bronchoscopy can effectively diagnose BOS after Allo-HSCT, and can also open bronchioles through respiratory interventional therapy to improve short-term lung function. [ABSTRACT FROM AUTHOR]

Purpose: Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). Methods: We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. Results: Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). Conclusions: CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restriction on PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT. [ABSTRACT FROM AUTHOR]

Lung and hematopoietic stem cell transplantation are therapeutic modalities in chronic pulmonary and hematological diseases, respectively. One of the complications in these patients is the development of bronchiolitis obliterans syndrome (BOS). The efficacy and safety of available treatment strategies in BOS remain a challenge. A few mechanisms have been recognized for BOS in lung transplant and graft- versus -host disease (GVHD) patients involving the TH-1 and TH-2 cells, NF-kappa B, TGF-b, several cytokines and chemokines, and cysteinyl leukotrienes (CysLT). Montelukast is a highly selective CysLT receptor antagonist that has been demonstrated to exert anti-inflammatory and anti-fibrotic effects in abundant experiments. One area of interest for the use of montelukast is lung transplants or GVHD-associated BOS. Herein, we briefly review data regarding the mechanisms involved in BOS development and montelukast administration as a treatment modality for BOS, and finally, the possible relationship between CysLTs antagonism and BOS improvement will be discussed. Plain language summary: A review of the therapeutic potential and possible mechanism of Montelukast in the treatment of bronchiolitis obliterans syndrome following lung and hematopoietic stem cell transplantation Lung and bone marrow transplantation are therapeutic modalities in chronic diseases of the lungs and the blood, respectively. One of the complications in these patients is the development of Bronchiolitis obliterans syndrome (BOS). The efficacy and safety of available treatment strategies in BOS remain a challenge. A few mechanisms for BOS in lung transplant and graft-versus-host disease (GVHD) patients involving many immune components have been recognized. Cysteinyl leukotrienes are products of plasma membrane phospholipids that increase smooth muscle contraction, microvascular permeability, and airway mucus secretion. Montelukast is a highly selective cysteinyl leukotriene receptor blocker demonstrated to exert anti-inflammatory and anti-fibrotic effects. One area of interest for the use of montelukast is in lung transplant- or GVHD-associated BOS. In this article, we briefly review data regarding the mechanisms involved in BOS development and montelukast administration as a treatment modality for BOS. Finally, the possible relationship between cysteinyl leukotriene inhibition and BOS improvement will be discussed. [ABSTRACT FROM AUTHOR]

The utility of measuring serum periostin levels for predicting the occurrence of bronchiolitis obliterans syndrome (BOS) after lung transplantation remains underexplored. We analyzed differentially expressed genes (DEGs) between initially transplanted lung tissue and lung tissue with BOS from four patients. Periostin levels were assessed in 97 patients who had undergone lung transplantation 1 year post-transplantation and at the onset of BOS. The association between periostin levels and BOS, as well as their correlation with the decline in forced expiratory volume in one second (FEV1), was evaluated. Periostin levels in the BOS group were significantly higher than those in the control group (p < 0.001) and the stable group (p < 0.001). Periostin levels at the onset of BOS were significantly higher than those 1 year post-transplantation in the BOS group (p < 0.001). The serum periostin levels at the time of BOS diagnosis showed a positive correlation with the reduction in FEV1 (%) (r = 0.745, p < 0.001). The increase in the serum periostin levels at the time of BOS diagnosis compared with those 1 year post-transplantation was positively correlated with reduction in FEV1 (%) (r = 0.753, p < 0.001). Thus, serum periostin levels may serve as biomarkers for predicting a decline in lung function in patients with BOS after lung transplantation.

The article provides a review of the year 2023 for the journal LUNG. The journal experienced growth and progress, with a rise in impact factor and strong numbers of article downloads. The field of cough was a focus, with articles covering various aspects of cough and antitussive drug development. Other topics covered in the journal included sarcoidosis, bronchiectasis, obstructive airways disease, lung cancer, COVID-19, pulmonary infectious diseases, lung transplantation, critical care, and preclinical and translational research. The editorial team is motivated to continue improving the journal and expanding its readership. [Extracted from the article]

Extracorporeal photopheresis (ECP) is used by few lung transplant centers to treat chronic lung allograft dysfunction (CLAD). Although reported results suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of this study is to analyze outcomes of ECP in a large multicenter European cohort. The primary endpoint was patient survival after initiation of ECP. This study included 631 patients, 87% suffered from bronchiolitis obliterans syndrome (BOS), and 13% had restrictive allograft syndrome (RAS). Long-term stabilization was achieved in 42%, improvement in 9%, and no response in 26%. Within the first 12 months of therapy, 23% of patients died. Patients' survival after initiation of ECP at 5 years was 56% in stable, 70% in responders, and 35% in nonresponders (p = 0.001). In multivariable Cox regression, both stabilization (HR: 0.48, CI: 0.27-0.86, p = 0.013) and response (HR: 0.11, CI: 0.04-0.35, p < 0.001) to ECP were associated with survival. Absolute FEV1 at baseline was also protective (HR: 0.09, CI: 0.01-0.94, p = 0.046). RAS phenotype was the only risk factor for mortality (HR: 2.11, 1.16-3.83, p = 0.006). This study provides long-term outcomes of ECP use in CLAD patients in the largest published cohort to date. Two-thirds of the cohort had a sustained response to ECP with excellent long-term results. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is one of the common manifestations of end‐stage lung disease. Chronic lung failure after lung transplantation is mainly caused by bronchiolitis obliterans syndrome (BOS) and is mainly characterized by lung tissue fibrosis. Pulmonary epithelial‐mesenchymal transformation (EMT) is crucial for pulmonary fibrosis. Telocytes (TCs), a new type of mesenchymal cells, play a protective role in various acute injuries. For exploring the anti‐pulmonary fibrosis effect of TCs in the BOS model in vitro and the related mechanism, rat tracheal epithelial (RTE) cells were treated with transforming growth factor‐β (TGF‐β) to simulate lung tissue fibrosis in vitro. The RTE cells were then co‐cultured with TCs primarily extracted from rat lung tissue. Western blot, Seahorse XF Analysers and enzyme‐linked immunosorbent assay were used to detect the level of EMT and aerobic respiration of RTE cells. Furthermore, anti‐hepatocyte growth factor (anti‐HGF) antibody was exogenously added to the cultured cells to explore further mechanisms. Moreover, hexokinase 2 (HK2) in RTE cells was knocked down to assess whether it influences the blocking effect of the anti‐HGF antibody. TGF‐β could induce lung tissue fibrosis in RTE cells in vitro. Nevertheless, TCs co‐culture decreased the level of EMT, glucose metabolic indicators (lactate and ATP) and oxygen levels. Furthermore, TCs released hepatocyte growth factor (HGF). Therefore, the exogenous addition of anti‐HGF antibody in the co‐culture system blocked the anti‐lung tissue fibrosis effect. However, HK2 knockdown attenuated the blocking effect of the anti‐HGF antibody. In conclusion, TCs can protect against lung tissue fibrosis by releasing HGF, a process dependent on HK2. [ABSTRACT FROM AUTHOR]

After lung transplant, 2 common complications are calcineurin inhibitor (CNI) induced nephrotoxicity and bronchiolitis obliterans syndrome. The objective of this study was to investigate the long-term effects of sirolimus conversion after lung transplantation. This was a retrospective cohort study of patients who had undergone lung transplantation at a single center from June 2003 to December 2016. We compared patients converted to a sirolimus-based regimen to those maintained on our standard tacrolimus-based regimen. Kidney function, pulmonary function, and immunosuppression concentrations were compared between the groups. Additionally, indications, toxicity monitoring parameters, and discontinuation rates for sirolimus were collected. During the study period, 176 of the 205 patients who underwent lung transplants were converted to a sirolimus-containing regimen (86%). The most common reason for sirolimus initiation was impairment of kidney function or CNI-associated neurotoxicity. Sirolimus was initiated at a median of 150 days post-transplantation and continued for a medium time of 5.02 (2.27-7.85) years. Of those patients converted to sirolimus, 39 (22%) had sirolimus subsequently discontinued secondary to an adverse event. No difference in pulmonary function was found between the groups at 1- and 3-years post-transplantation. In the sirolimus group, the median estimated glomerular filtration rate improved by 8.6 mL/min/1.73 m2 at 3 months post-conversion (P <.001) , which was maintained at both 1 and 3 years (P =.014 and.025, respectively). Sirolimus is a viable immunosuppressant option after lung transplant, which successfully allows for the reduction or withdrawal of the CNI, resulting in sustained improvement in kidney function. [ABSTRACT FROM AUTHOR]

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of death after the first postoperative years of lung transplantation (LTx). Objective: To assess the number of disability-adjusted life years (DALYs) per patient with severe CLAD. Methods: The clinical and demographic data of patients who received their lung transplantation between 2010 and 2020 in the Hanover Medical School (Germany) were evaluated. Results: A total of 1025 lung transplant patients were followed for a median of 51 months (4.25 years); the median age at transplantation was 52.8 (interquartile range (IQR) 19) years. More than a quarter of transplant patients (271/1025 or 26.4%) developed CLAD, mostly (60%) of the bronchiolitis obliterans syndrome (BOS) phenotype. Of the CLAD patients, 99, or 36.5%, suffered from significant disability, which on average occurred after 2 years (IQR 2.55). The survival of CLAD patients with disability after transplantation was significantly lower compared to that of patients without CLAD (median 4.04 versus 5.41 years). Adjusted to the DALY estimation approach, CLAD patients lost 1.29 life years (YLL) and lived for 0.8 years with their disability (YLD), adding up to 2.09 DALYs (range 1.99–2.72) per patient. Conclusions: CLAD after lung transplantation is a major public health problem and is associated with substantial disability and costs. Further work is needed to develop therapeutic interventions that reduce its development.

Lung transplant recipients are at higher risk of developing COVID-19 infection compared to other solid organ transplants. The risk further increases in the unvaccinated patients. We present a case of a 43-year-old male who underwent bilateral sequential lung transplantation for pulmonary alveolar microlithiasis (PAM) and had an uneventful recovery. However, two years post-transplantation, the patient developed chronic lung allograft dysfunction (CLAD) with bronchiolitis obliterans syndrome and two episodes of COVID-19 infection. During the second episode of COVID-19 infection, the patient developed sepsis and multi-organ dysfunction ultimately resulting in death. Our case report highlights the increased susceptibility of PAM patients' post-lung transplant to COVID-19 infection. Continuous follow-up of PAM patients' post-lung transplantation is necessary to prevent unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Bronchiolitis obliterans (BO) is a form of graft-versus-host disease (GVHD) in the lung and manifests as moderate to severe airflow obstruction after hematopoietic stem cell transplantation (HCT). New-onset airflow obstruction on spirometry is considered diagnostic of bronchiolitis obliterans syndrome (BOS). BOS affects about 5% of all HCT recipients. In general, BO is thought of as a late complication of HCT, usually occurring after day 100 post-transplantation. However, the onset of airflow obstruction can be rapid and is most often irreversible even with treatment. We describe a patient who rapidly developed severe airflow obstruction less than one month after transplantation following the development of upper airway symptoms. Despite aggressive immunosuppression, the patient had no improvement in airflow obstruction. We hypothesize that early screening and treatment may help prevent BOS after HCT.

Introduction: The percentage of low attenuation area (%LAA) on computed tomography (CT) is useful for evaluating lung emphysema, and higher %LAA was observed in patients with chronic lung allograft dysfunction (CLAD). This study investigated the relationship between the %LAA and the development of CLAD after bilateral lung transplantation (LT). Methods: We conducted a single‐center retrospective study of 75 recipients who underwent bilateral LT; the recipients were divided into a CLAD group (n = 30) and a non‐CLAD group (n = 45). The %LAA was calculated using CT and compared between the two groups from 4 years before to 4 years after the diagnosis of CLAD. The relationships between the %LAA and the percent baseline values of the pulmonary function test parameters were also calculated. Results: The %LAA was significantly higher in the CLAD group than in the non‐CLAD group from 2 years before to 2 years after the diagnosis of CLAD (P <.05). In particular, patients with bronchiolitis obliterans syndrome (BOS) exhibited significant differences even from 4 years before to 4 years after diagnosis (P <.05). Significant negative correlations between the %LAA and the percent baseline values of the forced expiratory volume in 1 s (r = −.36, P =.0031), the forced vital capacity (r = −.27, P =.027), and the total lung capacity (r = −.40, P <.001) were seen at the time of CLAD diagnosis. Conclusion: The %LAA on CT was associated with the development of CLAD and appears to have the potential to predict CLAD, especially BOS, after bilateral LT. [ABSTRACT FROM AUTHOR]

Objective: Chronic graft‐versus‐host disease (cGVHD) is the main cause of late non‐relapse mortality following hematopoietic cell transplantation. Oral mucosal (om‐) cGVHD is common, but diagnosis and assessment rely on clinical interpretation and patient‐reported symptoms. We investigated immunohistopathological profiles with respect to om‐cGVHD severity disease duration. Material and methods: Ninety‐four transplant patients and 15 healthy controls (n = 212 biopsies) were investigated by quantitative immunohistochemistry for T cells (CD4, CD8, and CD5), B cells (CD19 and CD20), macrophages (CD68), and Langerhans cells (CD1a). Results: We found significant increases in T (CD4, CD8) and monocytic (CD68) cells in om‐cGVHD, and a notable absence of B (CD19 and CD20) cells. Histopathological activity correlated with increased CD4, CD8 and CD68. However, CD4 was associated with mild om‐cGVHD, whereas CD8 and CD68 were found to be elevated in severe om‐cGVHD. CD8 and CD68 levels were raised at disease onset, but during late phase, the predominant CD68 population was accompanied by CD4. Conclusion: Oral cGVHD is a heterogenous clinical disorder, but our knowledge of the underlying biology remains limited. We highlight the importance of CD4, CD8 and CD68 immune profiling, together with histological grading for the staging of oral cGVHD, to broaden our understanding of the biology and individual disease course. [ABSTRACT FROM AUTHOR]

Lung transplantation is the major surgical procedure, which restores normal lung functioning and provides years of life for patients suffering from major lung diseases. Lung transplant recipients are at high risk of primary graft dysfunction, and chronic lung allograft dysfunction (CLAD) in the form of bronchiolitis obliterative syndrome (BOS). Regulatory T cell (Treg) suppresses effector cells and clinical studies have demonstrated that Treg levels are altered in transplanted lung during BOS progression as compared to normal lung. Here, we discuss levels of Tregs/FOXP3 gene expression as a crucial prognostic biomarker of lung functions during CLAD progression in clinical lung transplant recipients. The review will also discuss Treg mediated immune tolerance, tissue repair, and therapeutic strategies for achieving in-vivo Treg expansion, which will be a potential therapeutic option to reduce inflammation-mediated graft injuries, taper the toxic side effects of ongoing immunosuppressants, and improve lung transplant survival rates. [ABSTRACT FROM AUTHOR]

Background: Chronic graft‐versus‐host disease is a severe complication of allogeneic stem cell and bone marrow transplantation. First‐line immunosuppressive agents, such as steroids, are used to prevent this disease; however, they have multiple side effects. Therefore, bath psoralen plus ultraviolet‐A (PUVA) is an alternative second‐line treatment. This study aimed to evaluate the clinical efficacy of bath PUVA for managing chronic graft‐versus‐host disease. Methods: This retrospective, case–control study included 14 patients with extensive cutaneous chronic graft‐versus‐host disease, resistant to systemic corticosteroid, treated with bath PUVA. Major and partial responses were defined as clinical improvements of >70% and 50–70%, respectively. We analyzed the graft‐versus‐host disease clinical presentation and timing after allogeneic stem cell and bone marrow transplantation, bath PUVA doses, background diseases, additional treatments, and adverse effects. Results: We observed eight major (three lichenoid and five sclerodermatoid) and six partial (three lichenoid and three sclerodermatoid) responses after a mean of 28 treatment sessions. After 6 to 25 months, four of the eight patients with sclerodermatoid lesions and all those with lichenoid lesions experienced relapse but responded to additional treatment cycles. Conclusions: Bath PUVA is well‐tolerated and effective for extensive cutaneous chronic graft‐versus‐host disease. It allows rapid tapering of adjuvant immunosuppressants; however, most patients require prolonged maintenance phototherapy. [ABSTRACT FROM AUTHOR]

We reviewed the charts of 25 patients with SCD who presented for a HSCT at our center between January 2016 and September 2022, we excluded one patient that only had a chest CT, but no corresponding PFT because she was 4 years old. The estimated sensitivity of chest CT in detecting pulmonary abnormalities is 0.42 (95% CI: 0.15-0.72), indicating that CT failed to identify abnormalities in 58% of SCD patients. Pulmonary function test (PFT) plays a vital role in risk stratification before allogenic hematopoietic stem cell transplantation (HSCT) and is a useful tool for predicting and preventing unfavorable outcomes in HSCT recipients.[1] However, because PFT requires forced expirations and produces aerosols, there is an increased transmission risk of coronavirus and other respiratory disease during the procedure.[2] In response to this concern, Tamaki et al. recently, evaluated whether PFT findings could be reliably predicted from pre-HSCT chest computed tomography (CT) scan results.[3] Retrospective analyses of 390 patients that presented for HSCT with both chest CT and PFT done as part of their pretransplant work up, estimated a negative predictive value of 92% with specificity of 86% thus concluding that PFT can be replaced by chest CT scan for pre-transplantation pulmonary evaluation of HSCT.[3] We hypothesize that in the pediatric population, that infectious and other injurious processes to the lung take longer to show up on imaging and hence chest CT scans alone may not be reliable as a pre-transplantation pulmonary evaluation tool. [Extracted from the article]

Background: Pulmonary function test (PFT) impairments are common after allogeneic hematopoietic stem cell transplantation. The prognostic significance of these declines on outcomes is not well understood.The objectives were to determine the frequency of declines in pulmonary function (FVC, FEV1, and diffusing capacity for carbon monoxide [DLCO]) in the early post-transplantation period; and to determine the prognostic significance of these declines on mortality or development of bronchiolitis obliterans syndrome. Methods: This was a retrospective cohort study conducted at Mayo Clinic, Rochester, Minnesota. PFTs were obtained at baseline and at day +100. Competing risk survival models were developed, which accounted for pre-transplantation pulmonary function and relapse status. Results: Between January 1, 2005, and December 31, 2020, 1,145 subjects underwent allogeneic hematopoietic stem cell transplantation and had a pre-transplantation PFT performed. Of these, 900 (78.6%) survived to day 100 and had post-transplantation PFTs performed (median [interquartile range] 97 [94-103] d). A decline of ≥10% in FEV1, FVC, or DLCO was seen in 401 of 900 subjects (44.5%). Declines of ≥20% in FEV1 (hazard ratio 1.65, 95% CI 1.07-2.56; P = .02), FVC (hazard ratio 1.72, 95% CI [1.11-2.67]; P = .02), and DLCO (hazard ratio 1.46, 95% CI 1.04-2.07; P = .028) were all associated with reduced survival when compared with those with < 10% decline in PFT measures. These findings were independent of pre-transplantation pulmonary function or relapse status. Bronchiolitis obliterans syndrome was diagnosed in 118 subjects (10.3%), and there was no relationship between early PFT decline and a subsequent diagnosis of bronchiolitis obliterans syndrome. The subjects who received myeloablative conditioning with cyclophosphamide plus total body irradiation or cyclophosphamide plus fludarabine plus total body irradiation were more likely to have lower spirometry values after hematopoietic stem cell transplantation. The subjects who received reduced intensity conditioning or nonmyeloablative conditioning with fludarabine plus total body irradiation were more likely to have higher post-hematopoietic stem cell transplantation FEV1, FVC, and DLCO. Conclusions: An absolute decline of ≥20% in FEV1, FVC, or DLCO were associated with reduced survival independent of pre-transplantation pulmonary function or relapse status. In contrast to previous work, early declines in PFT measures were not associated with future development of bronchiolitis obliterans syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Chronic lung allograft dysfunction (CLAD) can take two forms: bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). The aim was to determine if chest-CT abnormalities after lung transplantation (LTx) could predict CLAD before respiratory functional deterioration. Materials and methods: This monocentric retrospective study analyzed consecutive patients who underwent LTx from January 2015 to December 2018. Initial CT post-LTx (CTi) and a follow-up CT at least 9 months post-LTx (CTf) were reviewed. CLAD was defined as a persistent respiratory functional decline (> 20% of basal FEV1) outside acute episode. A Cox regression was performed in univariate, then in multivariate analysis (including features with p < 0.01 in univariate or of clinical importance) to determine risk factors for CLAD. Subgroup analyses were made for BOS, RAS, and death. Results: Among 118 LTx patients (median (min–max) 47 (18–68) years), 25 developed CLAD during follow-up (19 BOS). The median time to CLAD since LTx was 570 days [150–1770]. Moderate pulmonary artery stenosis (30–50%) was associated with the occurrence of CLAD on CTi (hazard ratio HR = 4.6, CI [1.6–13.2]) and consolidations and pleural effusion on CTf (HR = 2.6, CI [1.3–4.9] and HR = 4.5, CI [1.5–13.6] respectively). The presence of mosaic attenuation (HR = 4.1, CI [1.4–12.5]), consolidations (HR = 2.6, CI [1.3–5.4]), and pleural effusions (p = 0.01, HR = 5.7, CI [1.4–22.3]) were risk factors for BOS on CTf. The consolidations (p = 0.029) and pleural effusions (p = 0.001) were risk factors for death on CTf. Conclusions: CTi and CTf in the monitoring of LTx patients could predict CLAD. Moderate pulmonary artery stenosis, mosaic pattern, parenchyma condensations, and pleural effusions were risk factors for CLAD. Critical relevance statement: There is a potential predictive role of chest CT in the follow-up of LTx patients for chronic lung allograft dysfunction (CLAD). Early chest CT should focus on pulmonary artery stenosis (risk factor for CLAD in this study). During the follow-up (at least 9 months post-LTx), parenchymal consolidations and pleural effusions were shown to be risk factors for CLAD, and death in subgroup analyses. Key points: • Pulmonary artery stenosis (30–50%) on initial chest-CT following lung transplantation predicts CLAD HR = 4.5; CI [1.6–13.2]. • Pleural effusion and consolidations 1 year after lung transplantation predict CLAD and death. • Early evaluation of lung transplanted patients should evaluate pulmonary artery anastomosis. [ABSTRACT FROM AUTHOR]

Background: Allo-HSCT is a definite approach for the management of a wide variety of lethal and debilitating malignant and non-malignant disorders. However, its two main complications, acute and chronic graft-versus-host disease (GVHD), exert significant morbidities and mortalities. BoS, as a manifestation of chronic lung GVHD, is a gruesome complication of allo-HSCT, and for those with steroid-refractory disease, no approved second-line therapies exist. Mesenchymal stem cells (MSCs) exert anti-inflammatory and growth-promoting effects, and their administration against a wide range of inflammatory and neurologic disorders, as well as GVHD, has been associated with promising outcomes. However, literature on the safety and effectiveness of MSC therapy for BoS and pediatric cGVHD is scarce. Methods: We designed a single-arm trial to administer adipose tissue (AT)-derived MSCs to pediatric patients with refractory BoS after allo-HSCT. AT-MSCs from obese, otherwise healthy donors were cultured in an ISO class 1 clean room and injected into the antecubital vein of eligible patients with a dose of 1 × 106/kg. The primary endpoints included a complete or partial response to therapy [in terms of increased forced expiratory volume in one second (FEV1) values and steroid dose reduction] and its safety profile. Results: Four eligible patients with a median age of 6.5 years were enrolled in the study. Steroid-induced osteoporosis and myopathy were present in three cases. A partial response was evident in three cases after a single injection of AT-MSCs. The treatment was safe and tolerable, and no treatment-related adverse events were noted. Two patients developed manageable COVID-19 infections one and 4 months after AT-MSC injection. After a median follow-up duration of 19 months, all cases are still alive and have had no indications for lung transplantation. Conclusions: AT-MSCs could be safely administered to our pediatric cases with BoS post-allo-HSCT. Considering their advanced stage of disease, their sub-optimal functional capacity due to steroid-induced complications, and COVID-19 infection post-treatment, we believe that AT-MSC therapy can have possible efficacy in the management of pediatric BoS. The conduction of further studies with larger sample sizes and more frequent injections is prudent for further optimization of AT-MSC therapy against BoS. Trial registration Iranian Registry of Clinical Trials (IRCT), IRCT20201202049568N2. Registered 22 February 2021, https://en.irct.ir/trial/53143. [ABSTRACT FROM AUTHOR]

Background: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is an uncommon strategy in Japan owing to the severe donor shortage and absence of urgent allocation policy. Moreover, the use of veno-venous (VV) ECMO for immunosuppressed patients is controversial; thus, applying ECMO to patients who await lung re-transplantation is challenging. Case presentation: A 16-year-old lung transplant recipient with grade 3 bronchiolitis obliterans syndrome was waitlisted for lung re-transplantation. Eleven months later, he fell into severe respiratory acidosis with hypercapnia, which were not resolved with mechanical ventilation. VV ECMO was introduced to minimize lung stress and strain. Tracheostomy was additionally performed on day 5 after the start of ECMO, and respiratory condition swiftly improved; hence, the weaning process from VV ECMO began on day 9. Rehabilitation became implementable, and bilateral re-lung transplantation was successfully performed 6 months after the ECMO treatment. No critical complication related to the precedent use of ECMO was noted. Conclusions: VV ECMO can be a feasible treatment option even for lung transplant candidates awaiting re-transplantation for a prolonged period. Introduction of ECMO and tracheostomy in the early deterioration stage may be crucial to successful subsequent patient management. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment modality, frequently used for patients suffering from haematological malignancies. In the last two decades, there have been multiple randomised controlled trials (RCTs), review articles, and meta-analyses addressing the efficacy of rabbit anti-thymocyte globulin (r-ATG) as a graft-versus-host disease (GvHD) prophylaxis. Nevertheless, only a few aimed to compare the effectiveness of different r-ATG formulations. Since the last article we retrieved comparing different r-ATGs in GvHD prophylaxis dates back to 2017, we performed a systematic literature review of articles published since 2017 to this day, utilising PubMed, Scopus, Cochrane, and MEDLINE, with the main endpoints being prophylaxis of acute GvHD (aGvHD) and chronic GvHD (cGvHD). We subjected to scrutiny a total of five studies, of which four compared the differences between Thymoglobulin (ATG-T) and Grafalon (ATG-G), and one discussed the impact of ATG-T dose. Overall, cGvHD, aGvHD grades II–IV, TRM, OS, NRM, LFS, relapse, overall infections, and EBV reactivation do not seem to be affected by the type of utilised rATG. However, data on aGvHD grades III–IV, GRFS, moderate–severe cGvHD, and CMV reactivation is conflicting. Through our research, we sought to summarise the most recent findings concerning r-ATGs in allo-HCT, and provide insight into the differences between the targets and origin of various ATG formulations. [ABSTRACT FROM AUTHOR]

Lung transplantation is the major surgical procedure, which restores normal lung functioning and provides years of life for patients suffering from major lung diseases. Lung transplant recipients are at high risk of primary graft dysfunction, and chronic lung allograft dysfunction (CLAD) in the form of bronchiolitis obliterative syndrome (BOS). Regulatory T cell (Treg) suppresses effector cells and clinical studies have demonstrated that Treg levels are altered in transplanted lung during BOS progression as compared to normal lung. Here, we discuss levels of Tregs/FOXP3 gene expression as a crucial prognostic biomarker of lung functions during CLAD progression in clinical lung transplant recipients. The review will also discuss Treg mediated immune tolerance, tissue repair, and therapeutic strategies for achieving in-vivo Treg expansion, which will be a potential therapeutic option to reduce inflammation-mediated graft injuries, taper the toxic side effects of ongoing immunosuppressants, and improve lung transplant survival rates.

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). 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. 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). 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. [ABSTRACT FROM AUTHOR]

Introduction: Bronchiolitis obliterans syndrome (BOS) is the most common form of CLAD and is characterized by airflow limitation and an obstructive spirometry pattern without parenchymal opacities. The protein signature of BOS lesions concerns extracellular matrix organization and aberrant basement membrane composition. In this pilot study, we investigated the presence of COL4A5 in the serum of patients with BOS. Methods: 41 patients who had undergone LTX were enrolled. Of these, 27 developed BOS and 14 (control group) were considered stable at the time of serum sampling. Of BOS patients, serum samples were analysed at the time of BOS diagnosis and before the clinical diagnosis (pre-BOS). COL4A5 levels were detected through the ELISA kit. Results: Serum concentrations of COL4A5 were higher in pre-BOS than in stable patients (40.5 ± 13.9 and 24.8 ± 11.4, respectively, p = 0.048). This protein is not influenced by comorbidities, such as acute rejection or infections, or by therapies. Survival analysis also reveals that a higher level of COL4A5 was also associated with less probability of survival. Our data showed a correlation between concentrations of COL4A5 and FEV1 at the time of diagnosis of BOS. Conclusion: Serum concentrations of COL4A5 can be considered a good prognostic marker due to their association with survival and correlation with functional parameters. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to provide a concise overview of the role of immune cells in rejection and infection after lung transplantation. Methods: Based on previous clinical and basic studies, the role of various types of immune cells in the development of rejection and infection after lung transplantation is summarized. Results: Immune cell functional status is strongly associated with common complications after lung transplantation, such as primary graft dysfunction, infection and occlusive bronchitis syndrome. Targeted balancing of immune cell tolerance and rejection is an important tool for successful lung transplantation. Conclusion: A comprehensive understanding of immune cell function and the mechanisms that balance immune tolerance and immune rejection may be a crucial factor in improving survival after lung transplantation. [ABSTRACT FROM AUTHOR]

2Chronology of emerging relapse evidence and survival graphs.A Swimmer plot of the 15 patients with relapse evidence and their outcomes, including 6 relapsed and 9 unrelapsed patients. Five patients showed only an increased I JAK2 i -MRD ratio, two patients showed only MC, and the remaining two patients showed MC followed by an increased I JAK2 i -MRD ratio with or without cytogenetic evolution. In addition to overt relapse, the prognostic relevance of cytogenetic changes (relapse or evolution), molecular relapse, and chimerism relapse was also investigated. [Extracted from the article]

Background: Bronchiolitis obliterans syndrome (BOS), induced by a chronic rejection, remains a significant obstacle for end-stage lung diseases after lung transplantation. We have previously determined that the small non-coding mRNA (miRNA) miR-27a-3p maintained the immature state of dendritic cells (DCs) via the interleukin 10 (IL-lO)-dependent regulatory pathway. Such status helped in preventing rejection and alleviating BOS. The present study explored mechanisms how miR-27a-3p may suppress the fibrosis as well as the maturation of DCs, ultimately attenuating BOS in vitro and in vivo. Methods/Results: In our tracheal transplantation mouse model, the expression of Smad2, Smad4, and aSMA were significantly decreased in the miR-27a-3p-transfected DCs (p < 0.0001, p 0.0006, and p = 0.0002 respectively). Moreover, the expression of fibrosis markers («-SMA, collagen I, and Fn) were potently inhibited in the miR-27a-3p-transfected NIH-3T3 cells (p < 0.0001, p = 0.00148, andp < 0.0001 respectively). At the same time, reversed results were observed in the inhibitor group (p = 0.0002, p < 0.0001, and p < 0.0001 respectively), indicating that miR-27a-3p could directly inhibit myofibroblast differentiation. Furthermore, in the tracheal transplanted mice, the population of Treg cells was significantly decreased (p < 0.0001). In contrast, Thl7 cells were downregulated in the miR-27a-3p-transfected DCs group (p < 0.0001), accompanied by the decreased IL-17 levels (p = 0.0007) and the induction of TGF-ßl and IL-10 (p < 0.0001 and p = 0.0016 respectively). Further mechanistic studies indicated that miR-27a-3p altered the maturation of DCs by targeting TLR4 and IRAK (p < 0.0001 and p = 0.0002 respectively). Conclusions: Our study suggests that miR-27a-3p selectively blocked the TGF-ßl/Smad pathways to suppress the myofibroblast differentiation and targeted the TRL4/IRAK4 pathway to restrain DCs maturation, thus attenuating BOS. Our findings suggest that miR-27a-3p is a potential active molecule on BOS management after lung transplantation. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Total ischaemic time (IT) is considered a limiting factor in lung transplantation. In this retrospective study, we investigate effects of IT and disease burden on outcomes after bilateral lung transplantation. METHODS A total of 1298 patients undergoing bilateral lung transplantation between January 2010 and May 2022 (follow-up 100%, median 54 months) were included. Pre-transplant diseases' severity (recipient body mass index, recipient age, previous lung transplantation, Tacrolimus immunosuppression, preoperative recipient extracorporeal membrane oxygenation support, lung volume reduction) for graft failure was individually calculated and—as IT—categorized. Vice versa adjusted Cox models were calculated. Considering competing risks, we assessed cumulative incidences of airway obstructive complications and chronic lung allograft dysfunction with death as competing risk factors for primary graft dysfunction were assessed by binary logistic regression. RESULTS Higher disease burden significantly accelerated chronic lung allograft dysfunction and death occurrence (P  < 0.001); IT did not. IT-adjusted disease burden strata showed 50% graft survival differences at 11 years after transplantation (range 24–74%), disease burden-adjusted IT strata 18% for all and 6% (54–60%) among those above 7 h. All significant primary graft dysfunction risk factors were diagnoses related, IT was not significantly important and odds ratios did not increase with IT. CONCLUSIONS The eventual graft survival disadvantage that results from an IT between 7 and at least 11 h is negligible in contrast to frequent recipients' disease-based risk levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a significant complication for patients who receive allogeneic hematopoietic stem cell transplantation. This disease is further complicated for patients who are refractory to steroids. This article reviews emerging therapies and supportive care for patients with steroid-refractory cGVHD. OBJECTIVES: This article provides foundational knowledge on steroid-refractory cGVHD, emerging treatment options, and related supportive care. METHODS: Current research on emerging therapies for patients with steroid-refractory cGVHD is summarized along with supportive care recommendations and a review of related nursing considerations. FINDINGS: Emerging therapies for steroidrefractory cGVHD offer opportunities for improved clinical outcomes for these patients. Nursing knowledge of new therapies and supportive care for patients with steroid-refractory cGVHD supports the provision of optimal nursing care for a complex population of patients. [ABSTRACT FROM AUTHOR]