Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, ...mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a
/
pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.
Organic light-emitting diodes (OLEDs) exploiting simple binary emissive layers (EMLs) blending only emitters and hosts have natural advantages in low-cost commercialization. However, previously ...reported OLEDs based on binary EMLs hardly simultaneously achieved desired comprehensive performances, e.g., high efficiency, low efficiency roll-off, narrow emission bands, and high operation stability. Here, we report a molecular-design strategy. Such a strategy leads to a fast reverse intersystem crossing rate in our designed emitter h-BNCO-1 of 1.79×10
s
. An OLED exploiting a binary EML with h-BNCO-1 achieves ultrapure emission, a maximum external quantum efficiency of over 40% and a mild roll-off of 14% at 1000 cd·m
. Moreover, h-BNCO-1 also exhibits promising operational stability in an alternative OLED exploiting a compact binary EML (the lifetime reaching 95% of the initial luminance at 1000 cd m
is ~ 137 h). Here, our work has thus provided a molecular-design strategy for OLEDs with promising comprehensive performance.
Restrictive allograft syndrome (RAS) is an aggressive variant of CLAD characterized by progressive restrictive ventilatory decline and persistent pleuro-parenchymal changes that can be seen on chest ...CT. We identified four lung transplant recipients with a progressive restrictive ventilatory defect due to lymphocyte-predominant exudative pleural effusions, but no pleuro-parenchymal abnormalities typical of RAS. Using molecular analysis, we also found increased levels of previously described immune markers of RAS, including NFkB, 20S proteasome, lipocalin, TNFα, and TGFβ, within the circulating small extracellular vesicles of the remaining living lung transplant recipient. Despite the absence of lung parenchymal changes, these patients had a poor prognosis with rapid deterioration in allograft function and no response to pleural-based interventions such as thoracentesis, decortication, and pleurodesis. We hypothesize that these cases represent a distinct CLAD phenotype characterized by progressive restriction due to pleural inflammation, lymphocyte-predominant pleural effusion, resultant compressive atelectasis, and eventual respiratory failure in the absence of lung parenchymal involvement.
Background
Lung transplant recipients are at heightened risk for nocardiosis compared to other solid organ transplant recipients, with incidence rates as high as 9% and up to 30% associated ...mortality. No controlled studies assessing risk factors for nocardiosis in this high‐risk population have been reported.
Methods
Patients undergoing lung transplantation at a single center between 2012 and 2018 and diagnosed with nocardiosis post‐transplant were matched 1:2 to uninfected control subjects on the basis of age, transplant date, and sex.
Results
The incidence of nocardiosis in this lung transplant population was 3.4% (20/586), occurring a median of 9.4 months (range 4.4‐55.2) post‐transplant. In multivariable analysis, consistent use of trimethoprim/sulfamethoxazole (TMP/SMX) in the 12 weeks prior to diagnosis was independently associated with protection against nocardiosis (OR 0.038; 95% CI 0.01‐0.29; P = .002). Augmented immunosuppression in the 6 months prior to diagnosis was independently associated with the development of nocardiosis (OR 9.94; 95% CI 1.62‐ 61.00; P = .013). Six case patients (30%) had disseminated disease; all‐cause 6‐month mortality was 25%. The most common species was Nocardia farcinica (7/17 isolates), which was associated with dissemination and mortality. The most active antibiotics were TMP/SMX (100%), linezolid (100%), and amikacin (76%). Imipenem was only active against 4/17 isolates (24% susceptibility), with two isolates becoming non‐susceptible later in therapy.
Conclusions
Trimethoprim/sulfamethoxazole prophylaxis was shown to be protective against nocardiosis in lung transplant recipients, while augmented immunosuppression conferred increased risk. Institutional epidemiologic data are needed to best guide empiric therapy for Nocardia, as historical in vitro data may not predict local susceptibilities.
Extracorporeal membrane oxygenation has been used as a bridge to lung transplantation in patients with rapid pulmonary function deterioration. The reported success of this modality and perioperative ...and functional outcomes are varied.
We retrospectively reviewed all patients who underwent lung transplantation at our institution over 1 year (January 1, 2015, to December 31, 2015). Patients were divided into 2 groups depending on whether they required extracorporeal membrane oxygenation support as a bridge to transplant; preoperative characteristics, lung transplantation outcomes, and survival were compared between groups.
Of the 93 patients, 12 (13%) received bridge to transplant, and 81 (87%) did not. Patients receiving bridge to transplant were younger, had higher lung allocation scores, had lower functional status, and were more often on mechanical ventilation at listing. Most patients who received bridge to transplant (n = 10, 83.3%) had pulmonary fibrosis. Mean pretransplant extracorporeal membrane oxygenation support was 103.6 hours in duration (range, 16-395 hours). All patients who received bridge to transplant were decannulated immediately after lung transplantation but were more likely to return to the operating room for secondary chest closure or rethoracotomy. Grade 3 primary graft dysfunction within 72 hours was similar between groups. Lung transplantation success and hospital discharge were 100% in the bridge to transplant group; however, these patients experienced longer hospital stays and higher rates of discharge to acute rehabilitation. The 1-year survival was 100% in the bridge to transplant group and 91% in the non–bridge to transplant group (log-rank, P = .24). The 1-year functional status was excellent in both groups.
Extracorporeal membrane oxygenation can be used to safely bridge high-acuity patients with end-stage lung disease to lung transplantation with good 30-day, 90-day, and 1-year survival and excellent 1-year functional status. Long-term outcomes are being studied.
The drug pirfenidone has been shown to slow the progression and decrease mortality of idiopathic pulmonary fibrosis (IPF). Its exact mechanism is unknown, but it likely inhibits pro-fibrotic cytokine ...transforming growth factor beta, a known contributor to wound healing. We evaluated whether patients taking pirfenidone until lung transplantation had increased risk of impaired wound healing post-transplant. This information could determine whether pirfenidone should be discontinued prior to listing to allow for a wash-out period.
We retrospectively reviewed patients who underwent lung transplantation for pulmonary fibrosis at Norton Thoracic Institute in Phoenix, Arizona, from January 2014 to December 2015.
We describe 18 patients who took pirfenidone up to a month before transplant. Aside from one patient who experienced sternal dehiscence due to a surgical issue, all remaining patients did well with no evidence of airway dehiscence. Each of these 17 patients had been on pirfenidone for at least 30 days; nine patients had been on pirfenidone for over 90 days. Baseline characteristics including age, sex, body mass index, renal function, liver function, glucose level, pre-transplant corticosteroid use, and post-transplant immunosuppressant therapy were similar.
In our experience, pirfenidone may be safely continued until lung transplantation. Only one patient in our series experienced impaired wound healing related to a surgical issue, even when pirfenidone was continued until lung transplantation. We found no evidence of impaired wound healing or airway complications after lung transplantation in patients who were treated with pirfenidone before lung transplantation.
Introduction Remdesivir (REM) and molnupiravir (MOL) are commonly used to treat lung transplant recipients (LTRs) with COVID-19; however, the clinical efficacy of these medications is yet to be ...compared. In this retrospective cohort study, we compared the clinical outcomes between LTRs with mild-to-moderate COVID-19 treated with REM and those treated with MOL. Methods and Results Between March 2020 and August 2022, 195 LTRs developed COVID-19 at our center. After excluding 82 who presented with severe disease requiring hospitalization, the remaining 113 were included in the analysis: 54 did not receive antiviral treatment, 30 were treated with REM, and 29 were treated with MOL. Adjusted multivariable logistic regression analysis showed similar rates of hospitalization (adjusted odds ratio (aOR) 1.169, 95% confidence interval (95% CI) 0.105–12.997, p = 0.899, ICU admission (aOR 0.822, 95% CI 0.042–16.220, p = 0.898), mechanical ventilation (aOR 0.903, 95% CI 0.015–55.124, p = 0.961), and COVID-19-related mortality (aOR 0.822, 95% CI 0.042–16.220, p = 0.898) between LTRs treated with REM and those treated with MOL for mild-to-moderate COVID-19, irrespective of SARS-CoV-2 strain. Conclusion MOL may be a suitable alternative to REM to treat LTRs with mild-to-moderate COVID-19, and the choice of antiviral therapy can be driven by practical considerations such as route of administration and drug availability.
Is There an Age Limit to Lung Transplantation? Biswas Roy, Sreeja, MBBS; Alarcon, Diana, BS; Walia, Rajat, MD ...
The Annals of thoracic surgery,
08/2015, Letnik:
100, Številka:
2
Journal Article
Recenzirano
Background Lung transplantation in patients older than 65 years is increasingly common, but questions remain regarding risk vs benefit and procedure choice. We identified short-term and long-term ...outcomes in older single-lung transplant (SLT) and bilateral-lung transplant (BLT) recipients. Methods We performed a retrospective review of United Network for Organ Sharing data for patients who underwent lung transplantation between May 2005 and December 2012. Patients were grouped by age, and we calculated short-term and long-term survival rates and compared survival distributions. Results Of the 11,776 patients who received lung transplants, 9,317 (79%) were aged 12 to 64 years, 1,902 (16%) were 65 to 69, 486 (4%) were 70 to 74, and 71 (1%) were 75 to 79. Short-term survival was similar across all age groups and procedure types except those aged 75 to 79, who had lower short-term survival for BLT. Those aged 12 to 64 had higher 5-year survival for SLT and BLT than all other groups ( p < 0.001), and BLT offered a long-term survival advantage over SLT in this group ( p < 0.0001). Older age groups trended toward better long-term survival for BLT compared with SLT (65 to 69, p = 0.059; 70 to 74, p = 0.079). Although data were lacking for 5-year survival for those aged 75 to 79, the 3-year survival for BLT in this group was inferior. Conclusions Lung transplant can be offered to select older patients up to age 74 with acceptable outcomes. SLT may be preferred for elderly patients, but BLT offers acceptable long-term outcomes without significant short-term risk. Patients older than 75 have acceptable short-term outcomes for SLT, but long-term outcomes for SLT and BLT in this group are poor.
Purpose of Review
Patients on antifungal therapy who develop breakthrough mold infections pose significant treatment challenges for clinicians. Treatment of these infections demands a multimodal ...approach, including a thorough patient assessment, immune restoration, and evaluation for nonadherence and drug–drug interactions. However, limited clinical trial data are available to guide therapeutic decision-making.
Recent Findings
Organisms associated with breakthrough mold infection have historically included
Aspergillus
species and the Mucorales; however, rare and resistant molds are increasing in prevalence. Treatment failure and mortality rates remain high with breakthrough infection, irrespective of the selected treatment. Therapeutic drug monitoring, dose optimization, and combination antifungal therapy have been increasingly used to treat refractory cases.
Summary
Switch therapy and combination antifungal therapy represent the major treatment strategies for breakthrough mold infection. Herein, preclinical and clinical data are reviewed supporting the merits of each approach. Additionally, recommendations for therapeutic drug monitoring are provided.
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