This article evaluates whether the development of tertiary lymphoid organ, or bronchus‐associated lymphoid tissue, is necessary for FoxP3+ regulatory T cell‐mediated lung transplant tolerance. See ...Tanaka et al's article on page 1251
Since the first reported success of lung transplantation over three decades ago, chronic allograft rejection has carried the highest burden of long-term mortality. ...this study may have a great ...clinical impact because it introduces the possibility of inhibiting the RAS/MEK/ERK pathway, using agents such as trametinib, after lung transplantation to suppress indirect allorecognition and reduce the incidence of chronic rejection. ...replacement of calcineurin inhibitors with a drug such as trametinib in human lung transplant recipients may lead to acute allograft rejection even at late time points after transplantation, assuming that its mechanism of action is suppression of indirect allorecognition. ...early introduction of MEK inhibitors may ameliorate both ischemia-reperfusion injury and chronic rejection.
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar ...macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.
Objectives Juxta-anastomotic stenosis (JAS) is one of the predominant causes of arteriovenous fistula (AVF) failure, with the reported incidence as high as 65%. We hypothesized that technical ...modification to alter the outflow vein configuration using the novel piggyback Straight Line Onlay Technique (pSLOT) would prevent JAS and improve AVF maturation. Methods Intention-to-treat analysis of the outcomes of consecutive distal radiocephalic (RC) fistulas performed by a single operator with three different anastomotic techniques using a prospectively maintained database. Traditional end-to-side technique (ETS), side-to-side straight-line onlay technique (SLOT, STS) and pSLOT in RC AVF created in 125 consecutive patients between 1/2004 and 12/2007 were compared. AVF maturation was evaluated by ultrasonography at 4 to 6 weeks and use for dialysis. Results The mean age of the study group was 53.1 ± 20.7 years, the male-to-female ratio was 61:64, and the races studied were African American (66; 52.8%) and Caucasian (54; 43.2%). The primary disease for renal failure was hypertension (54; 43.2%) and diabetes (51; 40.8%). Brachial artery flow at maturation was 1103 ± 531 mL/min. Incidence of early JAS was 9.8% and late 14.6%. The clinico-demographic variables between ETS (n = 57), STS (n = 12), and pSLOT (n = 54) were similar. The median follow-up between three groups: ETS (19 months), STS (12 months), and pSLOT (19 months; P = .1), was similar. There was a significant decrease in JAS development in pSLOT patients ( P = .04). pSLOT patients also revealed decreased overall fistula failure (ETS 40.3%, STS 33.3%, pSLOT 16.7%; P = .01). Conclusions There was significant reduction in JAS and improvement in AVF maturation with pSLOT. This study provides evidence highlighting the role of outflow vein configuration in AVF maturation. Minimal alteration of vein wall configuration and avoidance torsion using pSLOT technique improves AVF maturation.
To determine the effects and immunological mechanisms of low‐dose interleukin‐2 (IL‐2) in a murine model of chronic cardiac allograft rejection (BALB/c to C57BL/6) after costimulatory blockade ...consisting of MR1 (250 μg/ip day 0) and CTLA4‐Ig (200 μg/ip day 2), we administered low‐dose IL‐2 (2000 IU/day) starting on posttransplant day 14 for 3 weeks. T regulatory (Treg) cell infiltration of the grafts was determined by immunohistochemistry; circulating exosomes by western blot and aldehyde bead flow cytometry; antibodies to donor MHC by immunofluorescent staining of donor cells; and antibodies to cardiac self‐antigens (myosin, vimentin) by ELISA. We demonstrated that costimulation blockade after allogeneic heart transplantation induced circulating exosomes containing cardiac self‐antigens and antibodies to both donor MHC and self‐antigens, leading to chronic rejection by day 45. Treatment with low‐dose IL‐2 prolonged allograft survival (>100 days), prevented chronic rejection, and induced splenic and graft‐infiltrating CD4+ CD25+ Foxp3 Treg cells by day 45 and circulating exosomes (Foxp3+) with PD‐L1 and CD73. MicroRNA 142, associated with the TGFβ pathway, was significantly downregulated in exosomes from IL‐2‐treated mice. In conclusion, low‐dose IL‐2 delays rejection in a murine model of chronic cardiac allograft rejection and also induces graft‐infiltrating Tregs and circulating exosomes with immunoregulatory molecules.
In a murine model of cardiac allograft transplantation, low‐dose interleukin‐2 treatment attenuates chronic rejection and induces graft‐infiltrating T‐regulatory cells and circulating exosomes with immunoregulatory molecules.
Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly being used for acute respiratory distress syndrome and as a bridge to lung transplantation. After initiation of venovenous ECMO, ...systemic anticoagulation therapy is traditionally administered and can cause bleeding diathesis. Here, we investigated whether venovenous ECMO can be administered without continuous systemic anticoagulation administration for patients with acute respiratory distress syndrome.
This is a retrospective review of an institutional ECMO database. We included consecutive patients from January 2015 through February 2019. Overall, 38 patients received low levels of continuous systemic anticoagulation (AC+) whereas the subsequent 36 patients received standard venous thromboprophylaxis (AC−). Published Extracorporeal Life Support Organization guidelines were used for the definition of outcomes and complications.
Overall, survival was not different between the two groups (P = .58). However, patients in the AC+ group had higher rates of gastrointestinal bleeding (28.9%, vs AC− group 5.6%; P < .001). The events per patient-day of gastrointestinal bleeding was 0.00025 in the AC− group and 0.00064 in the AC+ group (P < .001). In addition, oxygenator dysfunction was increased in the AC+ group (28.9% and 0.00067 events per patient-day, vs AC− 11.1% and 0.00062 events per patient-day; P = .02). Furthermore, the AC+ group received more transfusions: packed red blood cells, AC+ group 94.7% vs AC− group 55.5% (P < .001); fresh frozen plasma, AC+ 60.5% vs AC− 16.6% (P = .001); and platelets, AC+ 84.2% vs AC− 27.7% (P < .001). There was no circuit thrombosis in either groups throughout the duration of ECMO support.
Our results suggest that venovenous ECMO can be safely administered without continuous systemic anticoagulation therapy. This approach may be associated with reduced bleeding diathesis and need for blood transfusions.
Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) ...attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications.
We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed.
Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19.
The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients.
National Institutes of Health. VIDEO ABSTRACT.
Bronchoendoscopic Repair of Tracheoesophageal Fistula Mozer, Anthony B; Michel, Eriberto; Gillespie, Colin ...
American journal of respiratory and critical care medicine,
09/2019, Letnik:
200, Številka:
6
Journal Article
Recenzirano
Odprti dostop
A 73-year-old woman presented with recurrent tracheoesophageal fistula (TEF; Figure 1A), leading to aspiration pneumonitis (Figure 1B), malnutrition, and sepsis, 3 years after surgical repair of an ...iatrogenic TEF sustained during a carotid endarterectomy. Because of the patient’s severe debilitation and prior neck operations, the risks of surgical repair were prohibitive. ...a staged minimally invasive bronchoendoscopic approach was developed. Anthony B. Mozer 1, Eriberto Michel 1, Colin Gillespie 1, 2, and Ankit Bharat 1, 2 1Division of Thoracic Surgery, Department of Surgery, and 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Background
Nonsmall‐cell lung cancer (NSCLC) is a common diagnosis among patients living in rural areas and small towns who face unique challenges accessing care. We examined differences in survival ...for surgically treated rural and small‐town patients compared to those from urban and metropolitan areas.
Methods
The National Cancer Database was used to identify surgically treated NSCLC patients from 2004 to 2016. Patients from rural/small‐town counties were compared to urban/metro counties. Differences in patient clinical, sociodemographic, hospital, and travel characteristics were described. Survival differences were examined with Kaplan–Meier curves and Cox proportional hazards models.
Results
The study included 366 373 surgically treated NSCLC patients with 12.4% (n = 45 304) categorized as rural/small‐town. Rural/small‐town patients traveled farther for treatment and were from areas characterized by lower income and education(all p < 0.001). Survival probabilities for rural/small‐town patients were worse at 1 year (85% vs. 87%), 5 years (48% vs. 54%), and 10 years (26% vs. 31%) (p < 0.001). Travel distance >100 miles (hazard ratio HR = 1.11, 95% confidence interval CI: 1.07–1.16, vs. <25 miles) and living in a rural/small‐town county (HR = 1.04, 95% CI: 1.01–1.07) were associated with increased risk for death.
Conclusions
Rural and small‐town patients with surgically treated NSCLC had worse survival outcomes compared to urban and metropolitan patients.
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