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.
Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) ...initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that IL-1β production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1β production by NCM was NLRP3 inflammasome dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL-1R-dependent activation of the PKC and NF-κB pathway. Accordingly, we show that IL-1β-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1β, or IL-1R antagonism and inflammasome inhibition abrogated recruitment of CM and PGD and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.
Chimeric antigen receptors (CARs) are used to redirect effector cell specificity to selected cell surface antigens. Using CARs, antitumor activity can be initiated in patients with no prior tumor ...specific immunity. Although CARs have shown promising clinical results, the technology remains limited by the availability of specific cognate cell target antigens. To increase the repertoire of targetable tumor cell antigens we utilized the immune system of the sea lamprey to generate directed variable lymphocyte receptors (VLRs). VLRs serve as membrane bound and soluble immune effectors analogous but not homologous to immunoglobulins. They have a fundamentally different structure than immunoglobulin (Ig)-based antibodies while still demonstrating high degrees of specificity and affinity. To test the functionality of VLRs as the antigen recognition domain of CARs, two VLR-CARs were created. One contained a VLR specific for a murine B cell leukemia and the other contained a VLR specific for the human T cell surface antigen, CD5. The CAR design consisted of the VLR sequence, myc-epitope tag, CD28 transmembrane domain, and intracellular CD3ζ signaling domain. We demonstrate proof of concept, including gene transfer, biosynthesis, cell surface localization, and effector cell activation for multiple VLR-CAR designs. Therefore, VLRs provide an alternative means of CAR-based cancer recognition.
Lung transplantation can potentially be a life-saving treatment for patients with nonresolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of ...SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with nonresolving COVID-19-associated respiratory failure. We performed single-molecule fluorescence in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single-cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm postmortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single-cell RNA sequencing data from the lungs of patients with late-stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.
IMPORTANCE: Lung transplantation is a potentially lifesaving treatment for patients who are critically ill due to COVID-19–associated acute respiratory distress syndrome (ARDS), but there is limited ...information about the long-term outcome. OBJECTIVE: To report the clinical characteristics and outcomes of patients who had COVID-19–associated ARDS and underwent a lung transplant at a single US hospital. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 102 consecutive patients who underwent a lung transplant at Northwestern University Medical Center in Chicago, Illinois, between January 21, 2020, and September 30, 2021, including 30 patients who had COVID-19–associated ARDS. The date of final follow-up was November 15, 2021. EXPOSURES: Lung transplant. MAIN OUTCOMES AND MEASURES: Demographic, clinical, laboratory, and treatment data were collected and analyzed. Outcomes of lung transplant, including postoperative complications, intensive care unit and hospital length of stay, and survival, were recorded. RESULTS: Among the 102 lung transplant recipients, 30 patients (median age, 53 years range, 27 to 62; 13 women 43%) had COVID-19–associated ARDS and 72 patients (median age, 62 years range, 22 to 74; 32 women 44%) had chronic end-stage lung disease without COVID-19. For lung transplant recipients with COVID-19 compared with those without COVID-19, the median lung allocation scores were 85.8 vs 46.7, the median time on the lung transplant waitlist was 11.5 vs 15 days, and preoperative venovenous extracorporeal membrane oxygenation (ECMO) was used in 56.7% vs 1.4%, respectively. During transplant, patients who had COVID-19–associated ARDS received transfusion of a median of 6.5 units of packed red blood cells vs 0 in those without COVID-19, 96.7% vs 62.5% underwent intraoperative venoarterial ECMO, and the median operative time was 8.5 vs 7.4 hours, respectively. Postoperatively, the rates of primary graft dysfunction (grades 1 to 3) within 72 hours were 70% in the COVID-19 cohort vs 20.8% in those without COVID-19, the median time receiving invasive mechanical ventilation was 6.5 vs 2.0 days, the median duration of intensive care unit stay was 18 vs 9 days, the median post–lung transplant hospitalization duration was 28.5 vs 16 days, and 13.3% vs 5.5% required permanent hemodialysis, respectively. None of the lung transplant recipients who had COVID-19–associated ARDS demonstrated antibody-mediated rejection compared with 12.5% in those without COVID-19. At follow-up, all 30 lung transplant recipients who had COVID-19–associated ARDS were alive (median follow-up, 351 days IQR, 176-555 after transplant) vs 60 patients (83%) who were alive in the non–COVID-19 cohort (median follow-up, 488 days IQR, 368-570 after lung transplant). CONCLUSIONS AND RELEVANCE: In this single-center case series of 102 consecutive patients who underwent a lung transplant between January 21, 2020, and September 30, 2021, survival was 100% in the 30 patients who had COVID-19–associated ARDS as of November 15, 2021.
Lung donation following SARS‐CoV‐2 infection Querrey, Melissa; Kurihara, Chitaru; Manerikar, Adwaiy ...
American journal of transplantation,
December 2021, Letnik:
21, Številka:
12
Journal Article
Recenzirano
Odprti dostop
There have been over 177 million cases of COVID‐19 worldwide, many of whom could be organ donors. Concomitantly, there is an anticipated increase in the need for donor lungs due to expanding ...indications. Given that the respiratory tract is most commonly affected by COVID‐19, there is an urgent need to develop donor assessment criteria while demonstrating safety and “efficacy” of lung donation following COVID‐19 infection. Accordingly, we report an intentional transplant using lungs from a donor with recent, microbiologically confirmed, COVID‐19 infection into a recipient suffering from COVID‐19 induced ARDS and pulmonary fibrosis. In addition to the standard clinical assays, both donor and recipient lungs were analyzed using RNAscope, which confirmed that tissues were negative for SARS‐CoV‐2. Immunohistochemistry demonstrated colocalized KRT17+ basaloid‐like epithelium and COL1A1+ fibroblasts, a marker suggestive of lung fibrosis in COVID‐19 associated lung disease, in the explanted recipient lungs but absent in the donor lungs. We demonstrate that following a thorough assessment, lung donation following resolved COVID‐19 infection is safe and feasible.
Lungs from carefully selected donors with resolved COVID‐19 are safe to transplant.
The magnitude of association and quality of evidence comparing surgical approaches for lung cancer resection has not been analyzed. This has resulted in conflicting information regarding the relative ...superiority of the different approaches and disparate opinions on the optimal surgical treatment. We reviewed and systematically analyzed all published data comparing near- (30-d) and long-term mortality for minimally invasive to open surgical approaches for lung cancer.
Comprehensive search of EMBASE, MEDLINE, and the Cochrane Library, from January 2009 to August 2019, was performed to identify the studies and those that passed bias assessment were included in the analysis utilizing propensity score matching techniques. Meta-analysis was performed using random-effects and fixed-effects models. Risk of bias was assessed via the Newcastle–Ottawa Scale and the ROBINS-I tool. The study was registered in PROSPERO (CRD42020150923) prior to analysis.
Overall, 1382 publications were identified but 19 studies were included encompassing 47,054 patients after matching. Minimally invasive techniques were found to be superior with respect to near-term mortality in early and advanced-stage lung cancer (risk ratio 0.45, 95% confidence interval CI 0.21-0.95, I2 = 0%) as well as for elderly patients (odds ratio 0.45, 95% CI 0.31-0.65, I2 = 30%), but did not demonstrate benefit for high-risk patients (odds ratio 0.74, 95% CI 0.06-8.73, I2 = 78%). However, no difference was found in long-term survival.
We performed the first systematic review and meta-analysis to compare surgical approaches for lung cancer which indicated that minimally invasive techniques may be superior to thoracotomy in near-term mortality, but there is no difference in long-term outcomes.
Primary graft dysfunction (PGD) affects over 50% of lung transplant recipients within the first 72 hours and remains the predominant cause of early mortality and chronic allograft rejection following ...lung transplant (Ankit Bharat et al., 2008b). In lung transplants secondary to COVID-19 lung disease, the rate of PGD is near 70% in comparison to the all-cause lung transplantation rate of 30% (Kurihara et al., 2022). The immunomechanistic pathway leading to PGD and its variation clinically is unknown. Using a murine orthotopic vascularized lung transplant model, we found that the common endogenous damage molecule HMGB1 activates MyD88 on retained donor non-classical monocytes (NCM) via toll-like receptors 2 and 4. Activation of these NCM leads to CXCL2 release, which attracts recipient neutrophils, the effector cell responsible for PGD development, into the allograft. Deletion of Itgam, the gene which encodes CD11b or the alpha-subunit of the MAC-1 complex, on NCM enhanced CXCL2 release. Agonism of CD11b using leukadherin-1 prior to lung transplantation abrogated CXCL2 production and PGD development. Our findings suggest that the utility of CD11b acts as a negative regulator of the damage pathway incited by NCM activation following lung transplantation. Utilization of this mechanism is an attractive therapeutic target to attenuate or prevent the development of PGD.
Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that ...bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.
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