Temporal correlation between postreperfusion complement deposition and severe primary graft dysfunction in lung allografts.

Growing evidence implicates complement in the pathogenesis of primary graft dysfunction (PGD). We hypothesized that early complement activation postreperfusion could predispose to severe PGD grade 3 (PGD-3) at 72 hours, which is associated with worst posttransplant outcomes. Consecutive lung transplant patients (n = 253) from January 2018 through June 2023 underwent timed open allograft biopsies at the end of cold ischemia (internal control) and 30 minutes postreperfusion. PGD-3 at 72 hours occurred in 14% (35/253) of patients; 17% (44/253) revealed positive C4d staining on postreperfusion allograft biopsy, and no biopsy-related complications were encountered. Significantly more patients with PGD-3 at 72 hours had positive C4d staining at 30 minutes postreperfusion compared with those without (51% vs 12%, P < .001). Conversely, patients with positive C4d staining were significantly more likely to develop PGD-3 at 72 hours (41% vs 8%, P < .001) and experienced worse long-term outcomes. In multivariate logistic regression, positive C4d staining remained highly predictive of PGD-3 (odds ratio 7.92, 95% confidence interval 2.97-21.1, P < .001). Hence, early complement deposition in allografts is highly predictive of PGD-3 at 72 hours. Our data support future studies to evaluate the role of complement inhibition in patients with early postreperfusion complement activation to mitigate PGD and improve transplant outcomes.

Predictors of Cytomegalovirus Recurrence Following Cessation of Posttransplant Prophylaxis.

INTRODUCTION: Cytomegalovirus (CMV) infection is associated with a poor prognosis after lung transplantation, and donor and recipient CMV serostatus is a risk factor for reactivation. CMV prophylaxis is commonly administered in the first year following transplantation to reduce CMV infection; however, the risk factors for long-term reactivation remain unclear. We investigated the timing and risk factors of CMV infection after prophylactic administration. METHODS: This study was a retrospective review of the institutional lung transplantation database from June 2014 to June 2022. Data on patient characteristics, pretransplantation laboratory values, postoperative outcomes, and CMV infection were collected. Donor CMV-IgG-positive and recipient CMV-IgG-negative groups were defined as the CMV mismatch group. RESULTS: During the study period, 257 patients underwent lung transplantation and received a prophylactic dose of valganciclovir hydrochloride for up to 1 y. CMV infection was detected in 69 patients (26.8%): 40 of 203 (19.7%) in the non-CMV mismatch group and 29 of 54 (53.7%) in the CMV mismatch group (P < 0.001). CMV infection after prophylaxis occurred at a median of 425 and 455 d in the CMV mismatch and non-CMV mismatch groups, respectively (P = 0.07). Multivariate logistic regression analysis revealed that preoperative albumin level (odds ratio [OR] = 0.39, P = 0.04), CMV mismatch (OR = 15.7, P < 0.001), and donor age (OR = 1.05, P = 0.009) were significantly associated with CMV infection. CONCLUSIONS: CMV mismatch may have increased the risk of CMV infection after lung transplantation, which decreased after prophylaxis. In addition to CMV mismatch, low preoperative albumin level and donor age were independent predictors of CMV infection.

Early initiation of physical and occupational therapy while on extracorporeal life support improves patients' functional activity.

PURPOSE: Managing acute respiratory distress syndrome (ARDS) patients on venovenous extracorporeal membrane oxygenation (V-V ECMO), without sedation/neuromuscular blockade to allow physical and occupational therapy (PT/OT) participation, is untraditional. Here, we investigate the impact of early PT/OT initiation on discharge functional activity for ARDS patients managed on V-V ECMO. METHODS: This is a retrospective review of 67 ARDS patients managed with V-V ECMO at a single academic center from February 2018 to June 2021. Data collected included patient characteristics, days of V-V ECMO support, day of PT/OT initiation, and ambulation distance and Activity Measure for Post-Acute Care (AMPAC) Six-Clicks score on day of discharge. RESULTS: Patients with >7 days of V-V ECMO support had decreased ambulation and AMPAC scores compared to those with <7 days (70.5 vs. 162.1, p < 0.01 and 12.3 vs. 16.4, p = 0.01, respectively). PT/OT initiation within 7 days after starting V-V ECMO significantly improved ambulation and AMPAC scores (163.5 vs. 59.5, p < 0.001, and 16.6 vs. 11.8, p < 0.01, respectively). Additionally, in patients with >7 days of V-V ECMO support, those who began PT/OT within 8 days of V-V ECMO cannulation had significantly improved ambulation and AMPAC scores (151.8 vs. 44.2, p < 0.01, and 16.5 vs. 11.0, p < 0.01, respectively). CONCLUSION: Early PT/OT initiation in severe ARDS patients managed on V-V ECMO is associated with improved patient functional activity on day of discharge. Our study further supports the use of V-V ECMO in treatment of severe ARDS without sedation/neuromuscular blockade and specifically demonstrates PT/OT should be started early following V-V ECMO cannulation.

Outcomes after extracorporeal membrane oxygenation support in COVID-19 and non-COVID-19 patients.

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (V-V ECMO) support is increasingly used in the management of COVID-19-related acute respiratory distress syndrome (ARDS). However, the clinical decision-making to initiate V-V ECMO for severe COVID-19 still remains unclear. In order to determine the optimal timing and patient selection, we investigated the outcomes of both COVID-19 and non-COVID-19 patients undergoing V-V ECMO support. METHODS: Overall, 138 patients were included in this study. Patients were stratified into two cohorts: those with COVID-19 and non-COVID-19 ARDS. RESULTS: The survival in patients with COVID-19 was statistically similar to non-COVID-19 patients (p = .16). However, the COVID-19 group demonstrated higher rates of bleeding (p = .03) and thrombotic complications (p < .001). The duration of V-V ECMO support was longer in COVID-19 patients compared to non-COVID-19 patients (29.0 ± 27.5 vs 15.9 ± 19.6 days, p < .01). Most notably, in contrast to the non-COVID-19 group, we found that COVID-19 patients who had been on a ventilator for longer than 7 days prior to ECMO had 100% mortality without a lung transplant. CONCLUSIONS: These findings suggest that COVID-19-associated ARDS was not associated with a higher post-ECMO mortality than non-COVID-19-associated ARDS patients, despite longer duration of extracorporeal support. Early initiation of V-V ECMO is important for improved ECMO outcomes in COVID-19 ARDS patients. Since late initiation of ECMO was associated with extremely high mortality related to lack of pulmonary recovery, it should be used judiciously or as a bridge to lung transplantation.

Clinical Characteristics and Outcomes of Patients With COVID-19-Associated Acute Respiratory Distress Syndrome Who Underwent Lung Transplant.

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.

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.

Comparative Effectiveness of Surgical Approaches for Lung Cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Successful surgical treatment of Stanford type A aortic dissection due to Salmonella aortitis.

BACKGROUND: Salmonella spp. cause infectious aortitis through the hematogenous spread of an intestinal Salmonella infection. Salmonella aortitis can result in extensive tissue damage in the aorta leading to complications including dissection, abscess formation, pseudoaneurysms, and rupture, which require early diagnosis and treatment with both surgery and antibiotic therapy. CASE PRESENTATION: We report a case of Salmonella aortitis complicated by Stanford type A aortic dissection. A 62-year-old man with a history of heroin use presented with chest pain, epigastric pain and vomiting. The computed tomography scan showed Stanford type A aortic dissection without malperfusion. At the time of surgery, an aortic dissection with purulent fluid and contained rupture was noted in the ascending aorta. Fluid culture was consistent with Salmonella. A composite valve-graft conduit aortic root replacement with ascending aorta and hemiarch replacement was performed. The patient recovered well and was discharged on long-term antibiotics. CONCLUSIONS: This rare case of a Stanford type A aortic dissection with contained rupture due to Salmonella aortitis was successfully treated with emergent surgery and antibiotic therapy.

Recipient, donor, and surgical factors leading to primary graft dysfunction after lung transplant.

Background: Primary graft dysfunction is a major cause of early mortality following lung transplantation. The International Society for Heart and Lung Transplantation subdivides it into 4 grades of increasing severity. Methods: A retrospective review of the institutional lung transplant database from March 2018 to September 2021 was performed. Patients were stratified into three groups: primary graft dysfunction grade 0 patients, grade 1 or 2 patients, and grade 3 patients. Recipient, donor, and surgical variables were analyzed by logistic regression analysis to identify risk factors for primary graft dysfunction grade 1 or 2 and grade 3. Results: Primary graft dysfunction grade 1 to 3 occurred in 45.0% of the cohort (n=68) of whom 33.3% (n=23) had primary graft dysfunction grade 3. Longer operative time was more common in primary graft dysfunction grade 1 to 3 patients (P<0.001). The 1-year survival of the patients with primary graft dysfunction grade 3 was lower than the others (grade 0-2 vs. 3, 93.7% vs. 65.2%, P=0.0006). Univariate analysis showed that acute respiratory distress syndrome, operative time, and intraoperative veno-arterial extracorporeal membrane oxygenation use were risk factors for primary graft dysfunction grades 1 or 2 and grade 3. Multivariate analysis identified that intraoperative veno-arterial extracorporeal membrane oxygenation use was an independent risk factor of primary graft dysfunction grade 1 or 2. Patients with an operative time of more than 8.18 hours had significantly higher incidence of primary graft dysfunction grade 3, acute kidney injury, and digital ischemia. Conclusions: The calculated predictors of primary graft dysfunction grade 1 or 2 were similar to those of primary graft dysfunction grade 3.

Primary graft dysfunction grade correlates with acute kidney injury stage after lung transplantation.

Background: Primary graft dysfunction (PGD) and acute kidney injury (AKI) are major early complications of lung transplantation and are associated with increased mortality. Lung injury after PGD can contribute to renal dysfunction; however, the association between PGD and AKI severity has not been thoroughly investigated. We analyzed the association between PGD grading and AKI staging, and the impact of AKI on subsequent changes to chronic kidney disease (CKD), including glomerular filtration rate (GFR), over time. Methods: This was a retrospective review of a single-center lung transplantation database between January 2018 and June 2022. AKI and GFR categories were classified according to the Kidney Disease: Improving Global Outcomes criteria. Spearman's and Kaplan-Meier tests were used to compare disease severity and assess survival. Results: In a total of 206 patients: 119 (57.8%), 25 (12.1%), 34 (16.5%), and 28 (13.6%) had PGD grades 0, 1, 2, and 3, respectively; 96 (46.6%), 47 (22.8%), 27 (13.1%), and 36 (17.5%) had AKI stages 0, 1, 2, and 3, respectively. Twenty-one of the 28 patients (75.0%) with PGD grade 3 had AKI stage 3. There was a significant correlation between PGD grade and AKI stage (P<0.001). There was also a significant correlation between AKI stage and GFR category of CKD at 3, 6, 9, and 12 months after lung transplantation (all P<0.001). For all AKI stages, GFR categories worsened with postoperative time. Conclusions: PGD grade was significantly correlated with AKI stage, and AKI stage was correlated with GFR categories of CKD.

Postreperfusion Pulmonary Artery Pressure Indicates Primary Graft Dysfunction After Lung Transplant.

BACKGROUND: Primary graft dysfunction is a risk factor of early mortality after lung transplant. Models identifying patients at high risk for primary graft dysfunction are limited. We hypothesize high postreperfusion systolic pulmonary artery pressure is a clinical marker for primary graft dysfunction. METHODS: This is a retrospective review of 158 consecutive lung transplants performed at a single academic center from January 2020 through July 2022. Only bilateral lung transplants were included and patients with pretransplant extracorporeal life support were excluded. RESULTS: Primary graft dysfunction occurred in 42.3% (n = 30). Patients with primary graft dysfunction had higher postreperfusion systolic pulmonary artery pressure (41 ± 9.1 mm Hg) than those without (31.5 ± 8.8 mm Hg) (P < .001). Logistic regression showed postreperfusion systolic pulmonary artery pressure is a predictor for primary graft dysfunction (odds ratio 1.14, 95% CI 1.06-1.24, P < .001). Postreperfusion systolic pulmonary artery pressure of 37 mm Hg was optimal for predicting primary graft dysfunction by Youden index. The receiver operating characteristic curve of postreperfusion systolic pulmonary artery pressure at 37 mm Hg (sensitivity 0.77, specificity 0.78, area under the curve 0.81), was superior to the prereperfusion pressure curve at 36 mm Hg (sensitivity 0.77, specificity 0.39, area under the curve 0.57) (P < .01). CONCLUSIONS: Elevated postreperfusion systolic pulmonary artery pressure after lung transplant is predictive of primary graft dysfunction. Postreperfusion systolic pulmonary artery pressure is more indicative of primary graft dysfunction than prereperfusion systolic pulmonary artery pressure. Using postreperfusion systolic pulmonary artery pressure as a positive signal of primary graft dysfunction allows earlier intervention, which could improve outcomes.

Indwelling Central Venous Catheters Drive Bloodstream Infection During Veno-venous Extracorporeal Membrane Oxygenation Support.

Blood stream infection (BSI) is a potentially lethal complication in patients receiving extracorporeal membrane oxygenation (ECMO). It may be particularly common in patients with veno-venous ECMO due to their long hospitalization in the intensive care unit. Given that these patients have concurrent indwelling central venous catheters (CVC), it is unclear whether the ECMO circuit, CVC, or both, contribute to BSI. This study evaluated the risk factors associated with BSI in patients receiving veno-venous ECMO in a single institution study of 61 patients from 2016 through 2019. All ECMO catheters and the circuit oxygenator fluid were aseptically collected and analyzed for microorganisms at the time of decannulation. New BSI was diagnosed in 15 (24.6%) patients and increased mortality by threefold. None of the ECMO catheters or oxygenator fluid were culture positive. BSI increased with CVC use of over 8 days and was significantly lowered when CVC were exchanged by day 8 compared with patients with exchanges at later points (15.0% vs. 42.8%, p = 0.02). Median length of CVC use in the BSI-negative and BSI-positive group were 6.3 ± 5.0 and 9.4 ± 5.1, respectively (p = 0.04). In summary, BSI is a potentially lethal complication in patients receiving ECMO. Indwelling CVC, not the ECMO circuitry, is the likely contributor for BSI, and exchanging CVC by day 8 can reduce the incidence of BSI.

MELD Score Predicts Outcomes in Patients Undergoing Venovenous Extracorporeal Membrane Oxygenation.

Venovenous extracorporeal membrane oxygenation (VV ECMO) is increasingly being used in the management of severe acute respiratory distress syndrome (ARDS). The Respiratory ECMO Survival Prediction (RESP) score is most commonly used to predict survival of patients undergoing ECMO. However, the RESP score does not incorporate renal and hepatic dysfunction which are frequently a part of the constellation of multiorgan dysfunction associated with ARDS. The Model for End-Stage Liver Disease (MELD) incorporates both liver and kidney dysfunction and is used in the risk stratification of liver transplant recipients as well as those undergoing cardiac surgery. The aim of this study was to assess the prognostic value of the MELD score in patients undergoing VV ECMO. Patients undergoing VV ECMO from 2016 to 2019 were extracted from our prospectively maintained institutional ECMO database and stratified based on MELD score. Baseline clinical, laboratory, and follow-up data, as well as post-ECMO outcomes, were compared. Of 71 patients, 50 patients (70.4%) had a MELD score <12 and 21 (29.6%) had a MELD score ≥12. The higher MELD score was associated with increased post-ECMO mortality but reduced risk of dialysis and tracheostomy. In multivariate analysis, higher MELD score (HR 1.35, 95% CI = 1.07-2.75), lower body surface area (HR 0.16, 0.04-0.65), RESP score (HR 0.75, 95% CI = 0.64-0.87), and platelet count (HR 0.99, 95% CI = 0.98-0.99), were significant predictors of postoperative mortality. We conclude that MELD score can be used complementarily to the RESP score to predict outcomes in patients with ARDS undergoing VV ECMO.

Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Institutes of Health. VIDEO ABSTRACT.

Comparative effectiveness and cost-efficiency of surgical approaches for thymectomy.

BACKGROUND: We compared the clinical outcomes and cost-efficiency of surgical approaches (sternotomy-open, video assisted thoracoscopic surgery, and robotic assisted thoracic surgery) for thymectomy. METHODS: This is a retrospective review of 220 consecutive patients who underwent thymectomy between January 1, 2007, and January 31, 2017. Surgical approach was determined by the surgeon, but we only included cases that could be resected using any of the 3 approaches. RESULTS: Open approach was used in 69 patients, whereas minimally invasive technique was used in 151 (97, video assisted thoracoscopic surgery; 54, robotic assisted thoracic surgery). Open surgery was associated with greater total hospital cost ($22,847 ± $20,061 vs $14,504 ± $10,845, P < .001). Open group also revealed longer duration of intensive care unit (1.2 ± 2.8 vs 0.2 ± 1.3 days, P < .001) and hospital stay (4.3 ± 4.0 vs 2.0 ± 2.6 days, P < .001). There were no differences in major adverse clinical outcomes. Long-term recurrence-free survival after resection of thymoma was similar between the groups. CONCLUSION: Minimally invasive techniques were equally efficacious compared with the open approach in the resection of the thymus. Additionally, their use was associated with decreased hospital duration of stay and reduced cost. Hence the use of minimally invasive approaches should be encouraged in the resection of thymus.

Lung transplantation for patients with severe COVID-19.

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.

Lung transplantation for pulmonary fibrosis secondary to severe COVID-19.

Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19 acute respiratory distress syndrome. Concerns limiting transplant include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and potential risk for allograft infection by pathogens associated with ventilator-induced pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to transplant. Here, we report the results of the first two successful lung transplantation procedures in patients with non-resolving COVID-19 associated acute respiratory distress syndrome in the United States. We performed smFISH to detect both positive and negative strands of SARS-CoV-2 RNA in the explanted lung tissue, extracellular matrix imaging using SHIELD tissue clearance, and single cell RNA-Seq on explant and warm post-mortem lung biopsies from patients who died from severe COVID-19 pneumonia. Lungs from patients with prolonged COVID-19 were free of virus but pathology showed extensive evidence of injury and fibrosis which resembled end-stage pulmonary fibrosis. Single cell RNA-Seq of the explanted native lungs from transplant and paired warm post-mortem autopsies showed similarities between late SARS-CoV-2 acute respiratory distress syndrome and irreversible end-stage pulmonary fibrosis requiring lung transplantation. There was no recurrence of SARS-CoV-2 or pathogens associated with pre-transplant ventilator associated pneumonias following transplantation in either patient. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is the only option for survival. SINGLE SENTENCE SUMMARY: Some patients with severe COVID-19 develop end-stage pulmonary fibrosis for which lung transplantation may be the only treatment.