Publications by authors named "Ankit Bharat"

140 Publications

Lung Transplantation of COVID-19 Patients: How I Do It.

Chest 2021 Aug 19. Epub 2021 Aug 19.

Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA.

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.
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http://dx.doi.org/10.1016/j.chest.2021.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373594PMC
August 2021

Lung donation following SARS-CoV-2 infection.

Am J Transplant 2021 Jul 31. Epub 2021 Jul 31.

Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

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.
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http://dx.doi.org/10.1111/ajt.16777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441925PMC
July 2021

Lung transplantation for COVID-19-associated ARDS - Authors' reply.

Lancet Respir Med 2021 09 2;9(9):e90. Epub 2021 Jul 2.

Department of Surgery, Division of Thoracic Surgery, University of Florida, Gainesville, FL, USA.

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http://dx.doi.org/10.1016/S2213-2600(21)00288-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253536PMC
September 2021

Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells.

bioRxiv 2020 Aug 7. Epub 2020 Aug 7.

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS) [1]. Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia [2]. We collected bronchoalveolar lavage fluid samples from 86 patients with SARS-CoV-2-induced respiratory failure and 252 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. We performed single cell RNA-Seq in 5 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours of intubation. In the majority of patients with SARS-CoV-2 infection at the onset of mechanical ventilation, the alveolar space is persistently enriched in alveolar macrophages and T cells without neutrophilia. Bulk and single cell transcriptomic profiling suggest SARS-CoV-2 infects alveolar macrophages that respond by recruiting T cells. These T cells release interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell recruitment. Our results suggest SARS-CoV-2 causes a slowly unfolding, spatially-limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 transcripts and T cells form a positive feedback loop that drives progressive alveolar inflammation. This manuscript is accompanied by an online resource: https://www.nupulmonary.org/covid-19/.

One Sentence Summary: SARS-CoV-2-infected alveolar macrophages form positive feedback loops with T cells in patients with severe COVID-19.
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http://dx.doi.org/10.1101/2020.08.05.238188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132268PMC
August 2020

Blood transfusions may adversely affect survival outcomes of patients with lung cancer: a systematic review and meta-analysis.

Transl Lung Cancer Res 2021 Apr;10(4):1700-1710

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Despite common use in clinical practice, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. The purpose of the current study is to perform an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients.

Methods: We searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to November 2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I test. Publication bias was explored via funnel plot and trim-and-fill analyses.

Results: We included 23 cohort studies with 12,175 patients (3,027 cases and 9,148 controls) for meta-analysis. Among these records, 22 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.35, 95% CI: 1.14-1.61, P<0.001, I=0%) and DFS (HR=1.46, 95% CI: 1.15-1.86, P=0.001, I=0%) of people with lung cancer. No evidence of significant publication bias was detected in funnel plot and trim-and-fill analyses (OS: HR=1.26, 95% CI: 1.07-1.49, P=0.006; DFS: HR=1.35, 95% CI: 1.08-1.69, P=0.008).

Conclusions: Blood transfusions were associated with decreased survival of patients with lung cancer.
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http://dx.doi.org/10.21037/tlcr-20-933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107741PMC
April 2021

Modern ECMO circuitry may obviate the need for continuous systemic anticoagulation.

Ann Thorac Surg 2021 May 8. Epub 2021 May 8.

Northwestern University Feinberg School of Medicine, 676 N. St Clair St, Suite 650, Chicago, IL 60611. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2021.04.073DOI Listing
May 2021

Automated, multiparametric monitoring of respiratory biomarkers and vital signs in clinical and home settings for COVID-19 patients.

Proc Natl Acad Sci U S A 2021 05;118(19)

Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL 60208;

Capabilities in continuous monitoring of key physiological parameters of disease have never been more important than in the context of the global COVID-19 pandemic. Soft, skin-mounted electronics that incorporate high-bandwidth, miniaturized motion sensors enable digital, wireless measurements of mechanoacoustic (MA) signatures of both core vital signs (heart rate, respiratory rate, and temperature) and underexplored biomarkers (coughing count) with high fidelity and immunity to ambient noises. This paper summarizes an effort that integrates such MA sensors with a cloud data infrastructure and a set of analytics approaches based on digital filtering and convolutional neural networks for monitoring of COVID-19 infections in sick and healthy individuals in the hospital and the home. Unique features are in quantitative measurements of coughing and other vocal events, as indicators of both disease and infectiousness. Systematic imaging studies demonstrate correlations between the time and intensity of coughing, speaking, and laughing and the total droplet production, as an approximate indicator of the probability for disease spread. The sensors, deployed on COVID-19 patients along with healthy controls in both inpatient and home settings, record coughing frequency and intensity continuously, along with a collection of other biometrics. The results indicate a decaying trend of coughing frequency and intensity through the course of disease recovery, but with wide variations across patient populations. The methodology creates opportunities to study patterns in biometrics across individuals and among different demographic groups.
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http://dx.doi.org/10.1073/pnas.2026610118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126790PMC
May 2021

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

Lancet Respir Med 2021 05 31;9(5):487-497. Epub 2021 Mar 31.

Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1016/S2213-2600(21)00077-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012035PMC
May 2021

Diaphragm and Phrenic Nerve Ultrasound in COVID-19 Patients and Beyond: Imaging Technique, Findings, and Clinical Applications.

J Ultrasound Med 2021 Mar 27. Epub 2021 Mar 27.

Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

The diaphragm, the principle muscle of inspiration, is an under-recognized contributor to respiratory disease. Dysfunction of the diaphragm can occur secondary to lung disease, prolonged ventilation, phrenic nerve injury, neuromuscular disease, and central nervous system pathology. In light of the global pandemic of coronavirus disease 2019 (COVID-19), there has been growing interest in the utility of ultrasound for evaluation of respiratory symptoms including lung and diaphragm sonography. Diaphragm ultrasound can be utilized to diagnose diaphragm dysfunction, assess severity of dysfunction, and monitor disease progression. This article reviews diaphragm and phrenic nerve ultrasound and describes clinical applications in the context of COVID-19.
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http://dx.doi.org/10.1002/jum.15706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250472PMC
March 2021

Unusual Complication of a Right Ventricular Support-Extracorporeal Membrane Oxygenation Cannula.

JAMA Cardiol 2021 Jun;6(6):723-724

Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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http://dx.doi.org/10.1001/jamacardio.2021.0284DOI Listing
June 2021

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

J Natl Compr Canc Netw 2021 03 2;19(3):254-266. Epub 2021 Mar 2.

29Mayo Clinic Cancer Center.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.
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http://dx.doi.org/10.6004/jnccn.2021.0013DOI Listing
March 2021

Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

Division of Thoracic Surgery and.

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.
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http://dx.doi.org/10.1172/jci.insight.147282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026186PMC
March 2021

Prophylactic Ureaplasma-directed Antimicrobials in Lung Donors Can Prevent Fatal Hyperammonemia.

Transplantation 2021 03;105(3):e35-e36

Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1097/TP.0000000000003540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905692PMC
March 2021

The lung microenvironment shapes a dysfunctional response of alveolar macrophages in aging.

J Clin Invest 2021 02;131(4)

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois, USA.

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
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http://dx.doi.org/10.1172/JCI140299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919859PMC
February 2021

Elevated CO Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation.

Front Physiol 2020 21;11:630910. Epub 2021 Jan 21.

Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.

Muscle dysfunction often occurs in patients with chronic obstructive pulmonary diseases (COPD) and affects ventilatory and non-ventilatory skeletal muscles. We have previously reported that hypercapnia (elevated CO levels) causes muscle atrophy through the activation of the AMPKα2-FoxO3a-MuRF1 pathway. In the present study, we investigated the effect of normoxic hypercapnia on skeletal muscle regeneration. We found that mouse C2C12 myoblasts exposed to elevated CO levels had decreased fusion index compared to myoblasts exposed to normal CO. Metabolic analyses of C2C12 myoblasts exposed to high CO showed increased oxidative phosphorylation due to increased fatty acid oxidation. We utilized the cardiotoxin-induced muscle injury model in mice exposed to normoxia and 10% CO for 21 days and observed that muscle regeneration was delayed. High CO-delayed differentiation in both mouse C2C12 myoblasts and skeletal muscle after injury and was restored to control levels when cells or mice were treated with a carnitine palmitoyltransfearse-1 (CPT1) inhibitor. Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury.
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http://dx.doi.org/10.3389/fphys.2020.630910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859333PMC
January 2021

Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia.

Nature 2021 02 11;590(7847):635-641. Epub 2021 Jan 11.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.
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http://dx.doi.org/10.1038/s41586-020-03148-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987233PMC
February 2021

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

ASAIO J 2021 08;67(8):871-877

From the Department of Medicine.

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.
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http://dx.doi.org/10.1097/MAT.0000000000001321DOI Listing
August 2021

Comparative Effectiveness of Surgical Approaches for Lung Cancer.

J Surg Res 2021 07 9;263:274-284. Epub 2020 Dec 9.

Division of Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

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, I = 0%) as well as for elderly patients (odds ratio 0.45, 95% CI 0.31-0.65, I = 30%), but did not demonstrate benefit for high-risk patients (odds ratio 0.74, 95% CI 0.06-8.73, I = 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.
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http://dx.doi.org/10.1016/j.jss.2020.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169528PMC
July 2021

Lung transplantation for patients with severe COVID-19.

Sci Transl Med 2020 12 30;12(574). Epub 2020 Nov 30.

Division of Pulmonary and Critical Care Medicine, Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

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.
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http://dx.doi.org/10.1126/scitranslmed.abe4282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050952PMC
December 2020

Comment on Let's Build Bridges to Recovery in COVID-19 ARDS, not Burn Them!

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Division of Thoracic Surgery, University of Florida, Gainesville, FL Division of Thoracic Surgery, University of Toronto, Toronto, Canada Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.

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http://dx.doi.org/10.1097/SLA.0000000000004623DOI Listing
November 2020

Lymphatic drainage from bronchus-associated lymphoid tissue in tolerant lung allografts promotes peripheral tolerance.

J Clin Invest 2020 12;130(12):6718-6727

Departments of Surgery.

Tertiary lymphoid organs are aggregates of immune and stromal cells including high endothelial venules and lymphatic vessels that resemble secondary lymphoid organs and can be induced at nonlymphoid sites during inflammation. The function of lymphatic vessels within tertiary lymphoid organs remains poorly understood. During lung transplant tolerance, Foxp3+ cells accumulate in tertiary lymphoid organs that are induced within the pulmonary grafts and are critical for the local downregulation of alloimmune responses. Here, we showed that tolerant lung allografts could induce and maintain tolerance of heterotopic donor-matched hearts through pathways that were dependent on the continued presence of the transplanted lung. Using lung retransplantation, we showed that Foxp3+ cells egressed from tolerant lung allografts via lymphatics and were recruited into donor-matched heart allografts. Indeed, survival of the heart allografts was dependent on lymphatic drainage from the tolerant lung allograft to the periphery. Thus, our work indicates that cellular trafficking from tertiary lymphoid organs regulates immune responses in the periphery. We propose that these findings have important implications for a variety of disease processes that are associated with the induction of tertiary lymphoid organs.
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http://dx.doi.org/10.1172/JCI136057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685742PMC
December 2020

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

medRxiv 2020 Oct 27. Epub 2020 Oct 27.

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.
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http://dx.doi.org/10.1101/2020.10.26.20218636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605582PMC
October 2020

Impact of Screening and Treatment of Ureaplasma spp on Hyperammonemia Syndrome in Lung Transplant Recipients: A Single Center Experience.

Clin Infect Dis 2020 Oct 17. Epub 2020 Oct 17.

Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Infection with Ureaplasma species (spp) has been linked to fatal hyperammonemia syndrome (HS) in lung transplant recipients. We sought to characterize the epidemiology of Ureaplasma spp in candidates and donors and describe outcomes of antimicrobial therapy in preventing and treating HS.

Methods: Candidate testing for Ureaplasma spp was performed with urine culture and PCR pre-transplant. Positive candidates were treated with levofloxacin. Donor testing was performed with bronchoalveolar lavage culture and PCR intraoperatively. From 7/2014-2/2017 patients were treated according to results; from 2/2017-10/2018 recipients received empiric levofloxacin and azithromycin at transplant until testing returned negative. HS was defined as new onset altered mental status after transplant with ammonia > 200 µmol/L.

Results: 60 patients who underwent lung transplant were included. 80% (n = 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (n = 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (n = 8) had positive donor BAL testing at the time of lung transplant. 3 patients developed HS a median of 7 days post-transplant; 2 died of HS. Recipients of organs with Ureaplasma spp who received empiric therapy did not develop HS. Donors with Ureaplasma spp were younger and more sexually active.

Conclusion: Donor-derived Ureaplasma spp in lung transplant was associated with HS. Screening lung donors for Ureaplasma spp might allow for targeted therapy to reduce risk for development of HS, but future confirmatory studies are needed.
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http://dx.doi.org/10.1093/cid/ciaa1570DOI Listing
October 2020

Malignant melanoma arising in a primary mediastinal germ cell tumor.

Pathol Res Pract 2020 Nov 11;216(11):153210. Epub 2020 Sep 11.

Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL, 60611, USA.

Primary mediastinal germ cell tumors with somatic malignancies are rare. We report a case of a 34-year old man with melanoma arising in a primary mediastinal mixed germ cell tumor. On initial biopsy, the patient was found to have a germ cell tumor containing yolk sac and embryonal components only. After chemotherapy, histopathological evaluation of the residual tumor in the wide local resection specimen revealed a mature teratoma with melanoma. Molecular studies demonstrated that the residual germ cell tumor harbored KIT and NRAS mutations associated with malignant melanoma.
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http://dx.doi.org/10.1016/j.prp.2020.153210DOI Listing
November 2020

Decline in Club Cell Secretory Proteins, Exosomes Induction and Immune Responses to Lung Self-antigens, Kα1 Tubulin and Collagen V, Leading to Chronic Rejection After Human Lung Transplantation.

Transplantation 2021 06;105(6):1337-1346

Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.

Background: Chronic lung allograft dysfunction (CLAD), is a major hurdle for long-term lung allograft survival after lung transplant and roughly 50% of lung transplant recipients (LTxRs) develop CLAD within 5 years. The mechanisms of CLAD development remain unknown. Donor-specific immune responses to HLA and lung self-antigens (SAgs) are vital to the pathogenesis of CLAD. Reduction in Club cell secretory protein (CCSP) has been reported in bronchoalveolar lavage (BAL) fluid samples from LTxRs with bronchiolitis obliterans syndrome (BOS). CCSP levels in BAL fluid and development of antibodies to lung SAgs in plasma were determined by ELISA. Cytokines in BAL fluid were analyzed by 30-plex Luminex panel. Exosomes from BAL fluid or plasma were analyzed for SAgs, natural killer (NK) cells markers, and cytotoxic molecules.

Results: We demonstrate that LTxRs with BOS have lower CCSP levels up to 9 months before BOS diagnosis. LTxRs with antibodies to SAgs 1-year posttransplant also developed DSA (43%) and had lower CCSP. BOS with lower CCSP also induced Interleukin-8 and reduced vascular endothelial growth factor. Exosomes from BOS contained increased SAgs, NK cells markers, and cytotoxic molecules.

Conclusions: We conclude lower CCSP leads to inflammation, pro-inflammatory cytokine production, immune responses to HLA and SAgs, and induction of exosomes. For the first time, we demonstrate that CCSP loss results in exosome release from NK cells capable of stimulating innate and adaptive immunity posttransplant. This increases the risk of BOS, suggesting a role of NK cell exosomes in CLAD development.
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http://dx.doi.org/10.1097/TP.0000000000003428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917153PMC
June 2021

Epithelial cell-specific loss of function of causes a spontaneous COPD-like phenotype and up-regulates expression in mice.

Sci Adv 2020 08 14;6(33):eabb7238. Epub 2020 Aug 14.

Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of , which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of , the receptor for SARS-CoV-2. Concomitant partial loss of κ prevented the development of COPD-like phenotype in -deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.
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http://dx.doi.org/10.1126/sciadv.abb7238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428331PMC
August 2020

Bacterial products in donor airways prevent the induction of lung transplant tolerance.

Am J Transplant 2021 01 5;21(1):353-361. Epub 2020 Sep 5.

Department of Surgery, Washington University, Saint Louis, Missouri.

Although postoperative bacterial infections can trigger rejection of pulmonary allografts, the impact of bacterial colonization of donor grafts on alloimmune responses to transplanted lungs remains unknown. Here, we tested the hypothesis that bacterial products present within donor grafts at the time of implantation promote lung allograft rejection. Administration of the toll-like receptor 2 (TLR2) agonist Pam Cys to Balb/c wild-type grafts triggered acute cellular rejection after transplantation into B6 wild-type recipients that received perioperative costimulatory blockade. Pam Cys -triggered rejection was associated with an expansion of CD8 T lymphocytes and CD11c CD11b MHC (major histocompatibility complex) class II antigen-presenting cells within the transplanted lungs. Rejection was prevented when lungs were transplanted into TLR2-deficient recipients but not when MyD88-deficient donors were used. Adoptive transfer of B6 wild-type monocytes, but not T cells, following transplantation into B6 TLR2-deficient recipients restored the ability of Pam Cys to trigger acute cellular rejection. Thus, we have demonstrated that activation of TLR2 by a bacterial lipopeptide within the donor airways prevents the induction of lung allograft tolerance through a process mediated by recipient-derived monocytes. Our work suggests that donor lungs harboring bacteria may precipitate an inflammatory response that can facilitate allograft rejection.
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http://dx.doi.org/10.1111/ajt.16256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775268PMC
January 2021

Circulating exosomes with lung self-antigens as a biomarker for chronic lung allograft dysfunction: A retrospective analysis.

J Heart Lung Transplant 2020 Jul 7. Epub 2020 Jul 7.

Norton Thoracic Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona. Electronic address:

Background: Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS.

Methods: Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software.

Results: Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs-containing exosomes at 6 and 12 months before BOS.

Conclusions: Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.
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http://dx.doi.org/10.1016/j.healun.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790863PMC
July 2020

The role of miRNA-155 in the immunopathogenesis of obliterative airway disease in mice induced by circulating exosomes from human lung transplant recipients with chronic lung allograft dysfunction.

Cell Immunol 2020 09 15;355:104172. Epub 2020 Jul 15.

Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA. Electronic address:

Human lung transplant recipients undergoing rejection induce circulatory exosomes with lung self-antigens (SAgs), K-alpha 1 Tubulin and Collagen V, and immunization of C57BL/6 mice with exosomes induced obliterative airway disease (HEI-OAD). We analyzed whether exosomes with SAgs induced immunity in microRNA-155 knockout mice (miR-155KO), as microRNA-155 is an immune regulator. C57BL/6 and miR-155KO were immunized with exosomes from stable or chronic rejection (bronchiolitis obliterans syndrome (BOS) and on day 30, induction of exosomes, antibodies (Abs) to SAgs and cellular immunity were determined. C57BL/6 immunized with exosomes from BOS developed OAD. These immunized animals also developed Abs to SAgs and increased frequency of SAg-specific IFNγ and IL17- producing cells. In contrast, Abs to SAgs did not develop in miR-155KO and there was reduction in frequency of cells producing IL10. Upregulation of suppressor of cytokine signaling for lung inflammation was also noted resulting in abrogation of induction of exosomes with SAgs OAD.
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http://dx.doi.org/10.1016/j.cellimm.2020.104172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433931PMC
September 2020
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