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Objectives The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. Methods We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. Results We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). Conclusions We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.

Context.— This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. Objective.— To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy. Design.— Comprehensive data from 135 autopsy evaluations of COVID-19–positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple-choice and open-ended survey responses. Results.— Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than 1 preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. Conclusions.— Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (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 pneumonia2. 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. Analysis of bronchoalveolar lavage fluid samples from patients with SARS-CoV-2-induced respiratory failure suggests that SARS-CoV-2 infects alveolar macrophages to cause release of T cell chemoattractants, thereby inducing local inflammatory cytokine release and further T cell activation, ultimately resulting in a positive feedback loop that drives alveolar inflammation.

Sarcoidosis is an antigen-mediated chronic multisystem inflammatory disease characterized by the formation of non-caseating epithelioid granulomas that disrupt tissue architecture, trigger fibrosis, and precipitate organ dysfunction. Cardiac involvement portends a poorer prognosis, presenting with conduction disease, heart failure, pulmonary hypertension, valvular disease, pericardial effusions, tamponade, ventricular arrhythmias, and sudden death. A 75-year-old man with a history of heart failure with mildly reduced ejection fraction, suspected ocular sarcoidosis, monoclonal gammopathy of uncertain significance and 6 months of exertional dyspnea and lower extremity edema presented with acute-on-chronic volume overload. His labs were notable for elevated inflammatory markers. Cardiac MRI showed pericardial thickening, complex pericardial fluid. The differential diagnosis included tamponade, restrictive cardiomyopathy or constrictive pericarditis secondary to paraproteinemia, viral/idiopathic, vasculitis, tuberculosis, lupus, or sarcoidosis. Simultaneous right and left heart catheterization was consistent with constriction. The patient underwent surgical pericardiectomy. The pathology was consistent with sarcoidosis and intraoperative cultures grew Propionibacterium acnes. This case reviews the mechanism and diagnosis of sarcoidosis, the diagnosis of constrictive pericarditis, and a possible role for P. acnes in the development of sarcoidosis. Constrictive pericarditis is a rare presentation of cardiac sarcoidosis, particularly when the only other suspected involvement of sarcoidosis is uveitis. P. acnes has been associated with granuloma formation in sarcoid, although the mechanism is still unknown. P. acnes may represent a potential therapeutic target once a mechanism is further elucidated.

A 54-year-old man with chronic obstructive pulmonary disease (COPD) presented with three days of chest pain, dyspnea on exertion, and orthopnea. Physical examination revealed jugular venous distention and lower extremity edema. Cardiac biomarkers were elevated. The differential diagnosis for the clinical presentation included: acute coronary syndrome, and type II myocardial infarction or myocardial injury due to acute decompensated heart failure. External records demonstrated recurrent admissions for similar signs and symptoms, with negative coronary angiogram. Shortly after admission, the patient developed acute cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation. Echocardiogram revealed biventricular failure and a possible mitral valve vegetation. The differential diagnosis was refined to include myocarditis (infectious and noninfectious causes), bacterial versus marantic endocarditis, and infiltrative cardiomyopathies. Transesophageal echocardiography revealed mass-like, bileaflet thickening of the mitral valve, not consistent with true vegetation. Infectious, rheumatologic, and hypercoagulable workups were negative. Given the lack of a unifying diagnosis, a right ventricular (RV) endomyocardial biopsy was pursued. This revealed myocardial necrosis and fibrosis, and a mural thrombus with extensive eosinophils. The primary data was then revisited, which revealed history of peripheral eosinophilia that was intermittently suppressed by steroids given for COPD. Cardiac magnetic resonance imaging (MRI) demonstrated diffuse biventricular subendocardial late gadolinium enhancement and RV thrombi. Evaluation for underlying causes of eosinophilia was negative leading to the diagnosis of Loeffler’s endocarditis due to idiopathic hypereosinophilic syndrome. This case demonstrates: (1) the important role of cardiac MRI in the evaluation of both unexplained myocardial injury and new cardiomyopathy, (2) a rare case of Loeffler’s endocarditis requiring mechanical circulatory support, and (3) the consequences of both availability bias and failure to fully “unpack” the primary diagnostic data, which rendered the true etiology of the patient’s cardiogenic shock “hidden in plain sight.”

Some patients with severe COVID-19 develop end-stage pulmonary fibrosis for which lung transplantation may be the only treatment., A surgical solution for severe COVID-19 Despite optimal medical therapy, some patients with severe COVID-19 develop irreversible lung injury. In these patients who cannot be weaned from mechanical ventilation or extracorporeal life support, lung transplantation may be the only life-saving option. Bharat et al. now report the results of lung transplantation in three patients who had COVID-19–associated respiratory failure. SARS-CoV-2 RNA could not be detected in the explanted lungs of these patients, but fibrotic pathology and transcriptional changes resembling those of lungs from patients with pulmonary fibrosis were observed., 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 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 summarySome patients with severe COVID-19 develop end-stage pulmonary fibrosis for which lung transplantation may be the only treatment.

Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

To systematically investigate the reproducibility of global and segmental left ventricular (LV) velocities derived from tissue phase mapping (TPM). Breath held and ECG synchronized TPM data (spatial/temporal resolution = 2 × 2 mm(2)/20.8 ms) were acquired in 18 healthy volunteers. To analyze scan-rescan variability, TPM was repeated in all subjects during a second visit separated by 16 ± 5 days. Data analysis included LV segmentation, and quantification of global and regional (AHA 16-segment modal) metrics of LV function [velocity-time curves, systolic and diastolic peak and time-to-peak (TTP) velocities] for radial (Vr), long-axis (Vz) and circumferential (VΦ) LV velocities. Mean velocity time curves in basal, mid-ventricular, and apical locations showed highly similar LV motion patterns for all three velocity components (Vr, VΦ, Vz) for scan and rescan. No significant differences for both systolic and diastolic peak and TTP myocardial velocities were observed. Segmental analysis revealed similar regional peak Vr and Vz during both systole and diastole except for three LV segments (p = 0.045, p = 0.033, and p = 0.009). Excellent (p

Rationale: Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure. Transforming growth factor-β (TGF-β) signaling is thought to be intricately involved in creation of atrial fibrosis. Objective: We hypothesized that gene-based expression of dominant-negative type II TGF-β receptor (TGF-β-RII-DN) in the posterior left atrium in a canine heart failure model will sufficiently attenuate fibrosis-induced changes in atrial conduction and restitution to decrease AF. Because AF electrograms are thought to reflect AF substrate, we further hypothesized that TGF-β-RII-DN would lead to increased fractionation and decreased organization of AF electrograms. Methods and Results: Twenty-one dogs underwent injection+electroporation in the posterior left atrium of plasmid expressing a dominant-negative TGF-β type II receptor (pUBc-TGFβ-DN-RII; n=9) or control vector (pUBc- LacZ ; n=12), followed by 3 to 4 weeks of right ventricular tachypacing (240 bpm). Compared with controls, dogs treated with pUBC-TGFβ-DN-RII demonstrated an attenuated increase in conduction inhomogeneity, flattening of restitution slope and decreased duration of induced AF, with AF electrograms being more fractionated and less organized in pUBc-TGFβ-DN-RII versus pUBc- LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, p-SMAD2/3 and p-ERK1/2. Conclusions: Targeted gene-based reduction of TGF-β signaling in the posterior left atrium—with resulting decrease in replacement fibrosis—led to beneficial remodeling of both conduction and restitution characteristics of the posterior left atrium, translating into a decrease in AF and increased complexity of AF electrograms. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.

Background Mobilization of the innate immune response to clear and metabolize necrotic and apoptotic cardiomyocytes is a prerequisite to heart repair after cardiac injury. Suboptimal kinetics of dying myocyte clearance leads to secondary necrosis, and in the case of the heart, increased potential for collateral loss of neighboring non-regenerative myocytes. Despite the importance of myocyte phagocytic clearance during heart repair, surprisingly little is known about its underlying cell and molecular biology. Objective To determine if phagocytic receptor MERTK is expressed in human hearts and to elucidate key sequential steps and phagocytosis efficiency of dying adult cardiomyocytes, by macrophages. Results In infarcted human hearts, expression profiles of the phagocytic receptor MER-tyrosine kinase (MERTK) mimicked that found in experimental ischemic mouse hearts. Electron micrographs of myocardium identified MERTK signal along macrophage phagocytic cups and Mertk −/− macrophages contained reduced digested myocyte debris after myocardial infarction. Ex vivo co-culture of primary macrophages and adult cardiomyocyte apoptotic bodies revealed reduced engulfment relative to resident cardiac fibroblasts. Inefficient clearance was not due to the larger size of myocyte apoptotic bodies, nor were other key steps preceding the formation of phagocytic synapses significantly affected; this included macrophage chemotaxis and direct binding of phagocytes to myocytes. Instead, suppressed phagocytosis was directly associated with myocyte-induced inactivation of MERTK, which was partially rescued by genetic deletion of a MERTK proteolytic susceptibility site. Conclusion Utilizing an ex vivo co-cultivation approach to model key cellular and molecular events found in vivo during infarction, cardiomyocyte phagocytosis was found to be inefficient, in part due to myocyte-induced shedding of macrophage MERTK. These findings warrant future studies to identify other cofactors of macrophage–cardiomyocyte cross-talk that contribute to cardiac pathophysiology.

Background Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma characterized by the selective growth of large lymphoma cells within smaller vessel lumina. With less than 500 reported cases, little is understood about this extranodal B-cell lymphoma. This entity is considered widely underdiagnosed due to its nonspecific clinical presentation, often not detected until autopsy. Cytogenetic and immunophenotypic analyses of IVLBCL cases have revealed the presence of numerous chromosomal aberrations and the non-germinal center (post-germinal center) activated B-cell phenotype. Chromosomal abnormalities and clonal immunoglobulin rearrangements have been reported, however, very few cases have been studied. Methods We performed an IRB-approved retrospective review of the electronic medical records in our institution from January 2007 to January 2015 and identified five cases of IVLBCL. Morphologic evaluation, immunohistochemical (IHC) stains and PCR analysis for clonality was performed using primers specific for the immunoglobulin heavy (IgH) and light chains (IgK and IgL). IHC was used to characterize the neoplastic cells into germinal center B cell (GCB) and non-GCB phenotypes according to the Hans criteria. Results We identified five patients with the pathologic diagnosis of IVLBCL, three of whom were autopsy cases and two that were living patients referred for consultation. The clinical and pathologic features of these cases are summarized in Table 1. All three autopsy cases had multiorgan involvement by IVLBCL evidenced by CD20 positivity (see Image 1) and with the diagnosis made for the first time post-mortem. The two living patients had an initial presentation of rash and skin involvement. Brain involvement was present in two cases; in the first, which was an autopsy case, it presented in a perivascular morphologic pattern, and in the second case, it presented six months following the intradermal diagnosis of IVLBCL and subsequent R-CHOP treatment, as an extravascular 4.5 cm mass-forming lesion. This patient has been disease-free since receiving autologous stem cell transplant. Of the four cases with available material for IHC, the neoplastic cells were of non-GCB phenotype for three cases and GCB phenotype for one case. Clonal IgH rearrangement was identified in one of the five cases. Clonal light chain rearrangements were identified in two cases. Conclusions IVLBCL is an elusive diagnosis and more than half of our cases were diagnosed first time post-mortem. Similar to literature described, this is a highly aggressive lymphoma. The two patients in our series with mostly skin involvement appear to have a better prognosis. We also observed IVLBCL may not always present intravascularly, particularly in the brain, where it may present as perivascular or even form extravascular mass lesions. PCR analysis could detect clonal immunoglobulin gene rearrangements. However, assessing heavy chain gene rearrangement alone is not sensitive. PCR of the immunoglobulin light chain, particularly IgK, is a useful technique to increase the sensitivity for detection of clonality for IVLBCL. However, PCR analysis for clonality is inderminate in two cases and this could be attributed to DNA degradation as well as low tumor volume. Future directions that will be explored include performing next generation sequencing on VDJ junctions for these cases. | Case | Age | Sex | Clinical Features | Organ Involvement by Histology | GCB vs. non-GCB | PCR | | ---- | --- | --- | ------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------------- | --------------- | ------------------------------------------------------------------------ | | 1 | 81 | M | Respiratory failure, splenomegaly, thrombocytopenia, coagulopathy. | Multiorgan | Non-GCB | IgH: Indeterminate IgL: Indeterminate IgK: Indeterminate | | 2 | 76 | F | Deceased; presented with encephalopathy. Bone marrow involvement present. | Multiorgan | Non-GCB | IgH: Indeterminate IgL: Indeterminate IgK: Clonal | | 3 | 61 | F | 6 month of progressive rash, weakness, SOB, fever. Presented 6 month later with 4.5 cm left frontal brain lymphoma. Currently in remission. | Skin initially. Subsequently brain. | GCB | IgH: Indeterminate IgL: Indeterminate IgK: Indeterminate | | 4 | 56 | F | Remote history of non-Hodgkins lymphoma who subsequently presented with rash. | N/A | N/A | IgH: Indeterminate IgL: Clonal IgK: Clonal | | 5 | 84 | M | Presented with 3 months of fevers, chills, new thrombocytopenia. | Multiorgan | Non-GCB | IgH: Clonal IgL: Clonal IgK: Clonal | Table 1. ![Figure 1.][1] Figure 1. Disclosures No relevant conflicts of interest to declare. [1]: pending:yes