A Large Postmortem Database of COVID-19 Patients Can Inform Disease Research and Public Policy Decision Making.

CONTEXT.­: Autopsies performed on COVID-19 patients have provided critical information about SARS-CoV-2's tropism, mechanisms of tissue injury, and the spectrum of disease. OBJECTIVE.­: To provide an updated database of postmortem disease in COVID-19 patients, assess relationships among clinical and pathologic variables, evaluate the accuracy of death certification, and correlate disease variables to causes of death. DESIGN.­: The 272 postmortem examinations reported in this paper were submitted by 14 pathologists from 9 medical or forensic institutions across the United States. The study spans the eras of the 3 principal COVID-19 strains and incorporates surveyed demographic, clinical, and postmortem data from decedents infected with SARS-CoV-2, including primary and contributing causes of death. It is the largest database of its kind to date. RESULTS.­: Demographics of the decedents reported here correspond well to national statistics. Primary causes of death as determined by autopsy and official death certificates were significantly correlated. When specifically cited disease conditions found at autopsy were correlated with COVID-19 versus non-COVID-19 death, only lung findings characteristic of SARS-CoV-2 infection or the absence of lung findings were significantly associated. CONCLUSIONS.­: Changes in hospitalization and disease likely stem from longer lifespans after COVID-19 diagnosis and alteration in treatment approaches. Although Omicron variants preferentially replicate in the upper airways, autopsied patients who died of COVID-19 in that time period showed the same lung damage as earlier decedents. Most importantly, findings suggest that there are still unelucidated risk factors for death from COVID-19 including possibly genetic susceptibility.

Intramyocardial Hematoma During Catheter Ablation for Scar-Related Ventricular Tachycardia.

BACKGROUND: Intramural hematoma during ablation for scar-related ventricular tachycardia (VT) is a rare but life-threatening complication. OBJECTIVES: The goal of this study was to describe the features and outcomes of intramural hematoma during ablation for scar-related VT. METHODS: From 2010 to 2022, >3,514 ablations for ventricular arrhythmias were performed at 2 institutions. Four cases of intramural hematoma complicating VT ablation for scar-related VT were identified. Intraprocedural details, imaging data, and surgical notes were reviewed to create a recognizable pattern of events highlighting this complication. RESULTS: In 3 of 4 cases, intramural hematoma occurred during catheter ablation with an open irrigated 3.5 mm tipped catheter using normal saline for irrigation. In one case, hematoma was noted after ablation using an investigational needle electrode catheter. The occurrence of a steam pop preceded detection of an expanding intramural hematoma in 3 cases. ST-segment elevation on electrocardiography was evident in 3 cases; intracardiac echocardiographic imaging detected the hematoma in all cases. Epicardial rupture and pericardial effusion requiring drainage occurred in 3 cases, whereas 1 hematoma was self-contained and did not require intervention. Surgical intervention was performed in 2 cases, with successful outcomes. One patient who was deemed not a surgical candidate died of progressive cardiogenic shock. CONCLUSIONS: Intramural hematoma during ablation for scar-related VT is a rare but potentially catastrophic complication that requires prompt recognition. Steam pops during ablation frequently precede the hematoma formation. Surgical intervention may be life-saving, although contained hematomas can occasionally be managed conservatively.

Differences between κ and λ light chain amyloidosis analyzed by a pathologic scoring system.

OBJECTIVES: Amyloid light chain (AL)-κ and AL-λ share common histopathologic changes; however, the potential difference in clinical manifestations, histologic findings, and clinical significance between the 2 subtypes remain unclear. METHODS: In a retrospective study, 94 kidney biopsies for AL amyloidosis were evaluated using the composite scarring injury score (CSIS) and amyloid score (AS). Results were then compared between AL-κ and AL-λ. RESULTS: Comparing AS and CSIS between AL-κ and AL-λ, the AS was significantly higher in AL-κ than in AL-λ, with 2 components of AS (capillary wall and vascular amyloid) scoring higher in AL-κ than in AL-λ, while mesangial and interstitial ASs were similar in the 2 cohorts. In addition, the proportion of periodic acid-Schiff strong-staining amyloid in AL-κ was markedly higher than in AL-λ. There was no significant difference in CSIS and its components between the 2 subtypes of AL amyloidosis. CONCLUSIONS: Overall, AL-κ presents with higher serum creatinine and a higher AS score than AL-λ at biopsy, which may indicate a worse prognosis and be an important reference for clinical management.

Kidney collecting duct cells make vasopressin in response to NaCl-induced hypertonicity.

Vasopressin has traditionally been thought to be produced by the neurohypophyseal system and then released into the circulation where it regulates water homeostasis. The questions of whether vasopressin could be produced outside of the brain and if the kidney could be a source of vasopressin are raised by the syndrome of inappropriate antidiuretic hormone secretion (vasopressin). We found that mouse and human kidneys expressed vasopressin mRNA. Using an antibody that detects preprovasopressin, we found that immunoreactive preprovasopressin protein was found in mouse and human kidneys. Moreover, we found that murine collecting duct cells made biologically active vasopressin, which increased in response to NaCl-mediated hypertonicity, and that water restriction increased the abundance of kidney-derived vasopressin mRNA and protein expression in mouse kidneys. Thus, we provide evidence of biologically active production of kidney-derived vasopressin in kidney tubular epithelial cells.

Cytomegalovirus pneumonia presenting as pulmonary nodules.

Cytomegalovirus (CMV) pneumonia is a well-known cause of morbidity and mortality in patients with a history of allogenic hematopoietic stem cell transplant. Radiographically, CMV pneumonia most commonly presents as bilateral ground glass opacities; however, the presentation is non-specific and can be variable, including presenting as areas of air-space consolidation or pulmonary nodules. We report a case of a 70-year-old man who presented with rapidly progressive bilateral pulmonary nodules approximately two months after receiving a bone marrow transplant. No infectious etiology was identified for the pulmonary nodules, and a bronchoscopy was unable to be performed due to a rapid decline in the patient's overall condition and respiratory status. The patient died shortly after the decision was made to transition to palliative care and a limited autopsy was performed to explore the pulmonary findings. Corresponding to premortem imaging were the postmortem gross findings of numerous bilateral pulmonary nodules and a large mass-like area of consolidation in the right upper lobe. Microscopic examination of the nodules demonstrated a necrotizing pneumonia with few foci of viral cytopathologic change consistent with CMV, which was confirmed by immunohistochemistry. While CMV is a common infectious agent in the immunocompromised population, CMV pneumonia continues to be a challenging entity due to difficulty in diagnosis and treatment. Rapidly enlarging pulmonary nodules in an immunosuppressed patient is highly suggestive of an infectious process and careful histologic examination for viral cytopathologic change is essential.

Herpes simplex virus-1 triggered hemophagocytic lymphohistiocytosis in a patient with granulomatosis with polyangiitis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive hyperinflammatory syndrome in which an inciting event triggers massive, uninhibited activation of T lymphocytes and macrophages. Although viral infections are the most common trigger of HLH, cases of HSV-1 induced HLH are rare in adults. We present the case and postmortem findings of a 27-year-old woman diagnosed with HLH in the setting of immunosuppression for the treatment of granulomatosis with polyangiitis (GPA). Autopsy revealed evidence of herpes simplex virus-1 (HSV-1) infection and no findings suggestive of GPA recurrence.

Cytomegalovirus pneumonia presenting as pulmonary nodules

Abstract Cytomegalovirus (CMV) pneumonia is a well-known cause of morbidity and mortality in patients with a history of allogenic hematopoietic stem cell transplant. Radiographically, CMV pneumonia most commonly presents as bilateral ground glass opacities; however, the presentation is non-specific and can be variable, including presenting as areas of air-space consolidation or pulmonary nodules. We report a case of a 70-year-old man who presented with rapidly progressive bilateral pulmonary nodules approximately two months after receiving a bone marrow transplant. No infectious etiology was identified for the pulmonary nodules, and a bronchoscopy was unable to be performed due to a rapid decline in the patient's overall condition and respiratory status. The patient died shortly after the decision was made to transition to palliative care and a limited autopsy was performed to explore the pulmonary findings. Corresponding to premortem imaging were the postmortem gross findings of numerous bilateral pulmonary nodules and a large mass-like area of consolidation in the right upper lobe. Microscopic examination of the nodules demonstrated a necrotizing pneumonia with few foci of viral cytopathologic change consistent with CMV, which was confirmed by immunohistochemistry. While CMV is a common infectious agent in the immunocompromised population, CMV pneumonia continues to be a challenging entity due to difficulty in diagnosis and treatment. Rapidly enlarging pulmonary nodules in an immunosuppressed patient is highly suggestive of an infectious process and careful histologic examination for viral cytopathologic change is essential.

Herpes simplex virus-1 triggered hemophagocytic lymphohistiocytosis in a patient with granulomatosis with polyangiitis

ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive hyperinflammatory syndrome in which an inciting event triggers massive, uninhibited activation of T lymphocytes and macrophages. Although viral infections are the most common trigger of HLH, cases of HSV-1 induced HLH are rare in adults. We present the case and postmortem findings of a 27-year-old woman diagnosed with HLH in the setting of immunosuppression for the treatment of granulomatosis with polyangiitis (GPA). Autopsy revealed evidence of herpes simplex virus-1 (HSV-1) infection and no findings suggestive of GPA recurrence.

Assessment of the Banff Working Group classification of definitive BK polyomavirus nephropathy.

Polyomavirus associated nephropathy (PyVAN) continues to be a burden in renal transplantation leading to allograft insufficiency or graft failure. A presumptive diagnosis of PyVAN is made based on the presence of BK polyomavirus in patients' plasma; however, kidney biopsy remains the gold standard to establish a definitive diagnosis. The Banff Working Group on PyVAN proposed a novel classification of definitive PyVAN based on polyomavirus replication/load level and the extent of interstitial fibrosis. The aim of our study was to test the newly defined classes of PyVAN using independent cohorts of 124 kidney transplant patients with PyVAN with respect to the initial presentation and outcome, and to compare our analysis to that previously reported. Detailed analysis of our cohort revealed that the proposed classification of PyVAN did not stratify or identify patients at increased risk of allograft failure. Specifically, while class 3 was associated with the worst prognosis, there was no significant difference between the outcomes in classes 1 and 2. We also found that the timing post-transplantation and inflammation in areas of interstitial fibrosis and tubular atrophy might be additional factors contributing to an unfavorable allograft outcome in patients with PyVAN.

Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.

Histopathological findings and clinicopathologic correlation in COVID-19: a systematic review.

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) pandemic has had devastating effects on global health and worldwide economy. Despite an initial reluctance to perform autopsies due to concerns for aerosolization of viral particles, a large number of autopsy studies published since May 2020 have shed light on the pathophysiology of Coronavirus disease 2019 (COVID-19). This review summarizes the histopathologic findings and clinicopathologic correlations from autopsies and biopsies performed in patients with COVID-19. PubMed and Medline (EBSCO and Ovid) were queried from June 4, 2020 to September 30, 2020 and histopathologic data from autopsy and biopsy studies were collected based on 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 58 studies reporting 662 patients were included. Demographic data, comorbidities at presentation, histopathologic findings, and virus detection strategies by organ system were collected. Diffuse alveolar damage, thromboembolism, and nonspecific shock injury in multiple organs were the main findings in this review. The pathologic findings emerging from autopsy and biopsy studies reviewed herein suggest that in addition to a direct viral effect in some organs, a unifying pathogenic mechanism for COVID-19 is ARDS with its known and characteristic inflammatory response, cytokine release, fever, inflammation, and generalized endothelial disturbance. This study supports the notion that autopsy studies are of utmost importance to our understanding of disease features and treatment effect to increase our knowledge of COVID-19 pathophysiology and contribute to more effective treatment strategies.

Diagnostic renal mass biopsy is associated with individual categories of PADUA and RENAL nephrometry scores: Analysis of diagnostic and concordance rates with surgical resection.

BACKGROUND: Renal mass biopsy (RMB) is a safe and accurate method for diagnosis and clinical management of renal masses. However, the non-diagnostic rate is a limiting factor. We tested the hypothesis that imaging characteristics and anatomic complexity of the mass may impact RMB diagnostic outcome using the preoperative aspects and dimensions used for an anatomical (PADUA) classification and radius-exophytic/endophytic-nearness-anterior/posterior-location (RENAL) score. MATERIAL AND METHODS: Single institution, retrospective study of 490 renal masses from 443 patients collected from 2001 to 2018. Outcome measurements include (1) diagnostic and concordance rates amongst RMB types and RMB with surgical resection specimens; (2) association between diagnostic RMB and anatomical complexity of renal masses. The analysis was conducted in unselected masses and small renal masses (SRMs). RESULTS: RMB was performed by fine needle aspiration (FNA), core needle biopsy (CNB), or both (FNA+CNB). Non-diagnostic rate was significantly higher for FNA compared to CNB and FNA+CNB in both unselected and SRMs. Subset analysis in the FNA+CNB group showed similar diagnostic rates for FNA and CNB. In unselected masses, specificity for FNA, CNB, and FNA+CNB was 100%. Sensitivity was higher for CNB (90.1%, P = 0.002) and FNA+CNB (96.3%, P = 0.004) compared to FNA (66.7%). For unselected masses, endophytic growth predicted a non-diagnostic CNB. R.E.N.A.L location entirely between the polar lines (central) and entirely above the upper polar line predicted a diagnostic CNB. Sonography-guidance predicted a diagnostic FNA. For SRMs, non-diagnostic CNB was associated with endophytic growth, while diagnostic CNB was associated with renal sinus invasion and operator experience. More cystic masses were sampled by FNA, but diagnostic results were similar for FNA and CNB. CONCLUSIONS: Endophytic growth consistently predicted a non-diagnostic CNB in unselected and SRMs, whereas sonography-guidance predicted a diagnostic FNA. Cystic masses could be adequately sampled by FNA.

Educational Case: AA Amyloidosis Complicating Common Variable Immunodeficiency.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Spectrum of Kidney Diseases in Patients With Hepatitis C Virus Infection.

OBJECTIVES: To study the pathologic spectrum of kidney diseases in patients with hepatitis C virus infection (HCV+). METHODS: Native kidney biopsy specimens in HCV+ patients were reviewed. RESULTS: A total of 9,836 native kidney biopsy specimens were evaluated from January 2007 to December 2016, of which 273 (2.8%) were from HCV+ patients, and of these, 115 (42.1%) had diagnoses consistent with HCV-associated glomerulonephritis (GN). Non-HCV-associated kidney diseases comprised most diagnoses (158 cases, 57.9%) including non-immune complex-mediated kidney diseases (127 cases, 46.5%) and other immune complex-mediated glomerular diseases (31 cases, 11.4%). Forty-one (40.6%) patients had HCV-associated GN among 101 HCV+ patients from 2007 to 2011 vs 74 (43.0%) patients with HCV-associated GN among 172 HCV+ patients from 2012 to 2016. HCV-associated GN showed five morphologic patterns: focal proliferative (5.2%), diffuse mesangial proliferative (50.4%), diffuse membranoproliferative (28.7%), proliferative GN with crescentic lesions (7.8%), and membranous patterns (7.8%). CONCLUSIONS: We found a spectrum of pathologic changes in renal biopsy specimens of HCV+ patients, with most having diseases unrelated to HCV infection, HCV-associated GN showing five morphologic patterns, and availability of effective HCV antiviral therapy not yet resulting in major changes in the spectrum of kidney diseases in these patients.

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multi-institutional Autopsy Survey Study.

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.

Instance segmentation for whole slide imaging: end-to-end or detect-then-segment.

Purpose: Automatic instance segmentation of glomeruli within kidney whole slide imaging (WSI) is essential for clinical research in renal pathology. In computer vision, the end-to-end instance segmentation methods (e.g., Mask-RCNN) have shown their advantages relative to detect-then-segment approaches by performing complementary detection and segmentation tasks simultaneously. As a result, the end-to-end Mask-RCNN approach has been the de facto standard method in recent glomerular segmentation studies, where downsampling and patch-based techniques are used to properly evaluate the high-resolution images from WSI (e.g., > 10,000 × 10,000 pixels on 40 × ). However, in high-resolution WSI, a single glomerulus itself can be more than 1000 × 1000 pixels in original resolution which yields significant information loss when the corresponding features maps are downsampled to the 28 × 28 resolution via the end-to-end Mask-RCNN pipeline. Approach: We assess if the end-to-end instance segmentation framework is optimal for high-resolution WSI objects by comparing Mask-RCNN with our proposed detect-then-segment framework. Beyond such a comparison, we also comprehensively evaluate the performance of our detect-then-segment pipeline through: (1) two of the most prevalent segmentation backbones (U-Net and DeepLab_v3); (2) six different image resolutions ( 512 × 512 , 256 × 256 , 128 × 128 , 64 × 64 , 32 × 32 , and 28 × 28 ); and (3) two different color spaces (RGB and LAB). Results: Our detect-then-segment pipeline, with the DeepLab_v3 segmentation framework operating on previously detected glomeruli of 512 × 512 resolution, achieved a 0.953 Dice similarity coefficient (DSC), compared with a 0.902 DSC from the end-to-end Mask-RCNN pipeline. Further, we found that neither RGB nor LAB color spaces yield better performance when compared against each other in the context of a detect-then-segment framework. Conclusions: The detect-then-segment pipeline achieved better segmentation performance compared with the end-to-end method. Our study provides an extensive quantitative reference for other researchers to select the optimized and most accurate segmentation approach for glomeruli, or other biological objects of similar character, on high-resolution WSI.

Standardization in the MSPE: Key Tensions for Learners, Schools, and Residency Programs.

The Medical Student Performance Evaluation (MSPE), which summarizes a medical student's academic and professional undergraduate medical education performance and provides salient information during the residency selection process, faces persistent criticisms regarding heterogeneity and obscurity. Specifically, MSPEs do not always provide the same type or amount of information about students, especially from diverse schools, and important information is not always easy to find or interpret. To address these concerns, a key guiding principle from the Recommendations for Revising the MSPE Task Force of the Association of American Medical Colleges (AAMC) was to achieve "a level of standardization and transparency that facilitates the residency selection process." Benefits of standardizing the MSPE format include clarification of performance benchmarks or metrics, consistency across schools to enhance readability, and improved quality. In medical education, standardization may be an important mechanism to ensure accountability of the system for all learners, including those with varied backgrounds and socioeconomic resources. In this article, members of the aforementioned AAMC MSPE task force explore 5 tensions inherent in the pursuit of standardizing the MSPE: (1) presenting each student's individual characteristics and strengths in a way that is relevant, while also working with a standard format and providing standard content; (2) showcasing school-specific curricular strengths while also demonstrating standard evidence of readiness for internship; (3) defining and achieving the right amount of standardization so that the MSPE provides useful information, adds value to the residency selection process, and is efficient to read and understand; (4) balancing reporting with advocacy; and (5) maintaining standardization over time, especially given the tendency for the MSPE format and content to drift. Ongoing efforts to promote collaboration and trust across the undergraduate to graduate medical education continuum offer promise to reconcile these tensions and promote successful educational outcomes.