Pathology Education Powered by Virtual and Digital Transformation: Now and the Future

[...]standing on the crest of yet another wave of change, driven by artificial intelligence (AI) and machine learning,2 pathology educators may soon be challenged to convey the best ways to apply these tools to the problems of diagnostic pathology for the coming generation of learners and the present corps of practitioners.3 Hence, this collaborative effort aims to describe the genetic code governing the transmission of pathology knowledge to subsequent generations of medical professionals.4 We aim to expose not just the code but also the supporting array of catalysts, enhancers, and other cofactors now in place to ensure we have a robust and potent supply of pathologists. APPLYING DP IN UNDERGRADUATE MEDICAL, DENTAL, VETERINARY, AND ALLIED HEALTH EDUCATION Beginning in 1985, this technology has been progressively more widely implemented in undergraduate medical, dental, veterinary, and allied health (nursing, pharmacy, medical technology, etc) education platforms in the United States and internationally.5,11-26 As noted above, virtual microscopy laboratories, available on personal devices or in school-based computer labs, have replaced fixed laboratories housing gross specimens, boxes of glass slides, and student microscopes. WSI with links to supplementary resources, such as gross and radiologic images and additional study material, provide enrichment for the teaching and learning experience in the new virtual environment. [...]significant exposure to microanatomy and the laboratory methods of pathology underpinning so much of diagnosis, therapy, and management is foundational.

Characterization of SARS-CoV-2 and host entry factors distribution in a COVID-19 autopsy series.

Background: SARS-CoV-2 is a highly contagious virus that causes the disease COVID-19. We have recently reported that androgens regulate the expression of SARS-CoV-2 host entry factors ACE2 and TMPRSS2, and androgen receptor (AR) in lung epithelial cells. We also demonstrated that the transcriptional repression of the AR enhanceosome inhibited SARS-CoV-2 infection in vitro. Methods: To better understand the various sites of SARS-CoV-2 infection, and presence of host entry factors, we extensively characterized the tissue distribution and localization of SARS-CoV-2 virus, viral replication, and host entry factors in various anatomical sites sampled via autopsy. We applied RNA in-situ-hybridization (RNA-ISH), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) approaches. We also assessed histopathological changes in SARS-CoV-2 infected tissues. Results: We detect SARS-CoV-2 virus and viral replication in pulmonary tissues by RNA-ISH and IHC and a variety of non-pulmonary tissues including kidney, heart, liver, spleen, thyroid, lymph node, prostate, uterus, and colon by qRT-PCR. We observe heterogeneity in viral load and viral cytopathic effects among various organ systems, between individuals and within the same patient. In a patient with a history of kidney transplant and under immunosuppressant therapy, we observe an unusually high viral load in lung tissue by RNA-ISH, IHC and qRT-PCR. SARS-CoV-2 virus is also detected in this patent's kidney, liver and uterus. We find ACE2, TMPRSS2 and AR expression to overlap with the infection sites. Conclusions: This study portrays the impact of dispersed SARS-CoV-2 infection in diverse organ systems, thereby facilitating avenues for systematic therapeutic approaches.

Usual Interstitial Pneumonia is the Most Common Finding in Surgical Lung Biopsies from Patients with Persistent Interstitial Lung Disease Following Infection with SARS-CoV-2.

BACKGROUND: There is increasing interest in persistent interstitial lung disease (ILD) following resolution of acute COVID-19. No studies have yet reported findings in surgical lung biopsies (SLB) from this patient population. METHODS: Our Michigan Medicine pathology database was queried for SLB reviewed between January 2020 and April 2021 from patients with persistent ILD following recovery from acute COVID-19. Slides for our retrospective observational study were independently reviewed by two thoracic pathologists, who were blinded to patient clinical data, radiographic findings, and previous pathologic diagnosis. FINDINGS: Eighteen cases met inclusion criteria. Of these, nine had usual interstitial pneumonia (UIP). These included two patients with superimposed acute lung injury (ALI). Five cases showed a spectrum of ALI that ranged from persistent diffuse alveolar damage to organizing pneumonia. Four patients had desquamative interstitial pneumonia (1), acute and organizing bronchopneumonia (1), or no diagnostic abnormality (2). Compared to patients without UIP, those with UIP tended to be older and have pre-existing lung disease prior to COVID-19. In patients with UIP, pre-SLB chest computed tomography changes included groundglass with interstitial thickening or peripheral reticulations with bronchiectasis; no UIP patients had groundglass only. The most common radiographic finding in patients without UIP was groundglass opacities only. INTERPRETATION: UIP was the most common pathologic finding in patients undergoing evaluation for post-COVID-19 ILD. Our preliminary data suggests that CT changes described as interstitial thickening, peripheral reticulations, and/or bronchiectasis may be helpful in identifying patients with underlying fibrotic chronic interstitial pneumonia for which UIP is the chief concern. FUNDING: No intramural or extramural funding sources supported this work.

Fatal COVID-19 and Non-COVID-19 Acute Respiratory Distress Syndrome Is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State without Fibrosis.

Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; recovery requires epithelial regeneration. During physiological regeneration in mice, type 2 AECs (AEC2s) proliferate, exit the cell cycle, transiently assume a transitional state, then differentiate into type 1 AECs (AEC1s); in humans, persistence of the transitional state is associated with pulmonary fibrosis. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiological regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or single-cell RNA sequencing revealed that transitional cells in mouse models of physiological regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis.

Postmortem Findings Associated With SARS-CoV-2: Systematic Review and Meta-analysis.

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome-associated Coronavirus 2 (SARS-CoV-2), has become a global threat to public health. COVID-19 is more pathogenic and infectious than the prior 2002 pandemic caused by SARS-CoV-1. The pathogenesis of certain disease manifestations in COVID-19 such as diffuse alveolar damage (DAD) are thought to be similar to SARS-CoV-1. However, the exact pathogenesis of COVID-19 related deaths remains poorly understood. The aim of this article was to systematically summarize the rapidly emerging literature regarding COVID-19 autopsies. A meta-analysis was also conducted based on data accrued from preprint and published articles on COVID-19 (n=241 patients) and the results compared with postmortem findings associated with SARS-CoV-1 deaths (n=91 patients). Both autopsy groups included mostly adults of median age 70 years with COVID-19 and 50 years with SARS-CoV-1. Overall, prevalence of DAD was more common in SARS-CoV-1 (100.0%) than COVID-19 (80.9%) autopsies (P=0.001). Extrapulmonary findings among both groups were not statistically significant except for hepatic necrosis (P <0.001), splenic necrosis (P<0.006) and white pulp depletion (P <0.001) that were more common with SARS-CoV-1. Remarkable postmortem findings in association with COVID-19 apart from DAD include pulmonary hemorrhage, viral cytopathic effect within pneumocytes, thromboembolism, brain infarction, endotheliitis, acute renal tubular damage, white pulp depletion of the spleen, cardiac myocyte necrosis, megakaryocyte recruitment, and hemophagocytosis.

Diffuse alveolar damage (DAD) resulting from coronavirus disease 2019 Infection is Morphologically Indistinguishable from Other Causes of DAD.

AIMS: Diffuse alveolar damage (DAD) is a ubiquitous finding in inpatient coronavirus disease 2019 (COVID-19)-related deaths, but recent reports have also described additional atypical findings, including vascular changes. An aim of this study was to assess lung autopsy findings in COVID-19 inpatients, and in untreated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive individuals who died in the community, in order to understand the relative impact of medical intervention on lung histology. Additionally, we aimed to investigate whether COVID-19 represents a unique histological variant of DAD by comparing the pathological findings with those of uninfected control patients. METHODS AND RESULTS: Lung sections from autopsy cases were reviewed by three pulmonary pathologists, including two who were blinded to patient cohort. The cohorts included four COVID-19 inpatients, four cases with postmortem SARS-CoV-2 diagnoses who died in the community, and eight SARS-CoV-2-negative control cases. DAD was present in all but one SARS-CoV-2-positive patient, who was asymptomatic and died in the community. Although SARS-CoV-2-positive patients were noted to have more focal perivascular inflammation/endothelialitis than control patients, there were no significant differences in the presence of hyaline membranes, fibrin thrombi, airspace organisation, and 'acute fibrinous and organising pneumonia'-like intra-alveolar fibrin deposition between the cohorts. Fibrinoid vessel wall necrosis, haemorrhage and capillaritis were not features of COVID-19-related DAD. CONCLUSIONS: DAD is the primary histological manifestation of severe lung disease in COVID-19 patients who die both in hospital and in the community, suggesting no contribution of hyperoxaemic mechanical ventilation to the histological changes. There are no distinctive morphological features with which to confidently differentiate COVID-19-related DAD from DAD due to other causes.

The pulmonary pathology of COVID-19.

A growing number of international postmortem studies identify acute and organizing diffuse alveolar damage (DAD) as the main pathologic feature of lung injury in patients with COVID-19. Other forms of acute lung injury, including organizing pneumonia, and acute fibrinous and organizing pneumonia are seen. Acute neutrophilic infiltrates have been observed, most frequently as the manifestation of a superimposed bacterial pneumonia. SARS-CoV-2 has been detected in type I and type II pneumocytes and bronchial epithelial cells using electron microscopy, immunohistochemistry, and in situ hybridization, and likewise, viral transcripts were localized with RNA probes in pneumocytes. However, the presence of true viral cytopathic effect seen with light microscopy remains to be defined. Interestingly, vascular changes are frequently observed in association with DAD, which include severe endothelial injury/endothelialitis, hemorrhage, and thrombotic and microangiopathic vasculopathy. Since similar vascular changes also occur in cases of DAD independent of the etiology, whether the vascular pathology in COVID lungs has unique features and represents a separate pathologic process is under investigation.