Progression to lung fibrosis in severe COVID-19 patients: A morphological and transcriptomic study in postmortem samples.

The development of lung fibrosis is a major concern in patients recovered from severe COVID-19 pneumonia. This study aimed to document the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and define the transcriptional programs involved. Morphological, immunohistochemical and transcriptional analysis were performed in lung samples obtained from autopsy of 33 severe COVID-19 patients (median illness duration: 36 days). Normal lung and idiopathic pulmonary fibrosis (IPF) were used for comparison. Twenty-seven patients with DAD and disease evolution of more than 2 weeks had fibrosis. Pathways and genes related with collagen biosynthesis and extracellular matrix (ECM) biosynthesis and degradation, myofibroblastic differentiation and epithelial to mesenchymal transition (EMT) were overexpressed in COVID-19. This pattern had similarities with that observed in IPF. By immunohistochemistry, pathological fibroblasts (pFBs), with CTHRC1 and SPARC expression, increased in areas of proliferative DAD and decreased in areas of mature fibrosis. Immunohistochemical analysis demonstrated constitutive expression of cadherin-11 in normal epithelial cells and a similar pattern of cadherin and catenin expression in epithelial cells from both normal and COVID-19 samples. Transcriptomic analysis revealed downregulation of the Hippo pathway, concordant with the observation of YAP overexpression in hyperplastic alveolar epithelial cells. Progression to fibrosis in severe COVID-19 is associated with overexpression of fibrogenic pathways and increased in CTHRC1- and SPARC-positive pFBs. Whereas the Hippo pathway seemed to be implicated in the response to epithelial cell damage, EMT was not a major process implicated in COVID-19 mediated lung fibrosis.

SARS-CoV-2-Infection (COVID-19): Clinical Course, Viral Acute Respiratory Distress Syndrome (ARDS) and Cause(s) of Death.

SARS-CoV-2-infected symptomatic patients often suffer from high fever and loss of appetite which are responsible for the deficit of fluids and of protein intake. Many patients admitted to the emergency room are, therefore, hypovolemic and hypoproteinemic and often suffer from respiratory distress accompanied by ground glass opacities in the CT scan of the lungs. Ischemic damage in the lung capillaries is responsible for the microscopic hallmark, diffuse alveolar damage (DAD) characterized by hyaline membrane formation, fluid invasion of the alveoli, and progressive arrest of blood flow in the pulmonary vessels. The consequences are progressive congestion, increase in lung weight, and progressive hypoxia (progressive severity of ARDS). Sequestration of blood in the lungs worsens hypovolemia and ischemia in different organs. This is most probably responsible for the recruitment of inflammatory cells into the ischemic peripheral tissues, the release of acute-phase mediators, and for the persistence of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autopsy studies have been performed mostly in patients who died in the ICU after SARS-CoV-2 infection because of progressive acute respiratory distress syndrome (ARDS). In the death certification charts, after respiratory insufficiency, hypovolemic heart failure should be mentioned as the main cause of death.

Impaired Dendritic Cell Homing in COVID-19.

The high mortality of COVID-19 is mostly attributed to acute respiratory distress syndrome (ARDS), whose histopathological correlate is diffuse alveolar damage (DAD). Furthermore, severe COVID-19 is often accompanied by a cytokine storm and a disrupted response of the adaptive immune system. Studies aiming to depict this dysregulation have mostly investigated the peripheral cell count as well as the functionality of immune cells. We investigated the impact of SARS-CoV-2 on antigen-presenting cells using multiplexed immunofluorescence. Similar to MERS-CoV and SARS-CoV, SARS-CoV-2 appears to be impairing the maturation of dendritic cells (DCs). DC maturation involves a switch in surface antigen expression, which enables the cells' homing to lymph nodes and the subsequent activation of T-cells. As quantitative descriptions of the local inflammatory infiltrate are still scarce, we compared the cell population of professional antigen-presenting cells (APC) in the lungs of COVID-19 autopsy cases in different stages of DAD. We found an increased count of myeloid dendritic cells (mDCs) in later stages. Interestingly, mDCs also showed no significant upregulation of maturation markers in DAD-specimens with high viral load. Accumulation of immature mDCs, which are unable to home to lymph nodes, ultimately results in an inadequate T-cell response.

Clinico-pathological features in fatal COVID-19 infection: a preliminary experience of a tertiary care center in North India using postmortem minimally invasive tissue sampling.

OBJECTIVES: To study the histopathology of patients dying of COVID-19 using post-mortem minimally invasive sampling techniques. METHODS: This was a single-center observational study conducted at JPNATC, AIIMS. Thirty-seven patients who died of COVID-19 were enrolled. Post-mortem percutaneous biopsies were taken from lung, heart, liver, kidney and stained with hematoxylin and eosin. Immunohistochemistry was performed using CD61 and CD163. SARS-CoV-2 virus was detected using IHC with primary antibodies. RESULTS: The mean age was 48.7 years and 59.5% were males. Lung histopathology showed diffuse alveolar damage in 78% patients. Associated bronchopneumonia was seen in 37.5% and scattered microthrombi in 21% patients. Immunopositivity for SARS-CoV-2 was observed in Type II pneumocytes. Acute tubular injury with epithelial vacuolization was seen in 46% of renal biopsies. Seventy-one percent of liver biopsies showed Kupffer cell hyperplasia and 27.5% showed submassive hepatic necrosis. CONCLUSIONS: Predominant finding was diffuse alveolar damage with demonstration of SARS-CoV-2 protein in the acute phase. Microvascular thrombi were rarely identified in any organ. Substantial hepatocyte necrosis, Kupffer cell hypertrophy, microvesicular, and macrovesicular steatosis unrelated to microvascular thrombi suggested that liver might be a primary target of COVID-19.

Recent Advances in Pathology: the 2021 Annual Review Issue of The Journal of Pathology.

The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

COVID-19: immunopathology, pathophysiological mechanisms, and treatment options.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

More than Pneumonia: Distinctive Features of SARS-Cov-2 Infection. From Autopsy Findings to Clinical Implications: A Systematic Review.

Despite safety recommendations for the management of corpses with COVID-19 infection and the high number of deaths worldwide, the post-mortem investigation rate is extremely low as well as the scientific contributions describing the pathological features. The first results of post-mortem investigations provided interesting findings and contributed to promoting unexplored therapeutic approaches and new frontiers of research. A systematic review is provided with the aim of summarizing all autopsy studies up to February 2020 in which a complete post-mortem investigation in patients with COVID-19 disease was performed, focusing on histopathological features. We included case reports, case series, retrospective and prospective studies, letters to the editor, and reviews. A total of 28 studies fulfilled the inclusion criteria, producing a pooled dataset of 407 full autopsies. Analyzing the medical history data, only 12 subjects had died without any comorbidities (for 15 cases the data were not available). The post-mortem investigation highlighted that acute respiratory distress syndrome (ARDS) and multiple organ failure represent the main clinical features of COVID-19 disease, often leading to pulmonary thromboembolism and superimposed bronchopneumonia. The discussed data showed a strict relationship among the inflammatory processes, diffuse alveolar, and endothelial damage. In light of these results, the full autopsy can be considered as the gold standard to investigate unknown infections or pathogens resulting in death.