Postmortem Examination of Patients With COVID-19

Schaller, Tina; Hirschbühl, Klaus; Burkhardt, Katrin; Braun, Georg; Trepel, Martin; Märkl, Bruno; Claus, Rainer

doi:10.1001/jama.2020.8907

Cited by 518 publications

(595 citation statements)

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“…Post-mortem examinations of COVID-19 patients reveal the aftermath of these disease dynamics: diffuse alveolar damage, multi-organ infiltration of lymphocytes and alveolar macrophages [1,7,15,16], and pneumocyte hyperplasia and peribronchiolar metaplasia in the epithelium resembling adenocarcinomas [15,16,17]. These morphological findings suggest local and systemic activation and infiltration of inflammatory immune cells that may contribute to the inflammatory injuries of the respiratory system consistent with ARDS phenotypes in severe COVID-19 [15].…”

Section: Introductionmentioning

confidence: 89%

“…Significant transcriptional changes in cells of the BALF were abundant in all cell types with the exception of plasma cells. We first directed our attention to the epithelium, where substantial morphological damage and histological atypia were observed in deceased COVID-19 patients [1,7,15,17,16]. At the level of individual gene regulation, we first noted a surprisingly strong significant upregulation of FOS and JUN, which code for proteins implicated in the development of cancer ( Figure 3A).…”

Section: Pathway-level Regulation Differentiates Mild and Severe Covimentioning

confidence: 99%

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Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Overholt

Krog

Bryson

2020

Preprint

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As the global COVID-19 pandemic continues to escalate, no effective treatment has yet been developed for the severe respiratory complications of this disease. This may be due in large part to the unclear immunopathological basis for the development of immune dysregulation and acute respiratory distress syndrome (ARDS) in severe and critical patients. Specifically, it remains unknown whether the immunological features of the disease that have been identified so far are compartment-specific responses or general features of COVID-19. Additionally, readily detectable biological markers correlated with strata of disease severity that could be used to triage patients and inform treatment options have not yet been identified. Here, we leveraged publicly available single-cell RNA sequencing data to elucidate the common and compartment-specific immunological features of clinically severe COVID-19. We identified a number of transcriptional programs that are altered across the spectrum of disease severity, few of which are common between the lung and peripheral immune environments. In the lung, comparing severe and moderate patients revealed severity-specific responses of enhanced interferon, A20/IκB, IL-2, and IL-6 pathway signatures along with broad signaling activity of IFNG, SPP1, CCL3, CCL8, and IL18 across cell types. These signatures contrasted with features unique to ARDS observed in the blood compartment, which included depletion of interferon and A20/IκB signatures and a lack of IL-6 response. The cell surface marker S1PR1 was strongly upregulated in patients diagnosed with ARDS compared to non-ARDS patients in γδ T cells of the blood compartment, and we nominate S1PR1 as a potential marker for immunophenotyping ARDS in COVID-19 patients using flow cytometry.HIGHLIGHTSCOVID-19 disease severity is associated with a number of compositional shifts in the cellular makeup of the blood and lung environments.Transcriptional data suggest differentially expressed cell surface proteins as markers for COVID-19 immunophenotyping from BALF and PBMC samples.Severity-specific features COVID-19 manifest at the pathway level, suggesting distinct changes to epithelia and differences between local and systemic immune dynamics.Immune-epithelial cellular communication analysis identifies ligands implicated in transcriptional regulation of proto-oncogenes in the lung epithelia of severe COVID-19 patients.Network analysis suggests broadly-acting dysregulatory ligands in the pulmonary microenvironment as candidate therapeutic targets for the treatment of severe COVID-19.

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Section: Introductionmentioning

confidence: 89%

Section: Pathway-level Regulation Differentiates Mild and Severe Covimentioning

confidence: 99%

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Overholt

Krog

Bryson

2020

Preprint

View full text Add to dashboard Cite

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“…Other publications report exudative DAD as the predominant injury, sometimes associated with the proliferative phase. The presence of the brotic phase has been reported by very few groups 14 . In contrast, we demonstrated brotic DAD in most patients, always in association of proliferative DAD.…”

Section: Discussionmentioning

confidence: 87%

“…Small series of autopsies report diffuse alveolar damage (DAD) as the fundamental injury in the lung [11][12][13][14][15][16][17] . Lung brosis is an uncommon feature in these studies, but it has been described as a progression of the disease that can worsen the prognosis 9 .…”

Section: Introductionmentioning

confidence: 99%

CT as a Tool to Depict Pulmonary Fibrosis in Patients With COVID-19: a Radiopathological Correlation

Alguersuari

Ortíz

Munné

et al. 2020

Preprint

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OBJECTIVESCT findings of COVID-19 infected patients has been well described, but it it’s roll in depicting signs of fibrosis in critically ill patients remains unclear. To our knowledge, there are no radiopathological correlations of the pulmonary pathology. Exudative and proliferative diffuse alveolar damage (DAD) are the most commonly reported injury. Few studies describe fibrosis, the last phase of DAD. Our study correlates post-mortem chest US and CT findings of COVID-19 infected patients with the histopathology from biopsies taken of the lung. It focuses on the role of CT to depict fibrosis. METHODSThis is a prospective observational study of six consecutive deceased patients infected with COVID-19. Post-mortem chest CTs and US were performed within 24 hours of death. CT and US were used to obtain biopsies of different radiological patterns. Pre-mortem CT examinations were also retrospectively evaluated. RESULTSOn CT, all patients presented with extensive areas of consolidation and ground-glass opacities affecting most segments of the lung. Pleural effusion was present in all cases. Four of the patients showed signs of fibrosis. On US, subpleural consolidation, pleural thickening, and B-pattern were present.All patients showed different stages of DAD, mostly proliferative DAD. Four patients presented with fibrotic DAD, all of which had been admitted for over three weeks and correlated with the CT findings of fibrosis. CONCLUSIONIn our study, signs of fibrosis on CT show a histopathological correlation. CT may be useful to identify the group of COVID-infected patients that develop fibrosis as a marker of poor prognosis, in the late stage of the disease.

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“…Such method is able to capture in ltrating immune cells in spite of non-immune cell types (i.e. epithelial cells), as shown by recent autopsy reports [43]. Lung biopsy represents an interesting alternative to BAL but is far riskier, especially for patients suffering from ARDS, such as severe COVID-19 patients, and the amount of available material is limited.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the state of immune silence in fatal COVID-19 patients

Amit

Bost

Sanctis

et al. 2020

Preprint

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Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocyto-sis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely imped-ing the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell RNA-seq analysis of more than 150.000 immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of COVID-19 patients and healthy controls, and integrated it with clinical, immunological and functional ex vivo data. We unveiled an immune sig-nature of disease severity that correlated with the accumulation of naïve lymphoid cells in the lung and an expansion and activation of myeloid cells in the periphery. Moreover, we demonstrated that myeloid-driven immune suppression is a hallmark of COVID-19 evolution and arginase 1 expression is significantly associated with monocyte immune regulatory features. Noteworthy, we found mon-ocyte and neutrophil immune suppression loss associated with fatal clinical outcome in severe pa-tients. Additionally, our analysis discovered that the strongest association of the patients clinical outcome and immune phenotype is the lung T cell response. We found that patients with a robust CXCR6+ effector memory T cell response have better outcomes. This result is line with the rs11385942 COVID-19 risk allel, which is in proximity to the CXCR6 gene and suggest effector memory T cell are a primary feature in COVID-19 patients. By systemically quantifying the viral landscape in the lung of severe patients, we indeed identified Herpes-Simplex-Virus 1 (HSV-1) as a potential opportunistic virus in COVID-19 patients. Lastly, we observed an unexpectedly high SARS-CoV-2 viral load in an immuno-compromised patient, allowing us to study the SARS-CoV-2 in-vivo life cycle. The development of myeloid dysfunctions and the impairment of lymphoid arm establish a condition of immune paralysis that supports secondary bacteria and virus infection and can progress to “immune silence” in patients facing death.

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Postmortem Examination of Patients With COVID-19

Cited by 518 publications

References 5 publications

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

CT as a Tool to Depict Pulmonary Fibrosis in Patients With COVID-19: a Radiopathological Correlation

Deciphering the state of immune silence in fatal COVID-19 patients

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