Insights into pathogenesis of fatal COVID‐19 pneumonia from histopathology with immunohistochemical and viral RNA studies

Abstract

IntroductionWe describe post‐mortem pulmonary histopathologic findings of COVID‐19 pneumonia in patients with a spectrum of disease course, from rapid demise to prolonged hospitalisation.Methods and resultsHistopathologic findings in post‐mortem lung tissue from eight patients who died from COVID‐19 pneumonia were reviewed. Immunohistochemistry (IHC) and next‐generation sequencing (NGS) were performed to detect virus. Diffuse alveolar damage (DAD) was seen in all cases with a spectrum of acute phase and/or organising phase. IHC with monoclonal antibodies against SARS‐CoV‐2 viral nucleoprotein and spike protein detected virus in areas of acute but not organising DAD, with intracellular viral antigen and RNA expression seen predominantly in patients with duration of illness less than 10 days. Major vascular findings included thrombi in medium‐ and large‐calibre vessels, platelet microthrombi detected by CD61 IHC and fibrin microthrombi.ConclusionsPresence of SARS‐CoV‐2 viral RNA by NGS early in the disease course and expression of viral antigen by IHC exclusively in the acute, but not in the organising phase of DAD, suggests that the virus may play a major role in initiating the acute lung injury of DAD, but when DAD progresses to the organising phase the virus may have been cleared from the lung by the patient's immune response. These findings suggest the possibility of a major change during the disease course of COVID‐19 pneumonia that may have therapeutic implications. Frequent thrombi and microthrombi may also present potential targets for therapeutic intervention.

Fibrotic progression and radiologic correlation in matched lung samples from COVID-19 post-mortems

“…Immunohistochemistry for SARS-CoV-2 nucleocapsid protein also showed modification during disease progression as intense immunostaining was seen in early exudative phase . e CT shows advanced parenchymal alterations with predominant dorsal consolidations (homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls as opposed to GGO-red asterisks); peripheral crazy paving pattern is seen anteriorly lesions, while little or no immunostaining was identified in proliferative and late/organizing fibrotic phases, similarly to findings in two recent studies [23,31].…”

“…Inflammation was also scored as absent (score 0), mild (score 1) or marked (score 2), and immunohistochemistry was used to distinguish T lymphocytes (CD3+ ), B lymphocytes (CD20+) and alveolar macrophages (CD68+, CD163+). CD61 was used for the detection of platelet microthrombi and megakaryocytes in all adequate samples [23].…”

Examining the effector mechanisms of Xuebijing Injection on COVID-19 based on network pharmacology.

“…SARS is associated with epithelial-cell proliferation and an increase in macrophages in the lung [57]. And diffuse alveolar damage was seen in COVID-19 cases [58]. Regarding the differences between COVID-19…”

The pulmonary pathology of COVID-19

“…The predominant pathology in the lungs of deceased patients with COVID-19 is diffuse alveolar damage (DAD). [1][2][3][4][5][6][7][8][9][10][11][12][13][14] This pattern of acute lung injury is the histologic finding observed in patients with acute respiratory distress syndrome regardless of the etiology. It results from epithelial and endothelial injury after an initial insult that leads to increased permeability of the alveolar-capillary barrier with consequent edema, release of proinflammatory and repair chemical mediators, impairment of the metabolism of surfactant, and abnormalities in the coagulation pathways.…”

“…In this regard, the virus has been detected in type I and type II pneumocytes using electron microscopy, immunohistochemistry and in situ hybridization, and RNA probes have localized viral transcripts in pneumocytes. 1,6,9,[12][13][14][23][24][25][26][27] However, specific morphologic features of a viral cytopathic effect in the lungs of patients with COVID-19 using light microscopy remain to be defined.…”