Pulmonary stromal expansion and intra-alveolar coagulation are primary causes of Covid-19 death

Abstract

SummaryMost Covid-19 victims are old and die from unrelated causes. Here we present twelve complete autopsies, including two rapid autopsies of young patients where the cause of death was Covid-19 ARDS. The main virus induced pathology was in the lung parenchyma and not in the airways. Most coagulation events occurred in the intra-alveolar and not in the intra-vascular space and the few thrombi were mainly composed of aggregated thrombocytes. The dominant inflammatory response was the massive accumulation of CD163+ macrophages and the disappearance of T killer, NK and B-cells. The virus was replicating in the pneumocytes and macrophages but not in bronchial epithelium, endothel, pericytes or stromal cells. The lung consolidations were produced by a massive regenerative response, stromal and epithelial proliferation and neovascularization. We suggest that thrombocyte aggregation inhibition, angiogenesis inhibition and general proliferation inhibition may have a roll in the treatment of advanced Covid-19 ARDS.

Cell-type-resolved quantitative proteomics map of interferon response against SARS-CoV-2

“…SEM for SARS-CoV-2 infected cells were performed as described previously (Szekely et al, 2020). Briefly, Cells grown on poly-L-lysin coated glass coverslips (Corning, United States) and 48h following infection the coverslips were fixed by immersion in 2.5% glutaraldehyde in 0.1M phosphate buffer, pH 7.4.…”

Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial

“…The suggestion in exploratory secondary analyses that there may be reduced need for extended oxygen supplementation in those treated with C21 hints that treatment with C21 may improve gas exchange at the alveolar level. This is interesting because AT2 progenitor cells, apparently the only cells in the lungs that express the AT2R, are the primary site for viral replication in the distal airways, prompting the hypothesis that C21 could restore lung function by a direct action on these cells [19 , 20] .…”

“…However, it has recently been described that the AT2R is highly expressed in alveolar type 2 (AT2) progenitor cells in the adult human lung and can be upregulated during repair and regeneration [14 , 19] . Moreover, the AT2 cells are the primary site of SARS-CoV-2 replication in the distal airways which is likely to contribute to the alveolar dysfunction and impaired gas exchange caused by the virus [20] .…”

The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial

“…The reduced need for extended oxygen supplementation indicates that treatment with C21 improves gas exchange at the alveolar level. The AT2 progenitor cells, apparently the only cells in the lungs that express the AT2R (18), are the primary site for viral replication in the distal airways (20), and it is suggested that C21 restores lung function by acting directly on these cells.…”

“…However, it has recently been described that the AT2R is highly expressed in alveolar type 2 (AT2) progenitor cells in the adult human lung (18) and can be upregulated during repair and regeneration (19). Moreover, the AT2 cells are the primary site of SARS-CoV-2 replication in the distal airways (20) which is likely to contribute to the alveolar dysfunction and impaired gas exchange caused by the virus.…”