Multisystemic cellular tropism of SARS-CoV-2 in autopsies of COVID-19 patients

Abstract

Background: Multiorgan tropism of SARS-CoV-2 has previously been shown for several major organs. Methods: We have comprehensively analyzed 25 different formalin-fixed paraffin-embedded (FFPE) tissues/organs from autopsies of fatal COVID-19 cases (n=8), using detailed histopathological assessment, detection of SARS-CoV-2 RNA using polymerase chain reaction and RNA in situ hybridization, viral protein using immunohistochemistry, and virus particles using transmission electron microscopy. Finally, we confirmed these findings in an independent external autopsy cohort (n=9). Findings: SARS-CoV-2 RNA was mainly localized in epithelial cells, endothelial and mesenchymal cells across all organs. Next to lung, trachea, kidney, heart, or liver, viral RNA was also found in tonsils, salivary glands, oropharynx, thyroid, adrenal gland, testicles, prostate, ovaries, small bowel, lymph nodes, skin and skeletal muscle. Viral RNA was predominantly found in cells expressing ACE2, TMPRSS2, or both. The SARS-CoV-2 replicating RNA was also detected in these organs. Immunohistochemistry and electron microscopy were not suitable for reliable and specific SARS-CoV-2 detection in autopsies. The findings were validated using in situ hybridization on external COVID-19 autopsy samples. Finally, apart from the lung, correlation of virus detection and histopathological assessment did not reveal any specific alterations that could be attributed to SARS-CoV-2. Conclusion: SARS-CoV-2 could be observed in virtually all organs, colocalizing with ACE2 and TMPRSS2 mainly in epithelial but also in mesenchymal and endothelial cells, and viral replication was found across all organ systems. Apart from the respiratory tract, no specific (histo-)morphologic alterations could be assigned to the SARS-CoV-2 infection.

Adrenal Gland Function and Dysfunction During COVID-19

“…Histopathological examination of adrenal glands obtained from autopsies revealed a high degree of local inflammation. While in some studies an inconspicuous 25 or sporadic focal inflammation 26 was found, other observations report a more pronounced and frequent infiltration of CD3- and CD8-lymphocytes in different layers of the adrenal cortex 27 or lymphoplasmacellular cells in perivascular regions of the adrenal gland 28 . Furthermore, one study reported a cellular hyperplasia in zona fasciculata of the adrenal cortex in 86% of investigated patients, which might be an indicator of impaired hormone production 29 .…”

“…However, vascular damage seems to be the most commonly confirmed complication of COVID-19 in adrenal glands. In particular, a high degree of endotheliitis of periadrenal adipose and parenchymal tissues was found 25 28 , along with acute fibroid necrosis and apoptotic debris of adrenal arteriole 30 . Moreover, histological 31 and routine computer tomography (CT) investigations 26 32 reported thrombi formation, infarctions, and hemorrhages in the adrenal glands of patients with COVID-19 33 34 .…”

“…The expression of these key receptors in adrenal cells suggests that SARS-CoV-2 might target adrenal glands 45 50 . Indeed, SARS-CoV-2 infection was detected in the adrenal glands of patients with COVID-19 using several techniques including in situ RNA and DNA hybridization, immunohistochemistry, and RT-qPCR 25 28 32 . In particular, SARS-CoV-2 was found in scattered cell populations of adrenocortical cells and in endothelial cells 28 32 .…”