The Adrenal Cortex, an Underestimated Site of SARS-CoV-2 Infection

Abstract

Background: The majority of the critically ill patients may have critical illness-related corticosteroid insufficiency (CIRCI). The therapeutic effect of dexamethasone may be related to its ability to improve cortical function. Recent study showed that dexamethasone can reduce COVID-19 deaths by up to one third in critically ill patients. The aim of this article is to investigate whether SARS-CoV-2 can attack the adrenal cortex to aggravate the relative adrenal insufficiency.

Methods: We summarized the clinical features of COVID-19 reported in currently available observational studies. ACE2 and TMPRSS2 expression was examined in human adrenal glands by immunohistochemical staining. We retrospectively analyzed serum cortisol levels in critically ill patients with or without COVID-19.

Results: High percentage of critically ill patients with SARS-COV-2 infection in the study were treated with vasopressors. ACE2 receptor and TMPRSS2 serine protease were colocalized in adrenocortical cells in zona fasciculata and zona reticularis. We collected plasma cortisol concentrations in nine critically ill patients with COVID-19. The cortisol levels of critically ill patients with COVID-19 were lower than those in non-COVID-19 critically ill group. Six of the nine COVID-19 critically ill patients had random plasma cortisol concentrations below 10 µg/dl, which met the criteria for the diagnosis of CIRCI.

Conclusion: We demonstrate that ACE2 and TMPRSS2 are colocalized in adrenocortical cells, and that the cortisol levels are lower in critically ill patients with COVID-19 as compared to those of non-COVID-19 critically ill patients. Based on our findings, we recommend measuring plasma cortisol level to guide hormonal therapy.

Keywords: adrenal cortex; adrenal insufficiency; coronavirus disease 2019; critically ill patients; severe acute respiratory syndrome coronavirus 2.

Figure 1

Immunohistochemical staining of ACE2 in human healthy lung tissues. small intestines and thyroid tissues. (A–C) in healthy lung tissue sections, ACE2 was widely expressed in pulmonary vascular endothelial cells, alveolar epithelial cells, bronchial mucosal epithelial cells, and on the apical surface of ciliated columnar epithelial cells. (D, E) in human normal small intestine sections, ACE2 was mainly expressed on the surface of villi epithelial cells. (F, G) ACE2 immunoreactivity was not observed in human normal thyroid tissue sections. Original magnification: (A–C, E, G): ×400; D&F:×100.

Figure 2

Haematoxilin-Eosin staining and immunohistochemical staining of ACE2 & TMPSS2 in human healthy adrenal tissues. (A–C) were the serial sections of the same adrenal cortex. Panel A showed Haematoxilin-Eosin (HE) staining. (B, C) were stained with antibodies aganist ACE2 (B) and TMPSS2 (C), respectively. Original magnification: ×100. Areas in black boxes in (A–C) were shown enlarged in (D–F) (×400), respectively.

Figure 3

Double immunofluorescence staining demonstrates the colocalization of CYP11B1/ACE2 (A), CYP11B1/TMPRSS2 (B) and ACE2/TMPRSS2 (C) in human healthy adrenal tissues. Original magnification: ×200. Scale bars correspond to 50 μm.

Figure 4

Immunohistochemical staining of ACE2 in human normal adrenal medulla and pheochromocytoma tissues. (A, B) were the serial sections of the same adrenal medulla. (C, D) were the serial sections of the same pheochromocytoma tissues. (A, C) showed Haematoxilin-Eosin (HE) staining. (B, D) were stained with antibodies aganist ACE2. Original magnification: ×100. Areas in black boxes in (A–D) were shown enlarged in (E–H) (×400), respectively. In the healthy adrenal tissues, c cells (pointed by black arrows) could only be distinguished in the adrenal medulla under high magnification (E, F), and exhibited no obvious ACE2 immunoreactivity. In sections obtained from pheochromocytoma tissues, ACE2 immunoreactivity was also not observed in pheochromocytoma cells (pointed by yellow arrows).

Figure 5

Flowchart of trial procedures. All the COVID-19 patients met the inclusion criteria: 1. Age ≥18 years, 2. Positive results of sars-cov-2 by qRT-PCR, 3. PaO2/FiO2 ≤ 200mmHg, 4. Total plasma cortisol was measured. Patients did not receive prolonged hormonal therapy, and do not have hypothalamus, pituitary gland, adrenal gland disease or mental illness; Female patients were not pregnant.

Figure 6

Plasma cortisol concentrations of critically ill patients with or without COVID-19. We collected data on plasma cortisol concentrations in nine critically ill patients with COVID-19, and the results showed that the cortisol levels of COVID-19 critically ill patients were considerably lower than those in non-COVID-19 critically ill patients.