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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsHigh 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.ConclusionWe 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.

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism

“…It was also indicated that ACE2 and TMPRSS2 are colocalized in adrenocortical cells. The cortisol concentrations were found to be lower in critically ill patients with COVID-19 than non-COVID-19 critically ill patients [60]. People with adrenal insufficiency may have a higher rate of respiratory infection-related deaths, possibly due to impaired immune function and thus need further care during COVID-19 [59].…”

Angiotensin peptides in the regulation of adrenal cortical function

“…Considering that ACE-2 is the receptor of SARS-CoV2, these findings indicated that the adrenal cortex is a potential target for SARS-CoV2 infection, which can account for cases of adrenal insufficiency in infected patients [18]. Of note, Mao et al [19] reported the colocalization of ACE2 and transmembrane serine protease 2 (TMPRSS2) in zona fasciculata and zona reticularis of adrenal cortex suggesting that SARS-CoV2 can directly interfere with cortisol secretion and increase the rate of critical illness-related corticosteroid insufficiency in COVID-19 patients.…”

Endocrine risk factors for COVID-19: Endogenous and exogenous glucocorticoid excess

“…Studies on the impact of COVID-19 on endocrine organs are limited. However, because of the expression of angiotensin-converting enzyme 2 (ACE2) in many endocrine glands [82,83], endocrine organs are likely to be involved in COVID-19 [6,84]. Alzahrani and colleagues reported on an impaired adrenocortical response in 28 patients with COVID-19 with plasma cortisol and ACTH concentrations indicating central adrenal insufficiency [85].…”

“…As the HPA axis function of the majority recovered within a year, the authors suggested a reversible hypophysitis or direct hypothalamic injury induced by the virus [89]. Whether the beneficial effects of dexamethasone in the treatment of COVID-19 is due to general supportive benefits of GCs in critical ill patients, mitigation of the cytokine release syndrome and ARDS [12,90], the treatment of undiagnosed adrenal insufficiency [83,85], or the suppression of endogenous cortisol secretion with reduced effects on mineralocorticoid receptors [53], has to be clarified in the future.…”