Management of Patients With Glucocorticoid-Related Diseases and COVID-19

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing's syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).

Keywords: ACE2; COVID-19; SARS-CoV-2; adrenal insufficiency; adrenocortical carcinoma; cushing’s syndrome; glucocorticoids; hyperaldosteronism.

Figure 1

Potential interaction between the hypothalamic-pituitary-adrenal axis (HPA) and SARS-CoV-2. (A) Normal function of the HPA axis in response to physiological cues and stress. The paraventricular nucleus of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the secretion of adrenocorticotropin hormone (ACTH) from the pituitary gland. Subsequently, ACTH stimulates the synthesis and release of cortisol from the adrenal cortex. In a negative feedback loop, cortisol inhibits further release of both ACTH and CRH, whereas ACTH inhibits CRH secretion. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) receptors are expressed at all levels of the HPA axis. (B) The hypothalamus and pituitary could be directly damaged by SARS-CoV-2, resulting in central hypocortisolism. (C) Direct damage of the normal adrenal gland secondary to SARS-CoV-2, which might result in primary adrenal insufficiency. In all cases of adrenal insufficiency, the negative feedback loop is compromised. Symbols: ↑, increased; ↓, decreased.

Figure 2

In silico analysis of genes involved in the SARS-CoV-2 cell entry mechanism in normal adrenal gland and adrenocortical tumors. In silico analysis from the high density oligonucleotide array data published by Giordano et al. (14) (deposited in the National Center for Biotechnology Information’s Gene Expression Omnibus, accession number GSE10927), evaluating the quantile-normalized and then log transformed mRNA expression of ACE2 (encoding the angiotensin-converting enzyme 2), TMPRSS2 (encoding the transmembrane protease serine 2), CTSB (encoding cathepsin B), CTSL (encoding cathepsin L), and FURIN (encoding furin) in normal adrenal glands (NAG, n=10), adrenocortical adenomas (ACA, n=22) and adrenocortical carcinomas (ACC, n=33). No significant differences between NAG, ACA and ACC were observed in the expression of the evaluated genes (per trend: P=0.29 for ACE2, P=0.14 for TMPRSS2, P=0.39 for CTSB, P=0.87 for CTSL, P=0.17 for FURIN). In details, median log₂ fold chance (FC) of ACE was: 2.24 (2.22-2.30) for NAG, 2.21 (2.14-2.27) for ACA and 2.26 (2.15-2.82) for ACC. Median log₂FC of TMPRSS2 was: 2.56 (2.49-2.70) for NAG, 2.59 (2.50-2.63) for ACA and 2.52 (2.45-2.58) for ACC. Median log₂FC of CTSB was: 3.94 (3.90-4.01) for NAG, 4.01 (3.91-4.08) for ACA and 3.91 (3.66-4.08) for ACC. Median log₂FC of CTSL was: 3.66 (3.59-3.68) for NAG, 3.65 (3.62-3.68) for ACA and 3.65 (3.60-3.77) for ACC. Median log₂FC of FURIN was: 2.91 (2.85-2.93) for NAG, 2.86 (2.80-2.92) for ACA and 2.94 (2.81-3.01) for ACC. Data are reported as median with the 25% and 75% percentile. For the details on the quantile-normalization procedures and the log transformed of the array data, see the published paper by Giordano et al. (14). Statistical analysis performed by Kruskal-Wallis test using GraphPad Prism (version 5.0, La Jolla, CA, USA).

Figure 3

Potential mechanisms associated with an increased risk of contracting SARS-CoV-2 and with a more severe form of the disease in patients with adrenocortical carcinoma. Adrenocortical carcinoma (ACC) expresses both ACE2 and TMPRSS2 at mRNA levels, which encode the receptors that mediate the entry of SARS-CoV-2 into the host cell. The peculiarity of ACC is its hormone secretion (in 50-60% of patients), resulting in hypercortisolism, hyperandrogenism and hyperaldosteronism. In addition, it is treated with mitotane therapy, which is used both as adjuvant treatment and in advanced cases and induces adrenal insufficiency. The effects of the hormone secretion and of mitotane are listed in the corresponding box. In addition, ACC patients also present other cancer-related factors that are associated with a high risk of severe manifestations of SARS-CoV-2, including advanced stage and immunosuppression related to chemotherapy. ACE2, angiotensin converting enzyme 2; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; TMPRSS2, transmembrane protease serine 2; vWF, von Willebrand factor; ↑, increased; ↓, decreased; RAAS, Renin-Angiotensin-Aldosterone System; DDP-4, dipeptidyl peptidase 4; IL, interleukine; TGF, tumor growth factor; Th, T helper.