Adrenal insufficiency in the COVID-19 era

to the editor: COVID-19 has resulted in more than 450,000 deaths in the United States (1). Latest reports suggest that the effects of the SARS-CoV-2 are not limited to the lungs, but affect a number of vital organs, including the endocrine glands. It was reported that patients with COVID-19 are subjected to structural adrenal gland changes during the illness course (2). Histological findings report focal necrosis of the adrenal gland and vasculitis of the small veins (2, 3). Furthermore, SARS-CoV-2 RNA was detected in the hypothalamic-pituitary system, suggesting the possibility of underlying hypophysitis (4). Thus, undiagnosed primary and secondary adrenal insufficiency may contribute to the high mortality rates associated with COVID-19.

Stress-induced cortisol secretion is an essential response to overcome severe disease, and relative adrenal insufficiency (AI) is a common condition in critical care patients (5, 6). Treatment with glucocorticoids is recommended for relative AI in critical care patients, including those with apparently normal basal cortisol levels (6). The diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) guidelines recommend the application of corticosteroids in those with early moderate-to-severe acute respiratory distress syndrome (ARDS) (5).

Previous studies on the SARS outbreak (2003) revealed that 39.2% of patients were diagnosed with hypocortisolism 3 mo after their recovery, and the majority (83.3%) of those who recovered were diagnosed with central hypocortisolism. A significant margin of that group (25%) continued to experience adrenal insufficiency and received hydrocortisone for 12 mo (4).

Several reasons may explain the SARS-CoV-2-related AI, including: 1) Relative AI is a common condition in critically ill patients (6). The cytokine storm caused by this coronavirus provides negative feedback toward the hypothalamic-pituitary-adrenal axis (5); 2) SARS viruses produce certain amino acid sequences mimicking the host ACTH, thus the production of the corresponding antibodies may contribute toward the development of central AI (4); 3) The pituitary, hypothalamus and adrenal glands express angiotensin-converting enzyme2 (ACE2). SARS RNA has been identified in hypothalamic autopsies of patients with COVID-19 (4). Thus, SARS-CoV-2 might cause hypophysitis and adrenalitis, which, in turn, may lead to secondary or primary AI.

Low-to-moderate doses of dexamethasone have been effective in the treatment of patients with COVID-19 (7). Hence, adrenal insufficiency may serve as a contributing factor in the numbers of COVID-19-related deaths. If our hypothesis stands correct, steroid hormone replacement therapy (HRT) (e.g., hydrocortisone, prednisone, and fludrocortisone), should be considered for in patients with COVID-19. As it was previously shown that hydrocortisone protects against endothelial barrier dysfunction (8, 9) and the development of COVID-19 is strongly associated with the impaired endothelium (10, 11), a multifaceted protective action of the HRT toward the current pandemic is highly possible.

GRANTS

This work was supported by the Medical University of Lodz Grants 503/1–153-06/503-11-003–17, 503/1–153-06/503-11-004–18, and 503/1–153-06/503-11-001–19-00 (to A.S.) and the National Institute of General Medical Science/National Institutes of Health Grants 5 P20 GM103424-15 and 3 P20 GM103424-15S1 (to N.B.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.S. and N.B. drafted manuscript; A.S. and N.B. edited and revised manuscript; A.S. and N.B. approved final version of manuscript.