Alterations in Cortisol and Interleukin-6 Secretion in Patients With COVID-19 Suggestive of Neuroendocrine-Immune Adaptations

Abstract Purpose: The beneficial effect of glucocorticoids in coronavirus disease (COVID-19) is established, but whether adrenal cortisol secretion is impaired in COVID-19 is not fully elucidated. In this case-control study we investigated the diurnal free bioavailable salivary cortisol secretion in COVID-19 patients. Methods: Fifty-two consecutive COVID-19 patients -before dexamethasone treatment- recruited between April 15 th -June15 th -2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8am, 12, 6, and 10pm), plasma adrenocorticotropin (ACTH) and aldosterone, and serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed. Diurnal salivary dehydroepiandrosterone (DHEA) and IL-6 were also assessed in subgroups of patients. Results Median CRP and IL-6 measurements were about 6-fold higher in patients than controls (both p<0.001) Morning salivary cortisol levels did not differ between the two groups, but patients exhibited higher median levels of evening and nocturnal salivary cortisol compared to controls [0.391(0.054, 0,663) vs. 0.081(0.054, 0.243)μg/dl, p<0.001 and 0.183(0.090, 0.834) vs. 0.054(0.054, 0.332)μg/dl, p<0.001, respectively], resulting in higher time-integrated area under the curve (AUC) (4.81±2.46 vs. 2.75±0.810, respectively, p<0.001 ). Circulating ACTH, DHEA, and aldosterone levels were similar in patients and controls. Serum IL-6, but not ACTH levels, WAS strongly correlated with nocturnal cortisol salivary levels (rho=0.555, p<0.001 ) in patients. Conclusion Increased evening and nocturnal but not morning cortisol secretion occur in even clinically mild COVID-19. In the context of acute viral infection (Covid-19), IL-6 may partially replace ACTH as a stimulus of the glucocorticoid-secreting adrenal zona-fasciculata without influencing the secretion of DHEA and aldosterone.