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 in cases required—recruited between April 15 to June 15, 2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8 a.m., 12, 6, and 10 p.m.), 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 sixfold 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, 0663) 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 ( ρ = 0.555, p < 0.001) in patients. Conclusions Increased evening and nocturnal but not morning cortisol secretion may 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. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT04988269?term=yavropoulou&draw=2&rank=3 (NCT04988269).

Background: Iatrogenic adrenal insufficiency (AI) secondary to long-term treatment with exogenous glucocorticoids (GC) is common in patients with systematic rheumatic diseases, including rheumatoid arthritis (RA). Moreover, a proportion of these patients is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs. Methods: We conducted a literature review up to December 2020 on (a) the incidence of AI in both long-term GC-treated and GC-treatment naïve RA patients; (b) the potential effects of increased levels of circulating proinflammatory cytokines, as well as of chronic stress, in adrenocortical function in RA; (c) the circadian cortisol rhythm in RA; and (d) established and evolving methods of assessment of adrenocortical function.Results: Up to 48% of RA patients develop glucocorticoid-induced AI; however, predictors are not established, while adrenocortical dysfunction may also occur in GC-treatment naïve RA patients. Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in RA. Although the underlying mechanisms are unknown, both proinflammatory cytokines and chronic stress may contribute the most in the adrenals hyporesponsiveness and the target tissue glucocorticoid resistance that have been described, but not systematically studied. A precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management. Conclusion: Apart from iatrogenic AI, an intrinsically compromised adrenal reserve in RA may have a pathogenetic role and interfere with effective management, thus deserving further research.

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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 15th -June15th-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.ResultsMedian 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.ConclusionIncreased 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.