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 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://ichgcp.net/clinical-trials-registry/NCT04988269?term=yavropoulou&draw=2&rank=3 (NCT04988269).

Keywords: Adrenocorticotropin; Aldosterone; Diurnal salivary cortisol; Diurnal salivary dehydroepiandrosterone; SARS-CoV-2.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Fig. 1

Flow diagram of finally included COVID-19 patients

Fig. 2

Diurnal variation of salivary cortisol levels in COVID-19 patients, stratified by disease status, and healthy controls. a Cumulative salivary cortisol levels within each group, b % change of salivary cortisol from 8 a.m., c time-integrated daily cortisol secretion (calculated as the area under the curve|). COVID-19 patients are classified according to the severity of the disease (https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/) and their clinical course during the 4-week follow-up period of the study as mild-stable, moderate-stable, and moderate-progressed. Values are shown as mean ± SEM, *p < 0.05, comparisons were performed with the morning values of salivary cortisol (8 a.m.). One-way repeated measures ANOVA with Bonferroni post hoc test was used for multiple comparisons between different time points of salivary cortisol within each group. **p < 0.05, comparisons were performed with the control group, using Kruskal–Wallis followed by Dunn’s multiple comparison test (comparing every group against the controls). AUC area under the curve

Fig. 3

Changes in the DHEA/Cortisol ratio during the day in COVID-19 patients, stratified by disease status, and healthy controls. a Cumulative DHEA/Cortisol ratio within each group, b Time-integrated changes of DHEA/Cortisol ratio during the day (calculated as the area under the curve|). COVID-19 patients are classified according to the severity of the disease (https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/) and their clinical course during the 4-week follow-up period of the study as mild-stable, moderate-stable, and moderate. **p < 0.05, comparisons were performed with the control group, using Kruskal–Wallis followed by Dunn’s multiple comparison test (comparing every group against the controls). AUC, area under the curve

Fig. 4

Correlations of serum IL-6 levels measured on the day of recruitment with salivary cortisol levels measured during the next day in COVID-19 patients: a morning (8 a.m.), b mid-day (12-noon), c evening (6 p.m.), and d night (10 p.m.). Only the evening and night correlations were significant. COVID-19 patients are classified according to the severity of the disease (https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/), and their clinical course during the 4-week follow-up period of the study, as mild-stable, moderate-stable, and moderate-progressed. Spearman’s rank correlation coefficient was used for associations between the parameters tested. *p < 0.05 is considered statistically significant. IL-6, interleukin-6

Fig. 5

Correlations of plasma ACTH measured on the day of hospital admission (Day 1) with salivary cortisol levels measured during the next day (Day 2) in COVID-19 patients: a morning (8 a.m.), b mid-day (12-noon), c evening (6 p.m.), and d night (10 p.m.). Correlations were not statistically significant. COVID-19 patients are classified according to the severity of the disease (https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/), and their clinical course during the 4-week follow-up period of the study. Spearman’s rank correlation coefficient was used for associations between the parameters tested. ACTH, adrenocorticotropin