Abstract
In the context of severe coronavirus disease 2019 (COVID-19) illness, we examined endogenous glucocorticoid concentrations, steroidogenic enzyme activity, and their correlation with inflammation and patient outcomes. This observational study included 125 hospitalized COVID-19 patients and 101 healthy individuals as a reference group. We utilized LC-MS to assess serum concentrations of 11-deoxycortisol, cortisol, and cortisone, as well as activities of steroidogenic enzymes (11β-hydroxylase and 11β-hydroxysteroid-dehydrogenase type 1). Cox proportional hazards regression analysis and competing risk analysis were employed to analyze associations between glucocorticoid concentrations and outcomes, adjusting for relevant factors. In patients with COVID-19, cortisol concentrations were higher and cortisone concentrations were lower compared to the reference group, while 11-deoxycortisol concentrations were similar. Steroidogenic enzyme activity favored cortisol production. Correlations between glucocorticoid concentrations and inflammatory markers were low. A doubling in concentrations cortisol, was associated with increased 90-day mortality and mechanical ventilation (HR: 2.40 95% CI: (1.03–5.59) , P = 0.042 and HR: 3.83 (1.19–12.31), P = 0.024). A doubling in concentrations of 11-deoxycortisol was also associated to mortality (HR: 1.32 (1.05–1.67), P = 0.018), whereas concentrations of cortisone were associated with mechanical ventilation (HR: 5.09 (1.49–17.40), P = 0.009). In conclusion, serum concentrations of glucocorticoid metabolites were altered in patients hospitalized with severe COVID-19, and steroidogenic enzyme activity resulting in the conversion of cortisone to biologically active cortisol was preserved, thus not favoring critical-illness-related corticosteroid insufficiency at the enzymatic level. Glucocorticoid release did not counterbalance the hyperinflammatory state in patients with severe COVID-19. High serum concentrations of 11-deoxycortisol and cortisol were associated with 90-day mortality, and high serum concentrations of cortisol and cortisone were associated with mechanical ventilation.
Introduction
Numerous investigations have reported significant fluctuations in endogenous cortisol release in the context of acute illness stemming from coronavirus disease 2019 (COVID-19) (1, 2, 3). Conversely, an opposing perspective has surfaced, wherein certain studies have documented inadequately low cortisol levels (4, 5, 6). The latter has partly been attributed to critical illness-related corticosteroid insufficiency (CIRCI), a recurring phenomenon in patients with critical illness including septic shock, community-acquired pneumonia (CAP), and acute respiratory distress syndrome (7, 8). In the management of hypoxic COVID-19, dexamethasone, a synthetic glucocorticoid, plays a crucial role in reducing mortality (9). In this context, the benefits of dexamethasone are likely anti-inflammatory. Cortisol has similar anti-inflammatory properties including reduction of T- and B-lymphocytes, monocytes, neutrophils, and eosinophils at sites of inflammation, as well as important inhibitory effects towards pro-inflammatory mediators such as interleukin 6 (IL-6) (10). Therefore, in appropriate responses to critical illness and hyperinflammation, glucocorticoid levels are upregulated, attaining levels up to six-fold, primarily through activation of the hypothalamic-pituitary-adrenal (HPA) axis and the concurrent reduction of corticosteroid-binding proteins (8). However, in CIRCI, target tissue resistance towards glucocorticoids may occur even in the presence of elevated levels of circulating cortisol by insufficient glucocorticoid α-mediated anti-inflammatory activity (10, 11).
Thus, in this context, we aimed to explore glucocorticoids in patients with COVID-19 by assessing serum concentrations of 11-deoxycortisol, cortisol, and cortisone alongside the function of selected steroidogenic enzymes, namely 11β-hydroxylase (converting 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone) and 11β-hydroxysteroid dehydrogenase type 1 (converting cortisone to cortisol). Furthermore, we aimed to explore the correlation between glucocorticoid concentrations and inflammatory levels as well as the association between glucocorticoid concentrations and progressive disease in COVID-19.
Methods
Single-center, observational cohort study including patients hospitalized with COVID-19 at the Department of Infectious Diseases at Copenhagen University Hospital – Hvidovre – with archived biobank specimens as described earlier (12, 13). Inclusion criteria for this study were 1) presence of SARS-CoV-2 confirmed by RT-PCR from either nasopharyngeal/oropharyngeal swab, sputum, or endotracheal aspirate, 2) age ≥ 18 years, and 3) COVID-19 illness requiring hospitalization. Exclusion criteria were 1) current treatment with glucocorticoids or 2) pituitary or adrenal insufficiency. Patients were included from March 16 until June 16, 2020. The reference groups were men and women aged > 70 years old (Health2006) as earlier described (14, 15).
Data collection
Data was obtained through manual review of health records. Extracted data included demographic variables, comorbidities, vital parameters (peripheral oxygen saturation, temperature, respiratory rate), plasma C-reactive protein, duration of symptoms, and clinical outcome (mechanical ventilation and/or death). Baseline oxygen requirements were ascertained as the highest level of respiratory support within 24 h from admission.
Biochemical analysis
Blood from patients with COVID-19 was drawn between 07:00 and 09:00 h within the first 4 days of admission. Hormones were tested once in all patients. Concentrations of 11-deoxycortisol, cortisol, and cortisone were determined for all groups by isotope dilution TurboFlow LC-MS/MS as previously described (16). Limits of quantification were 0.017 nmol/L for 11-deoxycortisol, 1.9 nmol/L for cortisol, and 0.19 nmol/L for cortisone, and inter-assay CVs were ≤ 7% for all analytes. Samples from Health2006 were analyzed similarly. Serum IL-6 was measured as previously described (12).
Statistical analysis
The study population was characterized using descriptive statistics; categorical variables were reported as counts (%), parametric continuous variables summarized with means and standard deviations (SDs), and non-parametric continuous variables with medians and interquartile ranges (IQRs). Comparison of baseline characteristics between the two cohorts were performed using χ2 test, one-way ANOVA, and Wilcoxon rank-sum test, as appropriate. Comparison of cortisol concentrations was done using Wilcoxon rank-sum test. Correlations between cortisol concentrations and IL-6 and CRP, respectively, were analyzed by linear regression. Skewed data was log2-transformed prior to analysis. Cox proportional hazards regression was used to evaluate the association between glucocorticoid concentrations and 90-day mortality in crude and adjusted models and expressed as hazard ratios (HRs) with 95% CI per two-fold increment of cortisol. The association of glucocorticoid concentrations and need of mechanical ventilation was done using Fine-Gray’s cumulative incidence function with competing risks: death, discharge, and mechanical ventilation. Schoenfeld residuals were applied to test proportional hazards assumptions. The multivariate models included predefined known confounders including sex, age, comorbidities (hypertension, cancer, asthma, diabetes, cardiovascular disease (CVD)), time from admission to blood sampling, and concentration of IL-6. Variables with > 10% missing values was not included in the regression model. Survival time was from the day of sampling and until day 90 or death, whichever came first. All statistical analyses were performed using R (version 3.6.0, R Core Team 2019).
Ethics
The study was approved by the Regional Data Protection Center (P-2020-260) and by the Danish Regional Committee on Health Research Ethics (H-20040649 and H-18024256). The measurements from Health2006 and Health2008, used for references, were approved by the Danish Regional Committee on Health Research Ethics (H-20059668 and H-KA-20060011). The requirement of individual informed consent was waived by the committee.
Results
In total, 125 patients were eligible for study inclusion, whereof 58% were men; one patient was excluded due to glucocorticoid treatment prior to admission. Baseline characteristics and clinical outcomes are given in Table 1. The median age was 72 (IQR 58–81) and the majority had one or more comorbidities. Individuals with COVID-19 had symptoms for 7 days, and the majority required supplemental oxygen at or within 24 h of admission. Plasma levels of CRP were 95 (IQR 50–151) mg/L and serum levels of IL-6 were 78 pg/mL (IQR 39–168). None were treated with remdesivir or dexamethasone.
Baseline characteristics and clinical outcome at day 90 in 125 patients hospitalized with COVID-19 stratified according to survival status within 90 days of hospitalization.
| All, n = 125 | Non-survivors, n = 39 | Survivors, n = 86 | P | |
|---|---|---|---|---|
| Age, years (IQR) | 72 (58–81) | 65 (53–76) | 78 (71–84) | < 0.001 |
| Sex, n (%) | ||||
| Female | 52 (42) | 35 (41) | 17 (44) | 0.91 |
| BMI, kg/m2 (IQR) | 28.3 (24.5–31.7) | 28.1 (24.2–31.1) | 28.4 (24.7–32.1) | 0.54 |
| Missing | 17 | 6 | 11 | |
| Comorbidity, n (%) | ||||
| Hypertension | 57 (46) | 31 (36) | 26 (67) | 0.003 |
| Diabetes | 41 (33) | 26 (30) | 15 (39) | 0.48 |
| Cardiovascular disease | 67 (54) | 39 (45) | 28 (72) | 0.007 |
| Cancer | 21 (17) | 11 (13) | 10 (26) | 0.13 |
| COPD | 9 (7) | 5 (6) | 4 (10) | 0.61 |
| Asthma | 17 (14) | 11 (13) | 6 (15) | 0.91 |
| Vitals | ||||
| Respiratory rate per minute | 21 (18–28) | 20 (18–26) | 23 (20–30) | 0.05 |
| Missing | 1 | 1 | 0 | |
| Temperature, °C | 38.1 (37.2–38.8) | 38.1 (37.0–38.7) | 38.2 (37.5–38.8) | 0.21 |
| Symptom duration, days (IQR) | 7 (5–10) | 7 (5–10) | 7 (5–11) | 0.93 |
| Missing | 24 | 9 | 15 | |
| Baseline oxygen requirement, n (%) | ||||
| No oxygen | 23 (18) | 18 (21) | 5 (13) | |
| Low flow | 58 (47) | 43 (50) | 15 (39) | |
| High flow | 44 (35) | 25 (29) | 19 (49) | |
| Mechanical ventilation | 0 | 0 | 0 | |
| Serum 11-deoxycortisol, nmol/L (IQR) | 0.9 (0.5–2.2) | 0.8 (0.4–1.4) | 1.7 (0.6–4.2) | 0.004 |
| Serum cortisol, nmol/L (IQR) | 532 (451–690) | 661 (486–725) | 518 (450–662) | 0.015 |
| Serum cortisone, nmol/L (IQR) | 41 (34–48) | 41 (34–46) | 42 (32–52) | 0.62 |
| Inflammatory markers (IQR) | ||||
| Plasma CRP, mg/L | 95 (50–152) | 87 (48–138) | 120 (53–197) | 0.07 |
| Missing | 19 | 7 | 12 | |
| Serum IL-6, pg/mL | 78 (39–168) | 57 (32–92) | 189 (102–303) | < 0.001 |
| Serum ALAT, U/L (IQR) | 33 (23–62) | 34 (27–63) | 31 (22–58) | 0.18 |
| Missing | 61 | 14 | 47 | |
| Treatment | ||||
| Remdesivir, n (%) | 0 (0) | |||
| Dexamethasone, n (%) | 0 (0) | |||
| Intensive care admission, n (%) | 20 (16) | 7 (8) | 13 (33) | < 0.001 |
| Intubation, n (%) | 19 (15) | 6 (7) | 13 (33) | < 0.001 |
| ECMO, n (%) | 7 (6) | 3 (4) | 4 (10) | 0.20 |
ALAT, alanine transaminase; BMI, body mass index; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; ECMO, extracorporeal membrane oxygenation; HR, hazard ratio; IL-6: interleukin 6.
In the reference group, the median age was 75 years old (IQR: 74–75) and 51% were men. Information on comorbidity was unavailable.
Serum concentrations of 11-deoxycortisol, cortisol, and cortisone
Specimens were collected a median of 2 days (IQR: 1–4) after admission to hospital. Concentrations of glucocorticoids are given in Fig. 1. When compared to the reference group, patients had similar concentrations of 11-deoxycortisol (41 nmol/L (34–47) vs 49 nmol/L (42–57), P =0.921), elevated concentrations of cortisol (532 nmol/L (451–690) vs 321 nmol/L (255–394), P <0.001), and reduced concentrations of cortisone (41 nmol/L (34–47) vs 49 nmol/L (42–57), P< 0.001).
Serum concentrations of 11-deoxycortisol, cortisol, and cortisone in patients hospitalized with COVID-19 and in a reference group of healthy individuals.
Citation: Endocrine Connections 13, 8; 10.1530/EC-24-0093
Ratios between 11-deoxycortisol, cortisol, and cortisone, respectively, are given in Fig. 2A and 2B. Compared to the reference group, the ratios between the concentrations of cortisol and either 11-deoxycortisol and cortisone, were higher in patients with COVID-19 and weighted towards cortisol.
A) Ratios between cortisol and 11-deoxycortisol in patients with COVID-19 compared to a healthy reference group. B) Ratios between cortisol and cortisone in patients with COVID-19 compared to a healthy reference group.
Citation: Endocrine Connections 13, 8; 10.1530/EC-24-0093
Correlation coefficients varied between IL-6 and 11-deoxycortisol (R = 0.28, P = 0.02), cortisol (R = 0.16, P = 0.06), and cortisone (R = 0.04, P = 0.69). Similarly, correlations between CRP and 11-deoxycortisol (R = 0.02, P = 0.86), cortisol (R = 0.06, P = 0.52), cortisone (R = −0.03, P = 0.73) were variable.
Glucocorticoids, disease severity, and mortality
By day 30, 27% of patients and by day 90, 31% of patients had died. During hospitalization, 20 (16%) patients required intensive care, 19 patients required mechanical ventilation and seven patients required extracorporeal membrane oxygenation. Patients who had died by day 90, had higher concentrations of 11-deoxycortisol and cortisol, than individuals who survived. Concentrations of cortisone were comparable between survivors and non-survivors (Table 1). Non-survivors by day 90 were characterized by higher age, higher frequency of hypertension and cardiovascular disease, higher respiratory rate, higher inflammatory markers (CRP and IL-6), and higher requirement of mechanical ventilation than survivors. Within the first 24 h of admission, 82% of the total population required either low-flow or high-flow oxygen supplementation. Non-survivors within 90 days of admission had a higher rate of high-flow oxygen requirement compared to survivors (49% vs 29%, P = 0.033), indicating a higher disease severity at baseline. After adjustment for sex, age, comorbidities (hypertension, cancer, asthma, diabetes, cardiovascular disease (CVD)), blood sampling day, baseline disease severity, and concentration of IL-6, a doubling in serum concentrations of 11-deoxycortisol (HR: 1.32 (95% CI: 1.05–1.67), P = 0.018) and cortisol (HR: 2.40 (95% CI: 1.03–5.59), P = 0.042) was associated with increased 90-day mortality. Furthermore, after adjustment a doubling in serum concentrations of cortisone (HR: 5.09 (1.49–17.40), P = 0.009) and cortisol (HR: 3.83 (1.19–12.31), P = 0.024) was associated with increased hazard of requiring mechanical ventilation (Table 2).
Crude and adjusted associations between two-fold increments of serum concentrations of 11-deoxycortisol, cortisol, and cortisone and, respectively, mortality and need of mechanical ventilation within 90 days in patients hospitalized with COVID-19.
| Crude HR (95 % CI) | P | Adjusted HR | P | |
|---|---|---|---|---|
| Mortality | ||||
| Cortisol | 3.54 (1.60–7.84) | 0.002 | 2.40 (1.03–5.59) | 0.042 |
| 11-deoxycortisol | 1.56 (1.25–1.94) | < 0.001 | 1.32 (1.05–1.67) | 0.018 |
| Cortisone | 1.48 (0.64–3.42) | 0.362 | 1.95 (0.94–4.04) | 0.072 |
| Mechanical ventilationa | ||||
| Cortisol | 3.50 (1.60–7.65) | 0.002 | 3.83 (1.19–12.31) | 0.024 |
| 11-deoxycortisol | 1.19 (0.96–1.48) | 0.107 | 1.31 (0.97–1.77) | 0.077 |
| Cortisone | 2.20 (0.70–6.92) | 0.176 | 5.09 (1.49–17.40) | 0.009 |
Values in bold indicate statistical significance.
aMechanical ventilation is computed using Fine–Gray cumulative incidence function with competing risks: death, discharge, and mechanical ventilation.
COVID-19, coronavirus disease 2019; HR, hazard ratio.
Discussion
Here we confirm that patients with COVID-19 had elevated serum concentrations of cortisol and diminished serum concentrations of cortisone compared to a healthy reference group. We found that an elevated concentration of cortisol was associated with increased mortality within 90 days and increased risk of requirement of mechanical ventilation. In addition, we here show that increased concentrations of the cortisol precursor, 11-deoxycortisol, was associated with mortality, while the cortisol metabolite, cortisone, was associated with mechanical ventilation. Further, we observed heightened activity of steroidogenic enzymes favoring increased cortisol production in COVID-19 patients. Lastly, we observed a tenuous or non-existing correlation between inflammatory markers (CRP and IL-6) and glucocorticoids.
Despite high serum concentrations of cortisol associated with COVID-19, additional glucocorticoid treatment has been effective in improving outcomes in patients with hypoxemic COVID-19 (9). This suggests an inadequate physiological stress response in COVID-19 patients. Our findings do not support the presence of CIRCI at an enzymatic level in COVID-19, contrary to previous studies (4, 5). However, as samples of this study were collected within the first 4 days of admission, exclusion of CIRCI only applies for the acute phase of COVID-19 and may develop in the later stages of the acute ill patients. While CIRCI may be associated with impaired enzymatic function in cortisol metabolism, our study indicates increased enzyme function of 11β-hydroxylase (converting 11-deoxycortisol to cortisol) and 11β-hydroxysteroid dehydrogenase type 1 (converting cortisone to cortisol) in acute severe COVID-19. However, CIRCI may theoretically occur in peripheral tissues, potentially limiting the full effectiveness of secreted cortisol. Intracellular tissue resistance might arise due to inadequate glucocorticoid receptor alpha (GR-α) activity observed in critical illness, which is characterized by reduced GR-α density. GR-α functions by binding to specific DNA regions and facilitating their transcription, which can inhibit pro-inflammatory cytokines, among other effects (12). Clinical studies on patients with acute respiratory distress syndrome (ARDS) have shown a correlation between the degree of intracellular glucocorticoid resistance and both disease severity and mortality (17). However, recent research indicates that down-regulation of GR-α occurs during the subacute stages of critical illness. The response to critical illness appears to be biphasic, with upregulation during the acute phase followed by downregulation in the subacute phase, compared to matched controls (18). Therefore, we expect that intracellular CIRCI is not present in the patients studied. Future research should investigate subacute development of CIRCI, including intracellular GR-α activity in the later stages of severe COVID-19.
As glucocorticoid access is a part of a stress response, more severe inflammatory disease is likely to lead to higher cortisol concentrations. Contrarily, our study revealed a tenuous or non-existent correlation between IL-6 or CRP and the concentrations of 11-deoxycortisol, cortisol, and cortisone. Furthermore, even after adjusting for IL-6, 11-deoxycortisol and cortisol remained predictive of mortality. This suggests that the increase of the glucocorticoids was not driven by inflammation alone but by the overall physiological stress response during severe COVID-19. However, the increase in cortisol appeared to be insufficient to counterbalance the hyperinflammatory response to severe COVID-19. Studies on patients with ARDS receiving glucocorticoid supplementation have shown an increase in both the number and function of GR-α, effectively reversing glucocorticoid resistance related to critical illness (17, 19). This could explain why exogenous glucocorticoid treatment serves a therapeutic role in severe COVID-19. In contrast to our study findings, Świątkowska-Stodulska et al. reported moderate correlations between cortisol concentrations and IL-6 (20). It is worth noting that they defined specific time points for the sample measurement (days 1, 4, and 10), potentially accounting for the disparities observed. In our study, blood samples were collected within 4 days and thus at different time points. Nevertheless, Świątkowska-Stodulska et al. too found that concentrations of cortisol were associated with outcome defined as mortality and vasopressor use.
Study strengths and limitations
Foremost among these is the use of LC-MS/MS for the precise biochemical analysis of hormonal parameters. Additionally, the study's strengths lie in its prospective enrollment strategy of consecutive patients hospitalized with COVID-19. In this context, the study was able to address glucocorticoid release with cortisol and its metabolites, cortisone and 11-deoxycortisol, and steroidogenic enzyme function, which to our knowledge is the first of its kind and adds novelty to the subject. This study had several limitations. First, blood was sampled up to 4 days of admission rather than on the same day. To account for effects of variable sampling, survival time was calculated from the day of sampling. Secondly, we only had one sample per patient, which do not account for the pulsatile nature of cortisol. However, samples were collected on the morning round for all patients (06:00–08:00 h), which enhances the comparability between patients. Thirdly, it would have been valuable to have ACTH-concentrations measured simultaneously with the other glucocorticoids. However, as ACTH is an elusive hormone with low accountability of a one-sample measurement, it would be hard to interpret within this study. Additionally, it was not possible to prepare the samples correctly for ACTH analysis, as it was from biobank samples. Lastly, it was not possible to exclude patients with inhaled glucocorticoids, as we lacked information on this matter.
In conclusion, glucocorticoid concentrations were altered, including elevated cortisol and diminished cortisone in patients hospitalized with COVID-19 with steroidogenic enzyme activity weighted towards cortisol. Glucocorticoid concentrations did not correlate well with inflammatory markers. Lastly, elevations in serum concentrations of both cortisol and 11-deoxycortisol were associated with increased 90-day mortality.
Declaration of interest
AJ received speaker’s fees from Novo Nordisk, IPSEN, and Sandoz outside of the submitted work. TB reports grants from Novo Nordisk Foundation, Lundbeck Foundation, Simonsen Foundation, GSK, Pfizer, Gilead, Kai Hansen Foundation, and Erik and Susanna Olesen’s Charitable Fund; personal fees from GSK, Pfizer, Bavarian Nordic, Boehringer Ingelheim, Gilead, MSD, PentaBase ApS, Becton Dickinson, Janssen, and Astra Zeneca outside of the submitted work. All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
The data that support the findings of this study are available on request from the corresponding author.
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