Association between high serum total cortisol concentrations and mortality from COVID-19
Authors: Tricia Tan, Bernard Khoo, Edouard G Mills, Maria Phylactou, Bijal Patel, Pei C Eng, Layla Thurston, Beatrice Muzi, Karim Meeran, A Toby Prevost, Alexander N Comninos, Ali Abbara, Waljit S Dhillo
Journal: The Lancet Diabetes & Endocrinology (2020)

In March, 2020, WHO declared COVID-19 a global pandemic. At the time of writing, the UK has the highest number of recorded fatalities in Europe, with London regarded as the epicentre of infection in the UK. Physiological stress from critical illness and elective surgery increases serum cortisol concentrations and bioavailability by activation of the hypothalamic–pituitary–adrenal axis, decreased metabolism of cortisol, and a reduction in the amount of binding proteins (eg, cortisol-binding globulin).1Teblick A Peeters B Langouche L Van den Berghe G Adrenal function and dysfunction in critically ill patients.Nat Rev Endocrinol. 2019; 15: 417-427Crossref PubMed Scopus (92) Google Scholar, 2Khoo B Boshier PR Freethy A et al.Redefining the stress cortisol response to surgery.Clin Endocrinol (Oxf). 2017; 87: 451-458Crossref PubMed Scopus (48) Google Scholar The increase in cortisol is an essential part of the body's stress response, triggering adaptive changes in metabolism, cardiovascular function, and immune regulation.1Teblick A Peeters B Langouche L Van den Berghe G Adrenal function and dysfunction in critically ill patients.Nat Rev Endocrinol. 2019; 15: 417-427Crossref PubMed Scopus (92) Google Scholar The effects of COVID-19 on cortisol are currently unknown. It has been suggested that severe acute respiratory syndrome coronavirus (SARS-CoV), the predecessor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), might trigger an immunogenic response to adrenocorticotropic hormone because of mimicry. Similar mechanisms might apply to SARS-CoV-2, theoretically amplifying morbidity and mortality by inducing a cortisol insufficiency related to critical illness.1Teblick A Peeters B Langouche L Van den Berghe G Adrenal function and dysfunction in critically ill patients.Nat Rev Endocrinol. 2019; 15: 417-427Crossref PubMed Scopus (92) Google Scholar, 3Pal R COVID-19, hypothalamo–pituitary–adrenal axis and clinical implications.Endocrine. 2020; 68: 251-252Crossref PubMed Scopus (113) Google Scholar To understand whether this process might be a contributor to the pathophysiology of COVID-19, we did a cohort study describing the acute cortisol concentrations observed in patients with COVID-19. Patients admitted to three large teaching hospitals (Charing Cross, Hammersmith, and St Mary's) in London, UK, with a clinical suspicion of COVID-19 were included in this series (appendix p 1). Patients who were suspected to have SARS-CoV-2 infection had a standard set of blood samples drawn, including a full blood count, creatinine, C-reactive protein (CRP), D-dimer, and serum total cortisol measurement. During the study period (admissions from March 9 to April 22, 2020; follow-up to May 8, 2020), a total of 621 patients were admitted with suspected COVID-19 who had at least one cortisol measurement during their admission. We included only baseline cortisol measurements made within 48 h of admission for suspected COVID-19 or diagnosis of COVID-19 during a hospital admission. We excluded patients with pre-existing hypoadrenalism, concurrent systemic glucocorticoid treatment, or who had cortisol measured as part of a diagnostic test (eg, a synacthen test). After these exclusions, a cohort of 535 patients with cortisol measurements were available for analysis. 403 patients were diagnosed with COVID-19 on the basis of either a positive result from real-time RT-PCR testing of a nasopharyngeal swab (356 [88%] patients) or a strong clinical and radiological suspicion of COVID-19, despite negative swab testing (47 [12%] patients). 132 (25%) individuals in this cohort were not diagnosed with COVID-19 (appendix p 2). In the group of patients with COVID-19, the mean age of the patients was 66·3 years (SD 15·7) and 240 (59.6%) were men (appendix p 2). The most frequent comorbidities in the cohort of patients with COVID-19 were hypertension (191 [47·4%] patients), diabetes (160 [39·7%] patients), cardiovascular disease (94 [23·3%] patients), chronic kidney disease (50 [12·4%] patients), and a current diagnosis of cancer (38 [9·4%] patients). 112 (27·8%) of patients with COVID-19 died during the study period, compared with 9 (6·8%) of patients without COVID-19 (p<0·0001) (appendix p 2). Median cortisol concentration in the group of patients with COVID-19 was 619 nmol/L [IQR 456–833] versus 519 nmol/L [378–684] in the patient group who did not have COVID-19 (p<0·0001) (appendix p 2). Univariable analysis of the group of patients with COVID-19 by Cox proportional hazards regression modelling showed that age 75 years and older had the highest risk of acute mortality, and age younger than 75 years was associated with a reduced relative risk of acute mortality (appendix p 5). The presence of diabetes, hypertension, current diagnosis of cancer, chronic kidney disease, or cardiovascular disease was significantly associated with acute mortality. Increased cortisol, CRP, neutrophil to leukocyte ratio, and creatinine were predictive of acute mortality (appendix p 5). Multivariable analysis showed that a doubling of cortisol concentration was associated with a significant 42% increase in the hazard of mortality, after adjustment for age, the presence of comorbidities, and laboratory tests (appendix p 3). An optimal cutoff for cortisol was selected by use of maximally selected rank statistics. Patients with COVID-19 whose baseline cortisol concentration was equal to or less than 744 nmol/L (268 patients [67%]) had a median survival of 36 days [95% CI 24–not determined]; whereas, patients with COVID-19 whose cortisol value was more than 744 nmol/L (135 patients [33%]) had a median survival of 15 days [10–36] (log-rank test p<0·0001; figure). To our knowledge, our analyses show for the first time that patients with COVID-19 mount a marked and appropriate acute cortisol stress response and that this response is significantly higher in this patient cohort than in individuals without COVID-19. In other words, our cohort did not obviously exhibit an adrenal insufficiency with SARS-CoV-2 infection in the acute setting. However, it is possible that patients might exhibit a relative adrenal insufficiency later on in the course of their disease, as has been observed for SARS-CoV infection3Pal R COVID-19, hypothalamo–pituitary–adrenal axis and clinical implications.Endocrine. 2020; 68: 251-252Crossref PubMed Scopus (113) Google Scholar and in the context of an extended stay in intensive care.1Teblick A Peeters B Langouche L Van den Berghe G Adrenal function and dysfunction in critically ill patients.Nat Rev Endocrinol. 2019; 15: 417-427Crossref PubMed Scopus (92) Google Scholar The cortisol stress responses observed in this cohort range up to 3241 nmol/L. Despite the non-linearity of the cortisol assay at this high range, these values indicate a marked cortisol stress response, perhaps higher than is observed in patients undergoing major surgery.2Khoo B Boshier PR Freethy A et al.Redefining the stress cortisol response to surgery.Clin Endocrinol (Oxf). 2017; 87: 451-458Crossref PubMed Scopus (48) Google Scholar Until now, data were not available to guide an evidence-based approach to tailor glucocorticoid stress regimens in patients with adrenal insufficiency and SARS-CoV-2 infection.4Isidori AM Pofi R Hasenmajer V Lenzi A Pivonello R Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection.Lancet Diabetes Endocrinol. 2020; 8: 472-473Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar Our data suggest that it is appropriate for patients with hypoadrenalism—a situation quite commonly encountered in the 3% of the population taking systemic glucocorticoid therapy5Laugesen K Jorgensen JOL Petersen I Sorensen HT Fifteen-year nationwide trends in systemic glucocorticoid drug use in Denmark.Eur J Endocrinol. 2019; 181: 267-273Crossref PubMed Scopus (49) Google Scholar— to take or be given supplemental glucocorticoids at a high dose to prevent an acute adrenal crisis if they acquire a SARS-CoV-2 infection. Furthermore, we found that high cortisol concentrations were associated with increased mortality and a reduced median survival, probably because this is a marker of the severity of illness.6Christ-Crain M Stolz D Jutla S et al.Free and total cortisol levels as predictors of severity and outcome in community-acquired pneumonia.Am J Respir Crit Care Med. 2007; 176: 913-920Crossref PubMed Scopus (110) Google Scholar In our cohort, cortisol seemed to be a better independent predictor than were other laboratory markers associated with COVID-19, such as CRP, D-dimer, and neutrophil to leukocyte ratio. Nonetheless, we note the following caveats. First, for simplicity's sake, this study confined itself to the analysis of a single baseline cortisol concentration measured within 48 h of hospital admission for COVID-19. Consequently, this analysis does not consider variations within and between individuals in the dynamics of cortisol response to stress, as we observed in our surgical series.2Khoo B Boshier PR Freethy A et al.Redefining the stress cortisol response to surgery.Clin Endocrinol (Oxf). 2017; 87: 451-458Crossref PubMed Scopus (48) Google Scholar Second, although we found that a cortisol concentration cutoff of more than 744 nmol/L was predictive of a reduced median survival, this finding is likely to differ with other cortisol assays. Third, any potential role for cortisol measurement at baseline and later during an inpatient stay with COVID-19 as a prognostic biomarker, either by itself or in combination with other biomarkers, will require validation in a prospective study. We declare no competing interests. TT and BK were joint first authors of this Correspondence. Download .pdf (.61 MB) Help with pdf files Supplementary appendix Cortisol concentrations and mortality from COVID-19In their report on the association between high serum total cortisol concentrations and mortality from COVID-19, Tan and colleagues1 appear to have overlooked the pulsatility of cortisol secretion. A recent study by Gibbison and colleagues2 showed that both adrenocorticotropic hormone and cortisol are pulsatile in critical illness. The nadir of cortisol pulses in 35% of the patients in their study dropped below the threshold for deficiency in critical illness, as defined by international guidelines, although values shortly before and shortly after were well above this threshold. Full-Text PDF Cortisol concentrations and mortality from COVID-19We congratulate Tan and colleagues1 for their work on serum cortisol concentrations and mortality from COVID-19. Although these results are novel in the context of COVID-19, the practical implications are debatable. Full-Text PDF Cortisol concentrations and mortality from COVID-19 – Authors' replyWe are grateful to Rimesh Pal and colleagues and Kay Choy for their interest in our work1 and their useful comments. As Choy correctly points out, pulsatility could affect cortisol levels. Gibbison and colleagues2 showed concordance of adrenocorticotropic hormone and cortisol pulses, crucially with significantly less pulsatility in critical illness compared with healthy volunteers. This finding suggests that pulsatility might not have as great an effect on cortisol levels in critically ill patients as they would in healthy patients. Full-Text PDF