Cortisol concentrations and mortality from COVID-19 – Authors' reply
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)

We are grateful to Rimesh Pal and colleagues and Kay Choy for their interest in our work1Tan T Khoo B Mills EG et al.Association between high serum total cortisol concentrations and mortality from COVID-19.Lancet Diabetes Endocrinol. 2020; 8: 659-660Summary Full Text Full Text PDF PubMed Scopus (179) Google Scholar and their useful comments. As Choy correctly points out, pulsatility could affect cortisol levels. Gibbison and colleagues2Gibbison B Keenan DM Roelfsema F et al.Dynamic pituitary–adrenal interactions in the critically ill after cardiac surgery.J Clin Endocrinol Metab. 2020; 105: 1327-1342Crossref Scopus (17) Google Scholar 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. With regard to the comment made by Pal and colleagues on the diagnosis of critical illness-related corticosteroid insufficiency, we note that the consensus statement of Annane and colleagues3Annane D Pastores SM Rochwerg B et al.Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.Intensive Care Med. 2017; 43: 1751-1763Crossref PubMed Scopus (192) Google Scholar on diagnostic criteria could not recommend the use of a short Synacthen (tetracosactide) test because the evidence was of low quality. An alternative definition of critical illness-related corticosteroid insufficiency is a cortisol concentration of less than 276 nmol/L (10 μg/dL). Of the 403 patients with COVID-19 in our cohort, we found that only 18 had a cortisol level below this cut-off (compared with 13 of 132 in the patients without COVID-19).1Tan T Khoo B Mills EG et al.Association between high serum total cortisol concentrations and mortality from COVID-19.Lancet Diabetes Endocrinol. 2020; 8: 659-660Summary Full Text Full Text PDF PubMed Scopus (179) Google Scholar This result suggests that critical illness-related corticosteroid insufficiency is not a widespread problem in the context of COVID-19 in a non-intensive care unit setting, but further data are needed. Pal and colleagues also comment that clinical practice for septic shock involves the use of hydrocortisone and other glucocorticoids. Of specific relevance, glucocorticoids (eg, dexamethasone) might confer benefit in severe COVID-19.4Horby P Lim WS et al.RECOVERY Collaborative GroupDexamethasone in hospitalized patients with Covid-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Google Scholar However, this benefit is less likely to be driven by any treatment of critical illness-related corticosteroid insufficiency per se, than by the anti-inflammatory and immunomodulatory effects of dexamethasone. Indeed, no benefit of dexamethasone was seen in patients with COVID-19 not requiring oxygen in the RECOVERY trial.4Horby P Lim WS et al.RECOVERY Collaborative GroupDexamethasone in hospitalized patients with Covid-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Google Scholar Choy points out that our analysis did not examine the effect of binding proteins (eg, cortisol-binding globulin). These proteins do indeed decrease in the context of physiological stress as we have previously documented,5Khoo 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 and this probably occurs in COVID-19. The net effect of an elevation in total cortisol and a reduction in cortisol-binding globulin will be to increase free cortisol levels.5Khoo 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 This supports our main finding, which is that COVID-19 is associated with a marked elevation in cortisol. Some immunoassays do indeed exhibit a positive bias versus gold-standard assays due to cross-reaction with other steroids in samples derived from critically ill patients. We used an Abbott immunoassay and we note that Dodd and colleagues6Dodd AJ Ducroq DH Neale SM et al.The effect of serum matrix and gender on cortisol measurement by commonly used immunoassays.Ann Clin Biochem. 2014; 51: 379-385Crossref PubMed Scopus (30) Google Scholar showed that this assay exhibits no significant bias in comparison with the gold-standard gas chromatography–mass spectrometry assay in the context of critical illness.6Dodd AJ Ducroq DH Neale SM et al.The effect of serum matrix and gender on cortisol measurement by commonly used immunoassays.Ann Clin Biochem. 2014; 51: 379-385Crossref PubMed Scopus (30) Google Scholar Therefore, assay interference does not plausibly explain the markedly elevated cortisol levels in our study. Both Pal and colleagues and Choy caution against the routine use of serum cortisol as a prognostic biomarker in the context of COVID-19. Cortisol is likely to co-vary with disease severity as a marker of physiological stress. Our dataset does not include all the variables necessary for construction of APACHE-II or SOFA scores to verify this hypothesis. However, we believe that the correspondents' comments support our contention that the potential use of cortisol levels as a prognostic marker in COVID-19 will require validation in a prospective study incorporating validated measures of disease severity. We declare no competing interests. TT and BK contributed equally. 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 Association between high serum total cortisol concentrations and mortality from COVID-19In 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. Full-Text PDF