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      Association between high serum total cortisol concentrations and mortality from COVID-19

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          Abstract

          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).1, 2 The increase in cortisol is an essential part of the body's stress response, triggering adaptive changes in metabolism, cardiovascular function, and immune regulation. 1 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.1, 3 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 ). Figure Kaplan-Meier plot of survival probability over time. The plot is categorised by baseline cortisol concentration above or equal to and below the cutoff of 744 nmol/L. Shading indicates 95% CI for each curve. 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 infection 3 and in the context of an extended stay in intensive care. 1 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. 2 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. 4 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 therapy 5 — 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. 6 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. 2 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.

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          Most cited references6

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          COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications

          Rimesh Pal (2020)
          A novel coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 1,000,000 individuals, claiming more than 56,000 lives in over 200 countries worldwide ever since its mysterious outbreak in Wuhan, China in December 2019. The largest case series from China had shown that majority of the patients belonged to the age group of 30–79 years. Most of the cases were mild (81%), while 14% cases were severe and only 5% critical. The overall case-fatality rate was 2.3% [1]. SARS-CoV-2 primarily affects the lungs, resulting in viral pneumonia often complicated by acute respiratory distress syndrome and sepsis. The virus is able to evade the host immune system by avoiding detection of their dsRNA and by inhibiting the host interferon-I pathway [2]. The pathogen enters the pneumocyte using the host angiotensin-converting enzyme 2 (ACE2) as a receptor. In addition, the enzyme is expressed on the arterial and venous endothelial cells of many organs including the adrenal glands. Autopsy studies on patients who died from SARS (the original outbreak in 2003) had shown degeneration and necrosis of the adrenal cortical cells. The SARS-CoV (the ‘cousin’ of SARS-CoV-2) was in fact identified in the adrenal glands, hinting towards a direct cytopathic effect of the virus. Hence it is likely that cortisol dynamics may be altered in patients with SARS (and COVID-19). However, the literature is scarce is this regard. One of the primary immunoinvasive strategy employed by the SARS-CoV, like influenza virus, is to knock down the host’s cortisol stress response. To achieve the same, SARS-CoV expresses certain amino acid sequences that act as molecular mimics of the host adrenocorticotropic hormone (ACTH). The first 24 amino acids of ATCH (ACTH1-24) are highly conserved between different mammalian species while ACTH25-39 represents the less conserved region. Six amino acids at position 26, 29, 31, 33, 37, and 39 represent the antigenically important positions for mammalian ACTH. SARS (and influenza virus) contain many permutations of amino acid sequences with homology to these probable ACTH key residues. Antibodies produced by the host to counteract the virus, in turn, would unknowingly destroy the host ACTH, thereby blunting the cortisol rise. This would imply that all patients with SARS might have had underlying relative cortisol insufficiency [3]. However, data on serum cortisol levels in patients with SARS (or COVID-19) are unavailable till date. SARS (and COVID-19) might affect the hypothalamic-pituitary-adrenal (HPA) axis as well. Biochemical evidence of HPA axis involvement in SARS was first reported by Leow et al. Sixty-one survivors of the SARS outbreak were evaluated at 3 months after recovery and periodically thereafter. Forty percent of patients had evidence of central hypocortisolism, majority of which resolved within a year. A small percentage of patients also had central hypothyroidism and low dehydroepiandrosterone sulfate. The authors had proposed the possibility of a reversible hypophysitis or a direct hypothalamic damage that could have led to a state of transient hypothalamo-pituitary dysfunction [4]. Infact, edema, and neuronal degeneration along with SARS-CoV genome have been identified in the hypothalamus on autopsy studies. Hypothalamic and pituitary tissues do express ACE2 and can therefore be viral targets. The portal of entry of the virus into the hypothalamus-pituitary could be either directly thorough the cribriform plate via hematogenous route. Nevertheless, frank hypocortisolism has never been documented in patients with active SARS (or COVID-19). A prospective study evaluating serum cortisol and ACTH in patients with severe COVID-19 is presently underway (ChiCTR20000301150). Irrespective of serum cortisol levels, glucocorticoids have been used in patients with critical illnesses including SARS. Glucocorticoids are also being used in patients with COVID-19, although the current interim guidance from the WHO (released Jan 28, 2020) advises against its routine use. Its use in COVID-19 is based on the premise that the virus is able to elicit a cytokine storm in the host that can be averted by the use of glucocorticoids. Glucocorticoids have been used in the treatment of other viral infections, notably, respiratory syncytial virus, influenza, and Middle East Respiratory Coronavirus, however, no clinical data exist to indicate any net benefit [5]. Benefits of glucocorticoids have been documented in patients with septic shock; shock in patients with COVID-19, although seen in about 5% of the cases, is often a result of increased intrathoracic pressure (due to invasive ventilation) that impedes cardiac filling. Thus, in the absence of septic shock, use of glucocorticoids in COVID-19 is debatable. A clinical trial on efficacy and safety of corticosteroids in COVID-19 is currently underway (NCT04273321). A report by Panesar et al. in patients with SARS had shown that lymphopenia, seen in about half of the patients, was related to prevailing serum cortisol levels. Patients with lymphopenia had higher serum cortisol and than those without lymphopenia. Similar data in patients with COVID-19 is lacking as of now. However, absence of lymphopenia in patients with COVID-19 could be used a marker of hypocortisolism (absolute or relative) and a low threshold could be kept for initiating glucocorticoid therapy in the presence of shock or acute respiratory distress syndrome. Nevertheless, people with known adrenal insufficiency should follow sick-day guidelines and in general, should double the dose of glucocorticoids in times of acute illness. In addition, individuals with adrenal insufficiency have an increased rate of respiratory infection-related deaths, possibly due to impaired immune function and hence need to take extra precautions amid the ongoing COVID-19 pandemic [6].
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            Adrenal function and dysfunction in critically ill patients

            Critical illnesses are characterized by increased systemic cortisol availability, which is a vital part of the stress response. Relative adrenal failure (later termed critical-illness-related corticosteroid insufficiency (CIRCI)) is a condition in which the systemic availability of cortisol is assumed to be insufficiently high to face the stress of the illness and is most typically thought to occur in the acute phase of septic shock. Researchers suggested that CIRCI could be diagnosed by a suppressed incremental cortisol response to an injection of adrenocorticotropic hormone, irrespective of the baseline plasma cortisol. This concept triggered several randomized clinical trials on the impact of large stress doses of hydrocortisone to treat CIRCI, which gave conflicting results. Recent novel insights into the response of the hypothalamic-pituitary-adrenal axis to acute and prolonged critical illnesses challenge the concept of CIRCI, as currently defined, as well as the current practice guidelines for diagnosis and treatment. In this Review, these novel insights are integrated within a novel conceptual framework that can be used to re-appreciate adrenocortical function and dysfunction in the context of critical illness. This framework opens new avenues for further research and for preventive and/or therapeutic innovations.
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              Free and total cortisol levels as predictors of severity and outcome in community-acquired pneumonia.

              High cortisol levels are of prognostic value in sepsis. The predictive value of cortisol in pneumonia is unknown. Routinely available assays measure serum total cortisol (TC) and not free cortisol (FC). Whether FC concentrations better reflect outcome is uncertain. To investigate the predictive value of TC and FC in community-acquired pneumonia (CAP). Preplanned subanalysis of a prospective intervention study in 278 patients presenting to the emergency department with CAP. TC, FC, procalcitonin, C-reactive protein, leukocytes, clinical variables, and the pneumonia severity index (PSI) were measured. The major outcome measures were PSI and survival. TC and FC, but not C-reactive protein or leukocytes, increased with increasing severity of CAP according to the PSI (P < 0.001). TC and FC levels on presentation in patients who died during follow-up were significantly higher as compared with levels in survivors. In a receiver operating characteristic analysis to predict survival, the area under the receiver operating characteristic curve (AUC) was 0.76 (95% confidence interval, 0.70-0.81) for TC and 0.69 (0.63-0.74) for FC. This was similar to the AUC of the PSI (0.76 [0.70-0.81]), and better as compared with C-reactive protein, procalcitonin, or leukocytes. In univariate analysis, only TC, FC, and the PSI were predictors of death. In multivariate analysis, the predictive potential of TC equaled the prognostic power of PSI points. Cortisol levels are predictors of severity and outcome in CAP to a similar extent to the PSI, and are better than routinely measured laboratory parameters. In CAP, the prognostic accuracy of FC is not superior to TC. Clinical trial registered with www.controlled-trials.com (ISRCTN04176397).
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                Author and article information

                Contributors
                Journal
                Lancet Diabetes Endocrinol
                Lancet Diabetes Endocrinol
                The Lancet. Diabetes & Endocrinology
                Elsevier Ltd.
                2213-8587
                2213-8595
                18 June 2020
                18 June 2020
                Affiliations
                [a ]Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
                [b ]Department of Endocrinology, Imperial College Healthcare National Health Service Trust, London, UK
                [c ]Department of Endocrinology, Division of Medicine, Faculty of Medical Sciences, Royal Free Campus, University College London, London, UK
                [d ]Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK
                Author notes
                [†]

                Contributed equally

                Article
                S2213-8587(20)30216-3
                10.1016/S2213-8587(20)30216-3
                7302794
                32563278
                e0404c6d-61c6-44de-b307-c0b8949b1a44
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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