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Disclosures: The authors report no relevant financial disclosures.
June 29, 2020
3 min read

Stress level may predict mortality risk in COVID-19

Disclosures: The authors report no relevant financial disclosures.
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An increased cortisol level at hospital admission for individuals with COVID-19 may serve as an independent predictor of worse disease course, mortality and reduced median survival, study data show.

An increase in cortisol is an essential part of the body’s stress response, triggering adaptive changes in metabolism, cardiovascular function and immune regulation; however, the effects of COVID-19 on cortisol are not known, Waljit S. Dhillo, MBBS, PhD, a National Institute for Health Research (NIHR) professor in endocrinology and metabolism at Imperial College London, and colleagues wrote in correspondence published in The Lancet Diabetes & Endocrinology. Research on severe acute respiratory syndrome (SARS) suggests that the novel coronavirus might trigger an immunogenic response to adrenocorticotropic hormone because of “mimicry,” the researchers wrote.

Image of empty hospital room
Source: Adobe Stock

“My team and I went back to full-time clinical care to care for patients with COVID-19 during the pandemic in London, and we knew there was some evidence that patients may develop adrenal insufficiency following SARS,” Dhillo told Healio. “We did not know if COVID-19 might lead to adrenal insufficiency. As such, we decided to investigate, as part of our routine care, to determine what the cortisol levels were in our patients admitted to our hospitals with suspected COVID-19. Patients who were subsequently found not to have COVID-19 formed our control group.”

Cortisol levels in COVID-19

Dhillo and colleagues analyzed data from 535 adults admitted to three large teaching hospitals for suspected COVID-19 between March 9 and April 22. The patients had at least one cortisol measurement during admission. Researchers included only baseline cortisol measurements made within 48 hours of admission for suspected COVID-19 or diagnosis of COVID-19; individuals with preexisting hyperadrenalism or systemic glucocorticoid treatment were excluded. Within the cohort, 403 patients were diagnosed with COVID-19 (mean age, 66 years; 59.6% men), with the most frequent comorbidities hypertension (47.4%), diabetes (39.7%) and cardiovascular disease (23.3%).

Waljit S. Dhillo

The median cortisol concentration for patients with COVID-19 was 619 nmol/L (22 μg/dL) vs. 519 nmol/L for controls (P < .0001).

In multivariable analysis, researchers found that a doubling of cortisol concentration

was associated with a 42% increase in mortality risk, with results persisting after adjustment for age, comorbidities and laboratory tests. Using an optimal cutoff for cortisol level determined by maximally selected rank statistics, researchers found that individuals with COVID-19 whose baseline cortisol concentration was 744 nmol/L (27 μg/dL) or less (67% of patients) had a median survival of 36 days, whereas patients with COVID-19 whose cortisol value was more than 744 nmol/L (27 μg/dL; 33% of patients) had a median survival of 15 days (P < .0001 for log-rank test).


The researchers noted that observed cortisol stress responses were as high as 3,241 nmol/L (117 μg/dL).

“Despite the nonlinearity 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,” the researchers wrote.

Interpreting findings

Dhillo said the findings show patients with COVID-19 do not routinely require steroid supplementation. Higher cortisol levels at the time of admission predict poor outcomes, as they are likely to identify the sickest patients.

Dhillo said recent data from Oxford University showing that dexamethasone is beneficial in individuals with COVID-19 who require oxygen or ventilation is “in keeping with our data.”

“That study showed no benefit of dexamethasone among COVID-19 patients not requiring oxygen or ventilation,” Dhillo said. “This is in keeping with our data that patients with COVID-19 mount a good endogenous cortisol response. The Oxford data did show a benefit of 6 mg of dexamethasone — 12 times the physiological replacement dose of steroid — in patients with COVID-19 requiring oxygen or ventilation. This makes sense, too, as this dose of dexamethasone will be anti-inflammatory and likely reduce the pulmonary inflammation in this subgroup of patients.”

Dhillo said data are needed on cortisol measurements among adults with COVID-19 throughout the course of their disease to better understand associations between cortisol level and development of adrenal insufficiency when on mechanical ventilation.

“It would also be useful to know if any adrenal insufficiency develops after recovery from COVID-19 with short synacthen tests,” Dhillo said.

The researchers cautioned that the study does not consider cortisol variations within and between individuals and noted that any potential role for cortisol measurement as a prognostic biomarker will require validation in a prospective study.


RECOVERY Collaborative Group. MedRxiv. 2020;doi:10.1101/2020.06.22.20137273.

For more information:

Waljit S. Dhillo, MBBS, PhD, can be reached at Imperial College London at Hammersmith Campus, Room 6N6E, 6th Floor, Commonwealth Building, Du Cane Road, London W12 ONN; email:; Twitter: @WaljitD .