Relationship between plasma cortisol concentration and Long COVID symptoms in the post-acute phase of COVID-19: a cross-sectional study and recommendations for future research

ABSTRACT BACKGROUND Low cortisol concentrations have been reported in some people with Long COVID (LC), but more data from diverse cohorts are needed to validate this observation. A subset of people with LC present with symptoms resembling those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The objective of this study was to compare cortisol concentrations in those with and without Long COVID, with a particular focus on people experiencing ME/CFS-like Long COVID. METHODS We measured plasma cortisol in 200 individuals 3-6 months following a SARS-CoV-2 infection. Banked biospecimens collected between 8 AM-12 PM were used. Participants met the case definition for Long COVID if they had ≥1 COVID-attributed symptom at least 3 months after symptom onset. People who did not report any symptoms at least 3 months after symptom onset served as recovered controls. Adapting the 2015 Institute of Medicine criteria for ME/CFS, we further defined those with LC resembling ME/CFS (LC-ME). RESULTS We found no difference in overall morning cortisol concentrations between people with LC (n=144) and those who fully recovered (n=56) (median 8.9 µg/dL vs. 8.8 µg/dL, p=0.97). Analyses of samples collected between 8-10 AM, however, revealed that, compared to those who fully recovered, cortisol concentrations were lower between 8-9 AM for those with LC-ME (median 8.2 vs. 14.8, p=0.02), but higher between 9-10 AM for those with severe LC (>=5 symptoms) (median 12.4 vs. 8.5, p=0.009) and those with LC-ME (median 13.7 vs. 8.5, p=0.02). CONCLUSION We found no difference in overall morning plasma cortisol concentrations between those with and without Long COVID. Although our data could be suggestive of altered morning cortisol dynamics in a subset of people with Long COVID, longitudinal measures of cortisol in individuals with Long COVID will be critical to further inform the biology of the condition.