John Murphy, The COVID 19 Long-haul Foundation
Abstract
Long COVID, a multifaceted syndrome emerging after acute SARS-CoV-2 infection, has challenged conventional models of post-viral recovery. Among its many physiological disruptions, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis—particularly involving cortisol—has garnered increasing attention. This article synthesizes current peer-reviewed findings on cortisol dynamics in long COVID, exploring adrenal pathology, immune modulation, and implications for chronic fatigue-like symptoms.
Introduction
Cortisol, a glucocorticoid hormone secreted by the adrenal cortex, plays a pivotal role in stress response, immune regulation, and metabolic homeostasis. In the context of long COVID, emerging evidence suggests that SARS-CoV-2 may disrupt cortisol synthesis and signaling, contributing to persistent fatigue, cognitive dysfunction, and immune dysregulation. This review integrates findings from recent studies to elucidate the role of cortisol in long COVID pathophysiology.
Adrenal Involvement and Cortisol Suppression
Autopsy studies have revealed direct adrenal involvement in fatal COVID-19 cases, including adrenalitis, ischemic necrosis, and vascular thrombosis, suggesting that SARS-CoV-2 may impair adrenal function even in non-lethal infections. Koch et al. (2024) reported that adrenal hypofunction persisted in some patients months after recovery, with reduced uptake on PET/CT imaging and suboptimal cortisol responses to Synacthen stimulation1. These findings raise the possibility of chronic adrenal insufficiency in a subset of long COVID patients.
Cortisol Levels and Symptomatology
A cross-sectional study by Dalhuisen et al. (2024) measured plasma cortisol in 200 individuals 3–6 months post-infection. Surprisingly, no significant difference in morning cortisol levels was found between those with long COVID and recovered controls (median 8.9 μg/dL vs. 8.8 μg/dL). However, a subgroup with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like symptoms showed trends toward lower cortisol, suggesting that cortisol dysregulation may be phenotype-specific within long COVID populations.
Immune Modulation and Cortisol Deficiency
Klein et al. (2023) conducted immune profiling of long COVID patients and identified reduced cortisol levels alongside altered cytokine signatures. The authors hypothesized that diminished cortisol may impair resolution of inflammation, perpetuating immune activation and viral persistence. This aligns with known anti-inflammatory roles of cortisol and its capacity to inhibit phospholipase A2, thereby modulating prostaglandin and leukotriene synthesis3.
Vaccine-Associated Cortisol Disruption
An intriguing case report described central adrenal insufficiency following mRNA vaccination, with undetectable ACTH and cortisol levels post-injection. While rare, this suggests that immune activation—whether via infection or vaccination—may transiently disrupt HPA axis function in susceptible individuals.
Mechanistic Insights and Therapeutic Implications
The SARS-CoV-2 spike protein’s affinity for linoleic acid (LA) may intersect with cortisol pathways. Corticosteroids inhibit LA conversion, potentially reducing spike-ACE2 binding and viral replication. Thus, low cortisol in long COVID could theoretically enhance viral persistence via reduced phospholipase inhibition. This mechanistic link supports the observed benefits of corticosteroid therapy in acute COVID and raises questions about its role in long COVID management.
Conclusion
Cortisol dysregulation in long COVID appears multifactorial, involving direct adrenal injury, immune-mediated suppression, and phenotype-specific alterations. While not universally present, low cortisol may contribute to fatigue, cognitive impairment, and immune dysfunction in select patients. Further longitudinal studies are needed to clarify causality, identify biomarkers, and guide therapeutic interventions targeting the HPA axis.