How does long Covid affect the hypothalamic-pituitary-adrenal (HPA) axis function?

Long COVID's Impact on the Hypothalamic-Pituitary-Adrenal (HPA) Axis

Long COVID causes dysfunction of the hypothalamic-pituitary-adrenal axis, resulting in low cortisol levels that are not compensated by increased ACTH production, which may contribute to fatigue and other persistent symptoms. 1

HPA Axis Dysfunction in Long COVID

Key Findings

• Recent studies show low blood cortisol levels in long COVID patients compared to controls, persisting more than one year after initial infection 1
• Normal compensatory increase in ACTH is absent, indicating central HPA axis dysfunction 1
• This pattern resembles findings in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 1
• Approximately 13.6% of COVID-19 survivors show evidence of adrenal insufficiency at least 3 months after recovery 2

Potential Mechanisms

1. Direct viral effects:

   • SARS-CoV-2 may directly affect the hypothalamus, pituitary, or adrenal glands via ACE2 receptors 3
   • Neuroinflammation affecting hypothalamic function 1

2. Immune-mediated mechanisms:

   • Inflammatory cytokines disrupting normal HPA signaling 3
   • Autoimmunity against components of the HPA axis 3

3. Vascular effects:

   • Microvascular damage and microthrombi affecting blood supply to endocrine organs 3
   • Endothelial dysfunction affecting hormone transport 4

4. Cortisol receptor resistance:

   • Impaired post-receptor signaling affecting cortisol action 3
   • Dissociation between ACTH and cortisol regulation 3

Clinical Manifestations and Diagnosis

Common Symptoms Related to HPA Dysfunction

• Fatigue and exercise intolerance 1, 4
• Cognitive dysfunction ("brain fog") 4
• Weakness and dizziness 5
• Muscular and joint pain 5

Diagnostic Approach

• Salivary cortisol measurements can reveal abnormally low cortisol levels 5
• Adrenal stress index (ASI) may show abnormalities even when routine lab tests are normal 5
• Short Synacthen test (SST) can identify adrenal insufficiency 2
• Monitoring morning serum cortisol levels is recommended 4

Clinical Implications

Relationship to ME/CFS

• About half of individuals with long COVID meet criteria for ME/CFS 1
• HPA axis dysfunction is a common feature in both conditions 1
• Similar patterns of neuroinflammation, mitochondrial dysfunction, and immune dysregulation 1

Prognosis

• HPA axis dysfunction may be transient in some patients, with spontaneous recovery observed at 12-month follow-up 2
• However, persistent symptoms can significantly impact quality of life and functional capacity 1, 4

Management Considerations

Monitoring and Assessment

• Screen for endocrine abnormalities, particularly thyroid dysfunction and cortisol levels 4
• Consider adrenal involvement in patients with persistent fatigue and cognitive symptoms 5
• Repeated basal cortisol measurements and ACTH stimulation tests may be necessary 6

Treatment Options

• Hydrocortisone acetate supplementation may be beneficial in cases with documented low cortisol 5
• Low-dose naltrexone has shown benefit for neurological symptoms and fatigue 4
• Antihistamines may help address mast cell activation symptoms 4
• Cognitive pacing and energy conservation strategies are essential 4

Cautions

• Avoid medications that may further disrupt endocrine function, such as tramadol in perimenopausal women 4
• Exercise intolerance is common, and graded exercise therapy may worsen symptoms in 75% of patients 4

Clinical Pearls

• HPA axis dysfunction should be considered in all long COVID patients with persistent fatigue
• Diagnosis of adrenal insufficiency in critically ill COVID-19 patients can be challenging due to lack of consensus on cut-off values 6
• The possibility of adrenal insufficiency should always be considered in patients with persistent post-COVID symptoms 6
• Standard laboratory tests may appear normal despite significant HPA axis dysfunction 5