Abstract:
An overactive sympathetic nervous system (SNS) may cause one subtype of Long COVID. People who are genetically at risk for noradrenergic nerve problems may develop an overactive SNS after an infection. Alternatively, genetic or virus-induced dysregulation of astrocytes could lead to overactivation of the SNS. An overactive SNS could disrupt regulation of immune cells, energy metabolism, sleep homeostasis, respiratory rate, gastrointestinal function, and systemic and cerebral blood pressure, causing fatigue and cognitive dysfunction.
Hypothesis: Long COVID refers to symptoms that continue for more than four weeks after onset of acute COVID-19 illness. This umbrella term includes a wide variety of symptoms and presentations. Long COVID patients may have different types of biological dysfunction, meaning that there may be distinct subtypes of Long COVID. One possible subtype is sympathetic nervous system (SNS) over-activation. This subtype may exist in both Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)1.
Underlying mechanisms of the SNS overactivation subtype: Theoretically, patients with this subtype already have a genetic dysregulation of neuronal norepinephrine (NE) release/clearance or noradrenergic receptor sensitivity2. This latent genetic dysfunction of NE signaling may not cause significant problems unless there is a trigger that causes excess NE release.
As NE affects immune cell signaling, this could result in an over-activation or prolonged activation of the immune system in response to infection with SARS-CoV-2, the virus that causes COVID-193 . This subtype could explain why ME/CFS is often triggered by a virus or brain injury, as these occurrences can trigger noradrenergic signaling3.
Possible mechanisms for the SNS overactivation subtype include viral reservoirs, antibody reaction, and dysregulation of noradrenergic receptor expression. In Long COVID patients, viral antigens and reservoirs that remain in the body long after the initial infection may keep the overactive immune system in an inflammatory state4,5. A healthy person may not react to these SARS-CoV-2 reservoirs, as their functional immune cells should develop immune tolerance. Another possibility is that the immune system is reacting to SARS-CoV-2 antibodies.
Finally, it is possible that excess extracellular NE could keep the SNS and noradrenergic systems in the brain stuck in an overactive state. A prolonged period of increased levels of extracellular NE could lead to dysregulation of noradrenergic receptor expression. The excess extracellular NE may be due to a prolonged release of excess NE during the initial infection, or a failure of the negative feedback mechanisms that should reduce NE release.
Symptoms of an overactive SNS: An overactive SNS explains many of the symptoms found in Long COVID patients, such as IBS/gastrointestinal symptoms6, heart palpitations7, and sleep disturbance8. Additionally, in orthostatic intolerance, which is common in Long COVID and ME/CFS, the release of NE causes pronounced tachycardia. This rapid heart rate may cause palpitations, breathlessness, and chest pain.
Dysfunctional energy metabolism causes fatigue and cognitive dysfunction: An important piece of the puzzle is to explain how a dysregulated SNS could lead to chronic fatigue and brain fog (cognitive dysfunction). The most likely explanation is a dysregulation of metabolic function. There are many ways excess NE could affect metabolism, including enhancing aerobic glycolysis and depleting glycogen stores.
Source: Carnac, T. (2023). Hypothesis: Astrocyte dysregulation of sympathetic nervous system causes metabolic dysfunction in subset of Long COVID and ME/CFS patients. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 36-43 https://patientresearchcovid19.com/hypothesis-astrocyte-dysregulation-of-sympathetic-nervous-system-causes-metabolic-dysfunction-in-subset-of-long-covid-and-me-cfs-patients-pghj-issue1-may2023/ (Full text)