Long COVID Part 8: POTS and Autonomic Dysfunction
Dr Graham Exelby January 2023
THIS SECTION IS CURRENTLY BEING REVISED -EXPECTED COMPLETION MID-SEPTEMBER
The major cause of morbidity and mortality in COVID-19 patients is from an exaggerated immune response resulting in hyper-inflammation, or “cytokine storm”.(6) Approximately 15–20% of COVID-19-infected patients suffer a severe form of the acute infection, characterized by activation of mast cells leading to histamine release and hyperinﬂammatory cytokine storms causing far more morbidity and mortality than from any direct viral cytotoxicity.(7)
While the acute impacts of COVID-19 were the initial focus of concern, it is becoming clear that in the wake of COVID- 19, many patients (up to 30% depending on studies) are developing chronic symptoms that have been called long COVID (PACS). Some of the symptoms and signs include those of Postural Orthostatic Tachycardia Syndrome (POTS).(29)
POTS has a wide range of clinical manifestations, such as postural tachycardia, dizziness, orthostatic intolerance, presyncope, and exercise intolerance. POTS commonly occurs after viral, parasitic or bacterial infections, eg Epstein-Barr virus infections. Because of increasing reports of post-COVID POTS, Blitshteyn et al (26) investigated patients with new autonomic disorders following COVID-19 infection.
Hira et al (271)in a Canadian study in December 2022, described over 70% of Long-COVID have cardiovascular autonomic disorder, 30% of these with POTS (Postural Orthostatic Tachycardia Syndrome)
After resolution of COVID-19 infection, most patients experienced fatigue, postural tachycardia, orthostatic intolerance, dizziness, and exercise intolerance that were chronic and disabling. Larsen et al (29) examined multiple reports and case studies of post- COVID syndrome and have proposed possible mechanisms for the changes. Their studies confirm the widespread nature of the post-COVID autonomic dysfunction.
Among the most common symptoms were those often reported by patients with autonomic disorders including fatigue, tachycardia, lightheadedness, difficulty concentrating (“brain fog”), insomnia, headache, gastrointestinal upset, and nausea. Many respondents reported no pre-existing conditions and 90% had not fully recovered 40 days after the onset of their illness.
All post-COVID POTS patients in overseas clinics were advised to utilize non-pharmacologic therapy for autonomic dysfunction, which consisted of increased sodium chloride and fluids intake, waist-high compression stockings and abdominal binders, and sitting or supine exercise. Most required pharmacological treatment for the autonomic dysfunction and co-morbid conditions which included beta blockers, fludrocortisone, midodrine, ivabradine, and other medications used for treatment of comorbid conditions, such as headache, neuropathic pain, or allergic symptoms associated with mast cell activation disorder. Six to 8 months after COVID-19, 85% of patients had residual autonomic symptoms, with 60% unable to return to work.
Nearly a third of the patients in this case series had confirmed mild abnormalities on cardiac or pulmonary testing, and 20% had abnormal markers of autoimmunity or inflammation, which might suggest that patients with persistent cardiovascular and neurologic symptoms after COVID-19 may have an underlying autoimmune and/or inflammatory process that affects cardiopulmonary, neurologic, and immunologic systems.
Blitshteyn et al (189) previously have demonstrated that patients with POTS had a higher prevalence of the autoimmune markers, such as anti-nuclear antibodies and anti-phospholipid antibodies, and co-morbid autoimmune disorders, including Hashimoto’s thyroiditis than the general population. This is in keeping with the 400 POTS patients that have been investigated at our clinic at Mermaid Central Medical Clinic.
More specifically to the autonomic nervous system, they found ganglionic N-type and P/Q type acetylcholine receptor antibodies, alpha 1, beta 1 and beta 2 adrenergic antibodies, muscarinic M2and M4 antibodies, angiotensin II type 1 receptor antibodies, and opioid-like 1 receptor antibodies were identified in POTS patients.
Although the etiology of post-COVID-19 autonomic disorders is largely unknown, they theorized that the SARS-CoV-2-generated antibodies cross- react with components of the autonomic ganglia, autonomic nerve fibres,G-protein-coupled receptors, or other neuronal or cardiovascular receptors, which can lead to dysfunction of the autonomic nervous system. (26) The more recent work from Larsen(29) and others implicates the cytokine storm causing microglial activation, and small fibre neuropathy that attributes to the autonomic chaos of POTS, whether from COVID-19 or other causes.
Other symptoms they found included the typical fatigue, “brain fog,” gastrointestinal issues (e.g., abdominal pain, bloating, gastroparesis, and nausea), chronic pain (e.g., headache, temporomandibular joint disorder, and ﬁbromyalgia), and sleep abnormalities. Co-morbidities included Ehlers-Danlos syndrome, mast cell activation syndrome, sensory neuropathy, or autoimmune disorders (e.g., lupus and Sjogren syndrome).(26)
Yang et al (269) in their study on famotidine activating the vagus inflammatory reflex to attenuate the cytokine storm provide a tantalising look at the role of the vagus in POTS symptoms.
The Autonomic nervous system (ANS) has been deﬁned by 3 components: the sympathetic nervous system, the parasympathetic nervous system and the enteric nervous system (EAS). The EAS expands the meaning of “autonomic” in 2 ways, neuroendocrine and neuroimmune. A pioneer in the ANS, William Cannon taught that activation of the sympathetic nervous system and adrenal gland in emergencies helps maintain homeostasis, a word he invented. Since then, other neuroendocrine systems have been described that are closely linked to components of the ANS. (94)
These include the hypothalamic-pituitary-adrenocortical (HPA) system, the renin-angiotensin- aldosterone system (RAS), and the arginine-vasopressin system. Across a variety of stressors, responses of plasma epinephrine (adrenaline) levels are more closely tied to those of adrenocorticotropin (the anterior pituitary hormone of the HPA axis) than of norepinephrine (noradrenaline)(NE, the neurotransmitter of the sympathetic noradrenergic system (SNS)).(94)
From Wikipedia: “The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on top of the kidneys). These organs and their interactions constitute the HPA axis.”(158)
“The HPA axis is a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. There is bi-directional communication and feedback between the HPA axis and the immune system. A number of cytokines, such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis, although IL-1 is the most potent.”(158)
“The HPA axis in turn modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from inflammation. During an immune response, proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through the blood-brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes.”(158)
Figure 1. The hypothalamic-pituitary-adrenal axis, or HPA axis- the interaction between the hypothalamus, pituitary gland, and adrenal glands; it plays an important role the body’s response to stress. The pathway of the axis results in the production of cortisol.
Source: Guy-Evans, O. (2021, Sept 27). Hypothalamic-Pituitary-Adrenal Axis. Simply Psychology. www.simplypsychology.org/hypothalamic–pituitary–adrenal-axis.html
These ﬁndings support a close association between the sympathetic adrenergic system (SAS) and the HPA axis. The SNS and SAS in turn are closely connected to the the renin-angiotensin- aldosterone system (RAS). Occupation of b1 adrenoceptors in renal juxtaglomerular cells releases renin, adrenomedullary chromafﬁn cells possess angiotensin receptors that when occupied evoke EPI secretion, and there is a central neural renin-angiotensin system that participates in the regulation of sympathetic outﬂow. Angiotensin- converting enzyme type 2 converts angiotensin II (AII) to angiotensin 1–7, which opposes the effects of AII. SARS-CoV-2 enters cells via binding to angiotensin-converting enzyme type 2. In addition to being a pressor and the body’s main water-retaining hormone, in the brain vasopressin augments baroreﬂexive restraint of sympathetic outﬂows.(94)
A second aspect of the EAS is neuroimmunity. Cortisol is well known to be the major anti-inﬂammatory compound of the HPA axis. The cytokine interleukin 6 (IL-6) activates the HPA axis and stimulates the production of aldosterone, demonstrating links between the immunological and neuroendocrine facets of the EAS. A cholinergic anti-inﬂammatory pathway involves cytokine-induced increases in vagal afferent trafﬁc and vagal efferent inhibitory effects on inﬂammasomal cytokine release.
Vagal stimulation inhibits the production of the cytokine TNFa, probably via the 2 main neurotransmitters of the ANS, acetylcholine and nor-adrenaline. No simple concept explains catecholaminergic inﬂuences on immunity. Although across a variety of stressful situations increases in EPI levels are associated with elevations of interleukin 6, bases for this relationship are poorly understood. Immune cells synthesize and release catecholamines, but the functional signiﬁcance is unknown.(94)
Table 1: Symptoms commonly reported in post-acute COVID syndrome, association with autonomic complications (a)
Cognitive impairment (brain fog)
Dyspnoea (shortness of breath)
Labile blood pressure(a)
GI symptoms eg abdominal pain, bloating(a)
Symptoms of Mast Cell Activation Syndrome (eg pruritis, urticaria, flushing, angioedema, wheezing, GI symptoms, tachycardia, labile BP)
(a) Symptoms of Autonomic Dysfunction
Source: Larsen,N.et al, Preparing for the long-haul: Autonomic complications of COVID-19 (29)
Mast Cell Activation
Mast Cell Activation Syndrome (MCAS) has an estimated prevalence of 17%.(7) This is similar in severe cases in the COVID-19 affected population. The wide range of symptoms in Long COVID are those seen in Postural Orthostatic Tachycardia Syndrome (POTS) and its auto-immune co-morbidities.(7) (Table 1)
A signiﬁcant number of fatal cases of COVID-19infection are due to cardiovascular complications such as pulmonary embolism, thromboembolism, sepsis and multi-organ failure. It has been shown that mast cells play a signiﬁcant role in promoting thrombotic diseases and complications; it has also been shown that stabilising mast cells helps to prevent fatal sepsis.(7)
H1 and H2 receptors blockers and other medication have been found helpful in modulating the severity of COVID infections and Long COVID symptoms, even though there is no apparent anti-viral activity from them. These also include cromolyn, ﬂavonoids, leukotriene inhibitors, dexamethasone, quercetin, ascorbic acid and low dose naltrexone.(7) The H1/H2 blockers in particular are considered to improve pulmonary symptoms by blocking the histamine-mediated “cytokine storm.”
Afrin believes that mast cell-targeted therapy commenced as soon as Covid exposure has occurred or suspicion of onset of Covid-19 illness might mitigate the severity of the illness.(7) The work by Lawrence Afrin et al (7) provides a tantalising explanation for the failure of the normal control mechanisms, and not only by recognition of people at risk of the hyperactivation but also a potential therapeutic target for reducing the inflammatory load in the long-COVID cases.
There are no guidelines for duration of treatment, but our clinic recommendations are discussed in “Long Covid Management.” The implications of the investigations in Long COVID are profound in specific problems, especially autoimmune diseases, fibromyalgia, POTS, Chronic Fatigue Syndrome, dysautonomia, and probably when combined with the research from Griffith University, I suspect Alzheimers and Parkinson’s diseases. I recommend reading Lawrence Afrin’s “Presentation, Diagnosis and Management of Mast Cell Activation Syndrome.” (16)
In our experience, controlling the mast cells makes an immediate effect on symptoms, especially the fatigue and sensitization issues.
Potential mechanisms of autonomic impairment in Post-Acute COVID syndrome (PACS)
Larsen et al(29)proposed the following mechanisms to account for the autonomic impairment.
1. Direct Tissue injury
Covid-19 enters cells via binding to angiotensin-converting enzyme type 2. In addition to being a pressor and the body’s main water-retaining hormone, in the brain vasopressin augments baroreﬂexive restraint of sympathetic outﬂows.(29)
Given that angiotensin converting enzyme-2 (ACE2) receptors are heavily expressed in endothelial cells lining many tissues throughout the human body—including those intricately involved in autonomic function such as endothelial cells in large and small arteries and veins, respiratory epithelium, enterocytes of all parts of the small intestine, proximal tubule of the kidney, and basal cell layer of the epidermis, chronic complications arising from direct injury inflicted during the para-infectious period of COVID-19 is quite possible.(29)
Finally, direct infection of neural tissues is possible. COVID-19 ribonucleic acid (RNA) has been isolated from the olfactory bulb, branches of the trigeminal nerve (including conjunctiva and cornea), the cerebellum, respiratory and cardiovascular nuclei in the medulla, and the carotid artery wall, the latter two sites being of utmost importance in baroreflex function.(29)
2. Immune-mediated mechanisms
Viral infections are commonly reported triggers of autonomic dysfunction and there are many viral pathogens that have been implicated. Prior research suggests that 41% of patients with POTS report symptom onset after a viral prodrome.(29) The mast cell overactivity and subsequent cytokine storm from COVID-19 gives credence to those who find their problems can be tracked to viruses.
3. Baroreflex impairment
The syncope seen in patients with COVID-19 infection is presumed to be neurally-mediated and possibly related to viral invasion or disruption of baroreflex pathways in the carotid artery or the nucleus tractus solitarius of the medulla which contains ACE2 receptors, though mechanistic studies have not been performed.(29)
4. Gender physiology
Based on available data, PACS appears to affect females more than males and especially so in autonomic cardiovascular domains such as orthostatic intolerance and inappropriate tachycardia.(29)
One of the emerging theories for the preponderance of females to males in POTS is as simple as neck shape and its impact on intravascular flow (see “Cervical spine with loss of lordosis and impeded glymphatics and association with Thoracic Outlet and Jugular Outlet Syndromes.”)
Cardiovascular deconditioning is a potential consequence of COVID- 19, as periods of prolonged bedrest can lead to resting tachycardia, reduced exercise capacity, and a predisposition to orthostatic intolerance. Cardiovascular deconditioning leading to persistent tachycardia has been described after SARS and may also play a role in post-COVID syndrome and its association with orthostatic intolerance.
Deconditioning alone however does not explain the many other symptoms present in POTS and also seen in post-COVID syndrome, including cognitive impairment, gastrointestinal upset, sleep disturbances, and neuropathic pain.
There seems little doubt that the evolving research into COVID-19 will ultimately resolve the perplexing complex problems underlying POTS pathogenesis, as well as giving credence to those multitudes of people suffering from POTS, whose life has been miserable, and largely ignored by doctors who have treated most as having a psychiatric problem.
POTS presents as autonomic and inflammatory chaos, with strong affiliations with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). POTS is also a common presentation of post-acute sequelae of SARS-CoV-2 infection (PASC), or “long COVID.” Our findings of how autonomic instability, fatigue, and inflammatory responses can be provoked by stress, infection (especially COVID-19), injury, or mechanical and dietary factors has given us a basis for working with POTS and its comorbidities.
A characteristic in POTS is the high level of “sensitization” which ideally needs to be controlled before the mechanical factors can be worked with. The autonomic instability then can be usually managed with “Kiiko Matsumoto Style Acupuncture” which targets the autonomic nervous system. COVID triggers the storm after activation of the mast cells by our immune system gate keepers, the threat receptors, or Toll-Like Receptors, releasing cytokines, which are small proteins involved in cell signalling, as well as other inflammatory products, in particular Interleukin 6 (or IL-6) and Tissue Necrosis Factor alpha (or TNFa).
SARS-CoV-2 (is a similar way to EBV, CMV, and other viruses) affects the mitochondria, causing mitochondrial dysfunction, and complicating mitochondrial dysfunctional fatigue by reactivating EBV (and likely others). Mitochondria are the powerhouses of our cells and are vital to maintaining the health and even survival of cells and play a key role in maintaining homeostasis and cell-mediated immunity. From this the POTS patients have chronic fatigue, aggravated it appears by the dysfunctional autonomic responses themselves, and from the emerging Griffith University research, the glymphatic function, as well as the fatigue associated with impaired autonomic function itself.
Figure 2 : Summary of post-acute COVID-19 by time and organ
Source: Euro Heart J Suppl, Vol 23, Issue Supplement E, October 2021. https://doi.ord/10.1093/eurheartj/suab080
Thanks to the work of epigeneticist Dr Valerio Vittone in decoding the DNA mutations in POTS patients, we can now “see” the underlying genetic processes in individual patients with POTS and PASC/Long Covid. As a result, we can now personalise management for these patients. Vittone’s work, along with neuroimmunological and genetic research from Professors Sonya Marshall-Gradisnik, Natalie Eaton-Fitch, Pete Smith, Lionel Barnden, and their team at Griffith University, as well as research by Weinstock and Afrin and others in mast-cell activation, provides an outline of the genetic and mechanical problems that drive the sensitisation and chaos that result in POTS and PASC.
DNA is so very important. A single mutation, by itself, is usually insufficient to cause the symptoms. However, we have been recognising patterns that allow clinicians to treat POTS . Then as the sensitisation is controlled, we can work with lifestyle change, epigenetic modification, and Kiiko Matsumoto acupuncture to target the autonomic instability and with appropriate physiotherapists, and vascular surgeons when appropriate, to control the mechanical drivers.
Using a technique called genetic imputation, it is now possible to use the ~750,000 SNPs that our sequencing machine in Germany provides on a chip into up to 83 million additional SNP variants with an accuracy rate of 98%. The mechanical and other activators and drivers do not necessarily cause symptoms in other people. DNA polymorphisms make the difference.
The primary DNA mutations we have found are in the histamine pathway (affecting mast-cell response), along with TRP mutations affecting NK cell, COMT mutations affecting catecholamine and oestrogen metabolism, as well as other mutations that alter methylation, especially the various notorious MTHFR, PEMT mutations, CRP, IL-6 and responses to oxidative stress. Details in: https://www.mcmc-research.com/post/long-covid-part-2-dna-mutations-that-underpin-pots-and-long-covid-1
Controlling POTS requires calming this sensitization, controlling the dysautonomia, and sorting out the mechanical, dietary and other lifestyle drivers. Knowing the mast cells are involved provides a starting point, and the histamine pathway needs immediate attention with change to the diet and addition of histamine blockers, usually fexofenadine or cetirizine for H1 blockade twice daily and famotidine for H2 blockade twice daily then H4 blockade if needed with Low Dose Naltrexone.
For most patients with POTS and Long-COVID POTS a solid history provides a path to the “perfect storm” with multiple findings with clues that may be found from birth, often with progressive symptoms until the main trigger. Neck trauma and postural change of neck shape (lordosis) are the most common denominator, and the scalene/thoracic outlet/posture complex affecting the brainstem in people with remarkably similar DNA patterns that when identified reveals the full picture.
Figure 3. The glymphatic systems in the brain and eye export fluid and solutes from metabolically active neural tissue. Fluids from both the brain and the eye drain via the cervical lymph vessels, which empty into the venous system at the level of the subclavian veins.
Source: Mogensen et al. The Glymphatic System (en)during Inflammation(124)
This complex problem linking the thoracic outlet to the scalene pull into C3 and loss of lordosis affecting intracranial vascular pressure is detailed in: https://www.mcmc-research.com/post/long-covid-part-12-the-glymphatic-system-with-loss-of-cervical-lordosis-and-association-with-thoraci This area is currently the main area of attention in our work.
While the most common “drivers” are in the thoracic outlet/ scalene/neck, especially with neck trauma and/or hypermobility, other significant drivers include Median Arcuate Ligament Syndrome, Superior Mesenteric Artery Compression, Nutcracker and May-Thurner Syndromes.
As studies unlock the association of COVID-19 with POTS the research take us closer to the causes and treatment of POTS. It seems that it is the microglial activation by cytokines that cause the small fibre neuropathy causing sensitization of the ANS and autonomic instability that characterizes POTS.
This then opens the door to Fibromyalgia(183) and other POTS co-morbidities. Adding the knowledge of the underlying DNA to “glymphatic system” and its potential obstruction in Jugular Compression and Thoracic Outlet Syndromes, and to the changes in intracerebral vascular flow in the neck and from thoracic outlet syndrome takes research to the place where the pieces of the puzzle start to finally fit together.
While it is likely mitochondrial dysfunction that is primarily associated with the post-infective fatigue, other factors are in play, including the impact of autonomic instability. Wells et al at Adelaide University confirmed altered intracerebral blood flow in POTS patients even without orthostatic symptoms when cognitive impairment (brain fog) was present. We are currently using SPECT brain scanning to examine the hyperperfusion and hypoperfusion states, and will attempt to match these to autonomic changes shown in dynamic electrophysiological studies.
Dr Leighton Barnden, NCNED, presented MRI data at the 2019 Organization for Human Brain Mapping Conference titled "Connectivity within the brainstem is impaired in chronic fatigue syndrome".(5) Impaired brainstem connectivity may explain reported autonomic and compensatory structural changes in Chronic fatigue syndrome as previously reported by NCNED (Barnden, 2015, 2016), and may also explain the impaired cognitive performance, sleep quality and pain of ME/CFS.(5)
Combining the work from Prof Marshall-Gradisnik et al(181) in ion channelopathy in chronic fatigue and its impact on functioning of the “glymphatic system,” with mechanical changes found in the thoracic outlet, as well as vascular flow change in necks we start to have a clearer picture of the pathology in play.
Electrophysiological studies at Mermaid Central Medical Clinic have mapped the increased sympathetic activity in POTS patients in mechanical “drivers” especially from the neck, the Thoracic Outlet Syndrome (TOS), and Median Arcuate Compression Syndrome. Holter monitors have confirmed the marked ANS overactivity, both sympathetic and parasympathetic which are mirrored in provocation studies. “Brain fog” has been shown to be related to TOS activity (probably a combination of cervical lymphatic obstruction and scalene pull on the top of the neck, the mechanism currently under close scrutiny), mast cell activation, neck function with changes in intracerebral blood flow (directly and by autonomic changes), diet and other drivers such as stress.
The pain of fibromyalgia has been tracked to IL-6, IL-8 and TNFa-driven small fibre glial cell neuropathy. Epigenetic -based change in diet with work from Dr Valerio Vittone(44) as well as dealing with stress, mast cell activation and mechanical factors are producing significant improvements in POTS symptoms, irrespective of traditional pharmacological intervention.
The continuing research here has shown that in the severe Long COVID with POTS-like severity there are predisposing DNA, mechanical and other issues so the COVID infection acts as the “activator” in a “perfect storm”. But with the DNA for POTS decoded by Dr Vittone,(44) we are finding the major DNA mutations are the same as those in POTS. The Long COVID POTS at this stage are complicated we believe by the microembolic damage and DNA mutations in PEMT, Apo E4 and Lipoprotein a and are currently areas we are investigating.
It is identification of the ongoing “drivers” that provides the best likely long term solutions once the mast cell response has been “tamed,” courtesy of the DNA mutation knowledge and work by Afrin and cohorts linked with the mechanical research from Kjeltil Larsen and others, which then appears to apply to the neck, glymphatics and intracranial vascular pressure.
The improvements start with desensitization of the central sensitization, usually achieved through mast cell blockade, and attention to posture and diet while investigations sort out “drivers.” The brain fog, and it’s altered cerebrovascular pressure is a major investigation area, as there appears to be both hypoperfusion and hyperperfusion. This latter area remains a subject of continuing research, although symptoms can be reduced or stopped with the improving physical therapy techniques and attention to lifestyle and especially posture with computers and phones.
We are also looking at the effect of sustained poor posture on this complex mechanism. And this now includes the impact of these on the glymphatic system, a recently discovered macroscopic system for waste clearance in the brain, using a system of channels around blood vessels, formed by astroglial cells, or neural cells, that are responsible for the defence of the central nervous system. It also helps to understand the enormous difficulties that physio and other therapists have had in managing POTS.
Discussions currently with Dr Vittone regarding the hypermobility, classically Ehlers-Danloss Syndrome have centered on the inflammatory activation of symptoms, and towards reducing inflammation, and improving the ATP enzyme function to improve connective tissue quality/quantity.
Research from Wells, Malik and Lau at Adelaide University(184) demonstrated impaired intracranial vascular flow when “brain fog” is present. We believe there is also an increased intracranial pressure that was not identified in this study. From this patients with brain fog can have craniovascular hypoperfusion or hyperperfusion. It does appear that there is relative hypoperfusion with postural change on a background of hyperperfusion. The research continues!