Following the initial surge of COVID-19 infections, there has been a shift in focus on a new group of illness survivors, those with “post-acute COVID.”  This group is also known as the “COVID long-haulers” or colloquially as “long COVID.” 

I am seeing this syndrome arise in about 20-25% of those who had mild to severe COVID-19, up to 50% of those who were hospitalized and 10-15% of those who were vaccinated.  This seems to correlate with the recently published data that others in the medical community are seeing (1, 2, 3).

Long-Haul COVID-19 Symptoms

The most common symptoms that have been seen in this long-haul COVID group are general body pain, breathing difficulty, loss of taste or smell, brain fog, elevated cholesterol profiles, malaise, fatigue and hypertension (elevated blood pressure). However, some of the more severe cases have low blood pressure and orthostatic hypotension (low blood pressure drops on change of position).

Not only am I seeing this in post-COVID infection, but I am also seeing these symptoms occur in patients post COVID-19 vaccination with all the vaccine types.  The vaccine was designed to stimulate the same immune response that COVID-19 caused.  They seem to experience the same symptoms above with additional bruising, elevated D-dimer (protein fragments from breakdown of a blood clot), and changes in patients clotting factors.

These symptoms and presentations are going unrecognized and/or ignored by a large number of physicians.  This under recognition is suggested by the fact that large patient support groups are forming at locations like wearebodypolitic.com and longcovidsos.org with trending hashtags of #longcovid on Twitter.

Autonomic Nervous System & COVID-19

Many of these symptoms seem to correlate with autonomic nervous system (ANS) dysfunction after infection or vaccination.  These symptoms (fatigue, shortness of breath, loss of taste or smell, light headedness, increased bruising) are commonly persisting for longer than four weeks.

Many of my patients experiencing post-COVID symptoms have been found to have ANS dysfunction with orthostatic intolerance syndromes (light-headedness with change of position).  This occurs in men and women, but the literature seems to demonstrate a higher prevalence among females in the 26-50 year old range (2). Post-COVID syndromes, however, seem to be more prevalent in men as noted in the FAIR Health study (1).

Orthostatic intolerance syndromes are controlled by the ANS and include orthostatic hypotension (low blood pressure on standing), vasovagal syncope (stress induced passing-out), and postural orthostatic tachycardia syndrome (POTS) causing pulse rates greater than 110 with standing or simple walking.  All of these symptoms point to an autonomic nervous system disruption.

When a healthy person stands, blood pools in the pelvis and legs, reducing venous return to the heart. This is detected by baroreceptors in the heart and aorta, which respond by increasing sympathetic neural and adrenergic tone (mediated by norepinephrine and epinephrine respectively). This results in tachycardia (thus compensating for reduced stroke volume). This is then followed by vasoconstriction in the splanchnic vascular bed, which increases venous return to the heart.

In orthostatic intolerance, the release of the adrenal hormones epinephrine and norepinephrine causes pronounced tachycardia (rapid heart rate), which is experienced as palpitations, breathlessness and chest pain (common symptoms of ‘long COVID’). Very high catecholamine levels can lead to paradoxical vasodilatation, sympathetic activity withdrawal and activation of the vagus nerve resulting in hypotension, dizziness and ultimately syncope (4-7).  If a person is ill, or already dehydrated, these symptoms can be prolonged or exacerbated.

In my office, we regularly assess the autonomic nervous system as part of the yearly wellness exam. This is a 15-20 minute test looking closely at heart rate variability, blood pressure and sweat response to some simple vagal maneuvers.

COVID-19 & Autoimmunity

There is hypothesis that COVID-19 infections and the immune response to vaccination affects the autonomic nervous system.  The relationship between the two is very complex leading to the well documented “cytokine response syndrome” and “cytokine storm” from sympathetic activation inducing a pro-inflammatory cytokine release throughout the body.   Vagal stimulation results in an anti-inflammatory response, and suggests that the autonomic nervous system is a possible therapeutic target of treatment.

Because autonomic disorders have been associated with autoantibodies (8), there is speculation that there may be an underlying autoimmune component to the post-COVID syndromes we are seeing (11,12).  

Post-COVID Syndrome is Complex

Significant impairment along any of the extended autonomic nervous system (EAS) pathways when affected by COVID-19 infection has the potential to lead to death.  This is a very complex system with multiple variables.  We’ve seen this over the last year in various presentations of COVID-19. 

Figure 2 below demonstrates the potential for various intervening variables to adversely affect the EAS system and lead to death (8). Five systems are interactive at the same time: Sympathetic Adrenergic System (SAS), Sympathetic Noradrenergic System (SNS), Arginine Vasopressin/Anti-Diuretic Hormone (AVP/ADH), Hypothalamic-Pituitary-Adrenocortical (HPA) Axis, and the Parasympathetic Nervous System (PNS).

Intravascular Clotting Problems

In the COVID-19 pandemic there has been an unexpectedly high frequency of intravascular clotting, manifested by deep vein thrombophlebitis, pulmonary embolism, myocardial infarction, or stroke. It has been proposed that an imbalance between coagulation and inflammation results in this hypercoagulable state. Thrombosis (clotting) initiated by the innate immune system may limit SARS-CoV-2 dissemination, but aberrant activation of this system could cause endothelial (lining of the blood vessel) injury, with dysregulation of fibrinolysis and formation of blood clots (9). The complex roles of neutrophilia, neutrophil extracellular traps, platelet activation, and proinflammatory cytokines are a subject matter of active investigation and ongoing clinical trials.

Adrenaline is also a potent hemostatic agent because of both vasoconstriction that it causes and promotion of platelet aggregation in part through its antagonizing effect at the alpha-2 adrenoceptors.  It’s contribution in clotting in COVID-19 patients is still unknown.

In December 2021, Yi Zheng and colleagues discover that the “SARS-CoV-2 spike protein can compete with anticoagulation factors. . . leading to exacerbated coagulation and other adverse consequences, especially in critically ill patients. This rapid coagulation response may be an additional independent factor for the inflammatory storm of severe COVID-19 patients.” (21)

In my office, this increased coagulation response can be identified by checking a D-Dimer level in the blood. I have found that the D-Dimer can be elevated for over 12 months in those with Long-Haul COVID symptoms after infection, and more commonly after vaccination.

Anxiety & Post-COVID Syndrome

It is theorized that feedback looping of the autonomic nervous system may be prevented with the use of benzodiazepines like alprazolam, or even L-DOPA to increase dopamine release. This has been seen clinically in those with anxiety as a part of their post-COVID syndrome.  These approaches are undergoing clinical trial currently.

Ketogenic Diets and Exogenous Ketones

Inhibition of the NLRP3 inflammasome has been shown to modulate the cytokine storm.  This can be done with ketogenic diets or the use of exogenous ketones.  The ketogenic state has been demonstrated to suppress the cytokine cascade in COVID-19 syndromes (10).

I have had great clinical success in my medial office through the use of ketogenic states (use of ketogenic diet and/or exogenous ketone salt use) to treat and prevent the post-COVID symptoms and syndromes when they present.

Mitochondrial Dysfunction

I have found in my clinical experience that the autonomic dysfunction correlates with mitochondrial dysfunction. Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in the excess fatigue and other symptoms that are common complaints in almost every chronic disease. At the molecular level, a reduction in mitochondrial function occurs as a result of the following changes: (1) a loss of maintenance of the electrical and chemical transmembrane potential of the inner mitochondrial membrane, (2) alterations in the function of the electron transport chain, or (3) a reduction in the transport of critical metabolites into mitochondria. In turn, these changes result in a reduced efficiency of oxidative phosphorylation and a reduction in production of adenosine-5′-triphosphate (ATP). Several components of this system require routine replacement, and this need can be facilitated with natural supplements (12).

Management of Post-COVID Syndrome

Education

Education, explanation and reassurance provide a cornerstone in understanding the post-COVID syndromes and orthostatic intolerances that can arise.

Exercise

Regular structured exercise that incorporates both aerobic and resistance elements help to re-balance the autonomic nervous system.  For those with severe orthostatic symptoms in upright positions, the use of recumbent exercise bikes or swimming may be used.

Fluids and Salt

Fluids cannot be emphasized enough.  Ensuring fluid repletion (2–3 liters or 64-100 oz of water per day and avoiding caffeine and alcohol) should be encouraged.  Additionally, one to two teaspoons of pink salt supplementation per day helps maintain plasma volume and avoid hypovolaemia (low intervascular volume).  I recommend the pink salts because of the additional magnesium, zinc and manganese these provide in fluid replete states.

Pharmacological Treatment

Discontinue any NRI’s like duloxeting, nortryptiline and tapentadol.  These just make the potential for cytokine release worse. Fludrocortisone can be used to expand fluid if hypovolemia persistently is present. However, fluid retention and hypokalemia can be a problem.

Midodrine is a sympathomimetic alpha-1 agonist and can increase vasoconstriction and venous return to the heart.  This may be helpful to treat the lower blood pressure and tachycardia that can arise.

Beta blockers may make the tachycardia and palpitations worse and should be avoided.  In severe cases L-methyldopa could be considered to help alleviate the hyper adrenergic symptoms with change of position.

For those with prolonged elevation in D-dimer levels, the use of colchicine 0.6mg daily has been found to effectively reduce the inflammatory and hyper-coagulability response to the virus and the vaccine. The GRECCO-19 randomized open-label trial in 105 hospitalized patients demonstrated colchicine to be effective in reducing the D-dimer levels and improving clinical outcomes (22). This approach to lowering the coagulation response was also demonstrated to be effective in the WHO R&D Blueprint (23). Ivermectin and hydroxychloroquine also have a significant effect on lowering the d-dimer levels.

Treating the Autonomic Dysfunction

Many pharmaceutical medications can have suppressive effects on the autonomic nervous system. These include medications that affect the heart, blood pressure and hormones of the brain.  The list of medications is vast and more than I can address here in this post. 

Thyroid dysfunction can also adversely affect the ANS and it is essential that the thyroid function is assess and balanced. Hashimoto’s and autoimmune thyroiditis must be treated as this will play a major roll in autonomic dysfunction.

Clinical trials have shown the notable improvement with using oral replacement supplements, such as l-carnitine, alpha-lipoic acid (α-lipoic acid [1,2-dithiolane-3-pentanoic acid]), coenzyme Q₁₀ (CoQ₁₀ [ubiquinone]), reduced nicotinamide adenine dinucleotide (NADH), membrane phospholipids, and other supplements. Combinations of these supplements have been effective in reducing the fatigue and other symptoms associated with COVID-19 and other chronic disease.  Supplementation has been shown to naturally restore mitochondrial function, even in long-term patients with intractable fatigue (13,14).

Clinically, I’ve found that effective refueling of the dysfunctional mitochondria and priming the autonomic nervous system can be done through the use of the following supplements (13-20).

• Pregnenolone: 30 mg nightly
• CoQ-10: 300-400 mg daily
• D-Ribose: 15-30 grams daily
• Magnesium glycinate: 400-600 mg daily
• NADH: 10 mg twice daily
• L-carnitine: 1000-2000 mg daily (Vegetarians and Vegans may need more as this is only found in red meat and avocados.)
• Alpha lipoid Acid: 300 mg daily
• Liposomal Glutathione 500 mg twice daily
• Rosmarinic Acid 300 mg twice daily

Finding all these supplements can be a challenge. I designed my multivitamin with mitochondrial dysfunction in mind it contains the CoQ-10, L-Carnitine, alpha lipoic acid you need. It also contains N-acytylcystine (NAC) the cofactor for glutathione and NADH production in your body.

If you are using my vitamin supplement, I’ve provided links below to make it easier if you are looking for the other components on the list above.

• Use of Redmond RealSalt contains 54mg of natural magnesium in each ¾ tsp.
• Your body slowly makes D-ribose naturally. However, it is essential to supplement if you have heart failure or heart disease.  It does energize my fibromyalgia and chronic fatigue patients effectively.  Designs for Health makes a good powder that can be found at https://amzn.to/35SjkYv.
• You can find pregnenolone 30mg (Designs For Health) https://amzn.to/3g8CfTu
• Dr. Nally’s KetoEssentials Multivitamin can be found here: https://ketoliving.com/products/ketoessentials-multivitamin-adult-formula
• I recommend the CORE brand of Liposomal Glutathion which can be found online at: https://amzn.to/3tp687N.
• You may find Rosmarinic acid in the form of Rosemary or Rosemary Extract at: https://amzn.to/2MxcqSa.

For those with long-haul COVID syndrome, the treatment protocol above combined with a ketogenic diet, and exogenous ketones where needed, has been a game changer.  Hopefully, this will help you as well.

If you need my one-on-one help, sign up for one of my membership programs and I’d love to help you return to better health.

References:

1. A Detailed Study of Patients with Long-Haul COVID. FAIR Health White Paper, June 15, 2021. (https://s3.amazonaws.com/media2.fairhealth.org/whitepaper/asset/A%20Detailed%20Study%20of%20Patients%20with%20Long-Haul%20COVID–An%20Analysis%20of%20Private%20Healthcare%20Claims–A%20FAIR%20Health%20White%20Paper.pdf)
2. Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin Med (Lond). 2021;21(1):e63-e67. doi:10.7861/clinmed.2020-0896.
3. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw Open. 2021;4(2):e210830. doi:10.1001/jamanetworkopen.2021.0830
4. Freeman R, Abuzinadah AR, Gibbons C, et al. Orthostatic hypotension: JACC State-of-the-Art Review. J Am Coll Cardiol 2018; 72:1294–309. 
5. Jardine DL, Wieling W, Brignole M, et al. The pathophysiology of the vasovagal response. Heart Rhythm 2018; 15:921–9.
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8.  Goldstein DS. The extended autonomic system, dyshomeostasis, and COVID-19. Clin Auton Res 2020;30:299–315
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11. Guilmot A, Maldonado Slootjes S, Sellimi A, et al. Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol 2020, in press ( 10.1007/s00415-020-10108-x).
12. Ruzieh M, Batizy L, Dasa O, et al. The role of autoantibodies in the syndromes of orthostatic intolerance: a systematic review. Scand Cardiovasc J 2017;51:243–7.
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15. Murugan S, Jakka P, Namani S, Mujumdar V, Radhakrishnan G. The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation. J Biol Chem. 2019 Mar 22;294(12):4596-4607. doi: 10.1074/jbc.RA118.005543. Epub 2019 Jan 15. PMID: 30647133; PMCID: PMC6433066.
16. Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018 Jan;72(1):105-111. doi: 10.1038/ejcn.2017.132. Epub 2017 Aug 30. PMID: 28853742; PMCID: PMC6389332.
17. Agadjanyan M, Vasilevko V, Ghochikyan A, et al. Nutritional supplement (NTFactor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr. 2003;11(3):23–26.
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19. Luan H, Kan Z, Xu Y, Lv C, Jiang W. Rosmarinic acid protects against experimental diabetes with cerebral ischemia: relation to inflammation response. . J Neuroinflammation.  2013;10:28. 
20. Rocha J, Eduardo-Figueira M, Barateiro A, Fernandes A, Brites D, Bronze R, Duarte CM, Serra AT, Pinto R, Freitas M, Fernandes E, Silva-Lima B, Mota-Filipe H, Sepodes B.. Anti-inflammatory effect of rosmarinic acid and an extract of Rosmarinus officinalis in rat models of local and systemic inflammation. Basic Clin Pharmacol Toxicol. 2015;116(5):398–413
21. Zheng Y, Zhao J, Li J, et al. SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate. Int J Biol Macromol. 2021;193(Pt B):1124-1129. doi:10.1016/j.ijbiomac.2021.10.112
22. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Netw Open. 2020;3(6):e2013136. doi:10.1001/jamanetworkopen.2020.13136
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