McMahan, J.B.

Disclaimer:  I’m not a medical professional and this is not medical advice.  I hope you can use this information to work with with your health care system.  The theoretical testing and treatment will be at the bottom of the reading.

About the Author

I’ve had covid for almost four years. It’s been a very difficult journey.  Hearing so many stories in person and online has let me know that I’m not alone.  I’ve been searching for the same thing I think we all have, a way to get my life back.

I am not a medical professional.  I am a biochemist.  I want to stress the point, work with your medical professionals.  I know some have had mixed experiences but there are exceptional professionals still out there.  I’m going to use myself as the case study/abstract below for reference.  I don’t feel comfortable using others medical information.

Background

In 2019 the SARS-CoV-2(Covid) virus infected many people across the world.  While some infections had deadly consequences, some managed to be infected, often with milder symptoms, but were left with lasting symptoms which lead to the coining of the term “Long Covid”.  Some with Long Covid had symptoms lasting years, and many still have symptoms.  Symptoms of Long Covid could include but were not limited to post exertion malaise, fatigue, muscle pain, shortness of breath, chest pain, cognitive dysfunction, anxiety, autonomic dysfunction, and poor circulation. Although there were apparent associated high risk factors with Covid and Long Covid, many seemingly previously healthy individuals obtained long covid.

Diagnosis of Long Covid also has been proving problematic.  We can see consistent symptoms and sometimes blood markers although there has been no definitive parameters set as of yet.  Immune system markers have been proving to be the most reliable currently but to define the disease by them is still challenging.

Initially most knew Covid as a respiratory disease and many thought that respiratory symptoms would accompany that disease.  Covid proved much more complex as symptoms reached into effecting every system in the body.

Abstract

A 36 year old male presented with a history of poor health due to metabolic disease that was undefined and mild untreated high stress.  The patient had contracted Covid roughly two weeks prior to July 23, 2021.  The strain most like contracted at the time was the Delta variant.  The patient had an incident on July 23, 2021.  On the day of the incident, the patient first noticed they had a high heart rate when their heart rate reached 120 bpm.  The patient’s heart rate proceeded to climb from 120 bpm to 170 bpm, which after a duration of 15 minutes resulted in syncope.  The patient was taken to a hospital where the only abnormal markers were a slightly high thyroid stimulating hormone level and heart enzyme levels showing an ischemic event.  No structural damage to the heart or circulatory system was noted at the time.  The patient was limited to a wheelchair for any activity beyond twenty feet.

The patient later would be diagnosed with tachycardia and autonomic dysfunction.

The symptoms experienced by the patient over the next almost four years included, autonomic dysfunction, intense stress, diminished cognition, tremors, muscle cramps, fatigue, intense post exertion malaise, poor circulation, weight fluctuation, and gastroparesis.

Methods of Determination

Initially due to the limited mobility,  I walked as far as I could each day until I built up to a mile over the course of a year.  The first small hills would bring tears to my eyes due to the exertion but I kept building. Dysautonomia does not allow for building endurance as normal exercise would but walking is generally good for autonomic dysfunction when possible although progress can be anything but linear.  I would later get reinfected and lose mobility.

With dysautonomia I was looking for ways to monitor and modulate the autonomic nervous system.  To understand the autonomic nervous system in its simplest terms, it contains a sympathetic branch and a parasympathetic branch.  The reality is more complex but it helps to think of it as self contained “fight or flight” and “rest and digest”. I obtained a heart rate monitor online and combined it with Kubios laboratory software to measure my nervous system.  I determined that I was severally sympathetic dominant at almost all times, although no measurements were taken during sleep.  I did try two rounds (2 left, 2 right) of stellate ganglion blocks to modulate my nervous system.  The first right block provided 7 hours of relief and showed me that it was possible to feel similar to before I was infected with Covid. The other blocks provided less relief time.  This provided more evidence as something was shifting the system back toward sympathetic quickly.  This lead me to look at the adrenergic system.

The adrenergic system contains amongst other items the alpha and beta receptors.  I was looking at alpha-1, alpha-2, beta-1, and beta-2 modulation.  Alpha-1 and alpha-2 tend to control peripheral function while beta 1 and beta 2 tend to control heart and longs function.  There are subtypes of each receptor type as well but its easier to think of them as  four receptors.

I then asked my doctor if he could prescribe a beta blocker, propranolol, as I had high blood pressure after the July 23, 2021 incident.  The beta blocker provided limited to no relief from long covid symptoms of autonomic dysfunction outside of tachycardia limitation . I then asked if I could add in an alpha-1 blocker as I still had high blood pressure.  Doxasozin was added with no benefit.  I later asked my doctor if I could switch the doxasozin to an alpha-2 agonist.  Alpha-2 agonisim îs thought to trigger parasympathetic activity to counter sympathetic dominance.  The alpha-2 agonist I requested, Guanfacine, provided a very noticeable benefit and lead to more parasympathetic dominant nervous system measurements.  This effect of Guanfacine was strongest during the first two days.  The results waned after two days although they provided some benefit including a noticeable increase in circulation and a decrease in felt stress.

Knowing that Guanfacine was providing a benefit but the effect was waning lead me to looking at why the norepinephrine reducing capability of Guanfacine was waning.  It appeared that norepinephrine production was outrunning the capability of the dosage of Guanfacine I was using.

I checked my blood work and the only thing that jumped out was a low-normal Vitamin D,25-hydroxy and several immune system markers that I’ll discuss below.  Vitamin D defficiency is known to cause elevated norepinephrine and that combined with a statement I heard early on in covid pushed me to look at Vitamin D.  The statement that seemed to hold some value was, “No one under 50 ng/ml vitamin d was receiving severe covid symptoms”.

Vitamin D Distinction

Many longcovid patients have tried vitamin d without success.  The distinction with vitamin d comes from where it is in the conversion process.  Most vitamin d effects come from its final, active form as calcitriol (1,25 di-OH Vitamin D).  Calcitriol is by prescription only in the United States of America.  All over the counter supplement forms of vitamin D in America are inactive. Calcitriol deficiency is known to cause many effects that will be familiar to long covid patients.  We’ll review several of the effects of calcitriol deficiency below.

Credit to Chaudhari et al’s 2001 paper for the below paragraph:

Vitamin D deficiency is known to increase norepinephrine levels in the body.  Vitamin D deficiency decrease the activity of phenylethanolamine n-methyltransferase (PNMT) which converts norepinephrine to epinephrine, resulting in larger norepinephrine to epinephrine levels.  Some POTS, a form of dysautonomia, patients will note that B-1 expression is usually more prominent than A-1 expression. Dr. Novelli et al’s study and Baski et al’s study reported that a vitamin D deficient diet induces a decrease in pressor response to Norepinephrine, which explains an apparent B-1 receptor super-expression (density or sensitivity) despite the relative increase in Norepineprhine, which is mostly an A-1 agonist.   This combined with a decrease in Epinephrine and decreased A-1 receptor expression, results in pots symptoms.  We can think of this of this as:  Vitamin D deficiency results in A-1 adrenergic resistance manifesting as tachycardia rather than a hypertensive response to norepinephrine.

Chaudhari et al’s paper highlights the consequences of vitamin D deficiency in the form of calcitriol deficiency.  The paper is a case study of a woman who lacked proper function of her 1-alpha hydroxylation enzyme, in other words she couldn’t convert calcediol (inactive vitamin d) to calcetriol (acvtive vitamin d). The woman lacked proper enzyme activity due to genetic factors.  It will be noted later in the paper but long covid does not appear to be directly linked to genetic deviation, but more so to the immune response deviation.  As will be noted later in the potential treatment section, the body still has tissues that are 25 OH Vitamin D dependent due to local production of active vitamin d in those tissues and possibly other factors.

Since knowing Calcitriol can lead to increased norepipnephrine and Guanfacine was initially effective at reducing norepinephrine levels I contacted my doctor and asked him to run the following tests, 1,25 di-OH vitamin d, 25 OH vitamin D, and calcium.  The calcitriol level was half of the lower normal range limit and the calcium was at the upper limit.  25 OH vitamin d was low-normal.

Additional testing conducted later before any vitamin D treatment included a check for phosphorus, a basic 8 piece metabolic panel including calcium and parathyroid hormone level checks. For those unfamiliar with parathyroid hormone, the hormone helps the body control calcium and phosphate within strict limits as well as manipulating vitamin d to help the body function.  Calcium was at the upper limit, and pth was below the normal range. 

I started on .25 mcg of calcitriol for 4 weeks and retested phosphorus, calcium, and calcitriol at  3 weeks to confirm that phosphorus and calcium were within safe levels and to see if calcitriol had fluctuated.  I had started taking an over the counter vitamin K2, and noticed no changes, feeling or in blood work.  The blood level of calcitriol had not changed with the initial dosage. I did also try to limit dietary calcium.  I did note some increase in strength in the first three days of this but it later dissipated.  The feeling and bloodwork lead me to think that the metabolic threshold was not exceeded and the body returned to it’s altered homeostasis.

After 4 weeks I switched doctors and was able to move to 1 mcg.  The same increase in strength happened after 2-3 days.  At day 6.5 I became ill in a similar way to how I was sick when I first had covid prior to the ischemic event above.  The illness involved excrustiating pain in the jawbone and primarily in the head on the right side about an inch above the front of the ear.  It felt about two inches inside the head but there isn’t a great way to know as feel and real are often different and only certain parts of the body have those type of receptors.  That excrutiating pain lasted about 8 to 9 hours and stopped.  I had the same pain the next night although it was reduced by about fifty percent of the night before.  The same thing happened the next several nights with the pain being reduced each night.  The pains started almost to the minute six hours and ten minutes after the consumption of 1 mcg of calcitriol.  There was also an accompanyning fever and chills each time.  The fever was quite excessive the first night.  It felt like the body’s immune system had come back online and was fighting the virus again.  Some had proposed the virus or fragments might be latent in the body and the feelings matched that to some degree and that may be true.  There may be other explanations and I’ll discuss them in the next section.  I did notice that after the intense pains and sleep afterword, I woke the next day feeling better than I had in years.  I had reduced dizziness, increased strength, reduced brain fog, reduced blood pooling, and had feeling of calm that had not surfaced in years.  Each subsequent day noted an improvement.

Calcitriol Production Disfunction

The question then becomes what is causing the decrease in calcitriol.  There are several factors in the bloodwork of many long covid patients that point to decrease in calcitrol.  Many have heard the term cytokine storm.  Pro inflammatory Cytokines are part of the immune response to viruses but they consist of several molecules.  Many long covid patients have seen increased levels of interlukin – 6, Tumor Necrosis Factor Alpha (TNFa), and interferon Gamma as part of the body’s responses to viral acitivty.  Interlukin – 6 has been shown to inhibit enzymatic production of 25 OH Vitamins.  TNFa has been shown to directly inhibit the 1-alpha hydroxylation enzyme.  TNFa appears to be the most likely effector of low 1-alpha hydroxylation enzyme activity.  Sometimes this inflammatory response is extended due to body’s want for a stronger inflammatory response in the face of viral activity.  That stronger response can also be accompanied with reduced vitamin d.  The body also sometimes limits excessive vitamin D during system inflammation to limit calcium which can be dangerous during those times.  I also noted an increase in C5a (C50) in long covid patients which has been linked to increased release of TNFa and interleukin -6.  I also noted increased C3 in long covid patients which has been linked to the down regulation of vitamin d receptors.  Chronic inflammation through inflammatory cytokines like TNFa and Interferon gamma also up regulate CYP24A1, an enzyme that breaks down both 25 OH Vitamin D and Calcitriol to calcitroic acid as a feedback mechanism to prevent excess vitamin d activity, which could suppress necessary immune responses.  Inadequate Vitamin D may lead to inappropriate immune responses.

There also could be a direct relation to calcium which seems very likely possible.  We have known that a significant number of people with HIV and Cancers also have hypercalcemia.  Calcium is known to play a significant role in the HIV replication cycle and influences processes like virus entry, protein expression, and vision maturation.  HIV and other viruses are known to modulate calcium  signaling to control apoptosis and create persistent infection.  In some cancers, calcium signaling can impact cancer cell survival and apoptosis resistance as it’s invlolved in cell growth, proliferation, and completion. Bone resorption, not absorption, could also be playing a larger role than typical. It may also not be viral persistence at all or alone, but include immune persistence.  Any one with autoimmunity issues surely knows what can happen with a runaway immune system.  Immune persistence could have caused a inflammatory reaction that is more harmful than helpful.

Many viruses and disease are know to be able to make their habitat more hospitable.  This could be one possible cause of why the calcium is high.  Most of the blood work I have seen of long covid patients contains high calcium.  I have heard of at least one person who had low calcium who claims they had long covid and that case makes me want to keep an open mind about direct 1-alpha hydroxylation issues.

With calcitriol levels low, the immune could also be operating nonoptimally.  The immune system has vitamin d receptors on many cells including immune cells, macrophages, T-cells, and B-cells.  Vitamin D helps to modulate the inflammatory response and can modulate inflammation.

There appears there could be an issue in the calcium and/or calcitriol chain that is causing symptoms and possibly viral persistence or immune persistence.  In thinking about the best way to treat a situation like this, is the answer to raise calcitriol directly, lower calcium, or both, or another method, I’m not sure.  I went the direct calcitriol way however getting a doctor to prescribe calcitriol to a person with a high normal calcium may prove quite difficult.  I was very fortunate to have a very intelligent and capable primary care physician.  In thinking about how a virus might work if it is still present, raising vitamin d could directly get the immune system back online, however a virus could adjust for lowering calcium and return that to it’s preferred environment.  This also raises the question, does treatment need to be perpetual or for a series of days or weeks.  At this point I’m not sure, although you would think the body’s immune system could take over a some point.  Knowing the current life cycle of other viruses in human history we can assume that a reasonable amount of time would be needed for the body to get ahead of something like this if possible.

 

Why Some Get Long Covid

No definitive answer as been presented but possible reasons could include:  preexisting inflammation, low dietary vitamin d, genetic factors, preexisting autoimmunity, phosphate consumption, calcium consumption, other preexisting diseases, sun exposure

Note on Transient Calcitriol Values

Calcitriol is known to fluctuate in concentration though the day. Usual variations are in the 20% range.  People with PTH dysfunction or low PTH values are usually closer to 10% variation.

Cyle Summary

Viral infection

Inflammatory cytokines, virus could create high calcium leading to pathway inhibition or direct pathway inhibition 

Impaired Vitamin D hydroxylation or production due to pathway inhibition

Furthered Vitamin D Deficiency 

Altered Immune Response (including T-cells and B-cells as these have vitamin D receptor)

Potential Diagnostic Criteria for Long Covid (may need refined)

PTH (TBC) – could be low or high but it’s relational data is useful

Calcium – likely high but could be low in some cases

Calcitriol (1,25 di-OH Vitamin D) – low (this may be the only one outside of PTH confirmation that may be useful, this is not a common test and many hospitals can’t run this test, there are national labs that runs this test)

25 OH Vitamin D – Likely lower end of normal

Optional 

High C3 and c50 – looking for higher than normal levels

TNFa, – looking for higher than normal levels (possibly unuseful)

Interferon Gamma  – looking for higher than normal levels (possibly unuseful) 

Interleukin 6  – looking for higher than normal (posibbly unuseful)

A check for parathyroid disease should also be confirmed negative.

Potential Treatment of Vitamin

Calcitriol (usual doses are in parts of micrograms)

Cholecalciferol (normalization of 25 OH Vitamin D level is still important as several tissues in the body convert locally, even outside of unwanted granulomas)

Vitamin K2 (this is a potential item and may not be required)

Other items (other items may be low from long term low calcitriol that may need remediation)

Treatment must be performed and monitored by an appropriate health care professional.  Treatment may not need to be indefinite.  The body’s hormone production may recover when other factors normalize or reach homeostasis.  The body might also need constant assistance as there could be underlying issues that caused issues with this pathway prior to infection. 

Additional Comment

I can also see where this type of vitamin d disregulation could also lead to potential items or share pathophysiology with some Cancer, OCD, Bipolar Disorder, PTSD, Trauma, GAD, ADHD, ADD, metabolic disorder, sleep disorders, depression, generational birth defects, diabetes, autoimmune diseases, chronic fatigue syndrome, and fertility issues.  I wrote up potential  pathophysiologies with these and several other conditions but want to focus on long covid with this paper.  There may be zero crossover, but I wanted to mention the similar appearance of pathology.

References

1. Baski SN, Hughes MJ, Chronić vitamind D deficiency in the weanling rat alters catecholamine metabolism the cortex. Brain Res 1982
2. Baski SN, Hughes MJ, Alteration of adrenal catecholamine levels in the rate after dietary calcium and vitamin D deficencies, J Auton Nerf Syst 1984
3. Baski SN, Hughes MJ. Deficiency in dietary vitamin D, not calcium alters noradrenergic responsiveness in rate attrisa in vitro. J Mol Cell Cardio 1986
4. Baski SN. Altered pressor response to norepinephrine in calcium- and vitamin D-deficient rats.Clin Exp Hyperens A 1988
5. E Novellis V, Loffreda A, Vitaliano S, et al. Effects of dietary vitamin D deficiency on the cardiovascular system.  Res Common Chem Pathol Pharmacy 1994
6. Shilpa Abhay Chaudhari, Alan Sacerdote, Gul Bahtiyar. 1-alpha hydroxylation defect in postural orthostatic tachycardia syndrome: remission with calcitriol supplementation. BMJ Case Rep 2012