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Abstract

Long Covid, now also reported in children, has become increasingly alarming. Perhaps a third of those who develop MIS-C go on to experience Long Covid. Etiology is elusive. The role of vitamin D in bone and immune health has been recognized but magnesium de ciency has escaped attention. A physiologic and biochemical argument for its culpability in Long Covid as well Chronic Fatigue Syndrome, Fibromyalgia, Epstein Barr Virus, and Cytomegalovirus is discussed.
Open Access Library Journal
2022, Volume 9, e8736
ISSN Online: 2333-9721
ISSN Print: 2333-9705
DOI:
10.4236/oalib.1108736 May 27, 2022 1
Open Access Library Journal
Long Covid, Short Magnesium
Patrick W. Chambers
Department of Pathology, Torrance Memorial Medical Center, Torrance, CA, USA
Abstract
Long Covid, now also reported in children, has become increasingly alarm-
ing. Perhaps a third of those who develop MIS-
C go on to experience Long
Covid. Etiology is elusive.
The role of vitamin D in bone and immune health
has been recognized but magnesium deficiency has escaped attention. A phy-
siologic and biochemical argument for its culpability in Long Covid as well
Chronic Fatigue Syndrome, Fibromyalgia, Epstein Barr Virus, and Cytome-
galovirus is discussed.
Subject Areas
Pathology
Keywords
Gamma Interferon, Bradykinin, Asthma, IgG3, C1-Inhibitor, Receptor Tyrosine
Kinases
1. Introduction
The definition of Long Covid varies. Some don’t differentiate between long pri-
mary infection and secondary recrudescence. Some require 60 days post-primary
infection, while others require 90 days. Furthermore, there appear to be two dis-
tinct unacknowledged subsets and this has hindered insight into etiology. These
will be delineated and physiologically separated. No previous study evaluating
the role of vitamin D deficiency mentions, much less includes, any appraisal of
magnesium status. This is because the active form is Mg2+. Only 1% of total
magnesium is circulating but about 50% is bound to carrier proteins, predomi-
nantly albumin. This analyte is not even included in the chem panel. Of the 99%
intracellular magnesium, only 1% - 2% is ionized and free Mg2+. This is critical
because ionized magnesium is the active form and is required for the synthesis
of active vitamin D.
How to cite this paper:
Chambers,
P.
W.
(20
22) Long Covid, Short Magnesium
.
Open Access Library Journal
,
9
: e8736.
https://doi.org/10.4236/oalib.1108736
Received:
April 17, 2022
Accepted:
May 24, 2022
Published:
May 27, 2022
Copyright © 20
22 by author(s) and Open
Access Library Inc
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Open Access
P. W. Chambers
DOI:
10.4236/oalib.1108736 2 Open
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In view of these difficulties, ignored by previous studies and meta-analyses, a
bottom-up approach is adopted, one reliant upon symptoms and less on indi-
vidual lab values. Currently, 25(OH)D levels are defined by the average or me-
dian population level. Our society over the past century has become increasingly
sun shy, driven by both cancer fears and cultural norms. In areas where this is
not the mindset, circulating 25(OH)D ranges from 135 to 225 nmol/L (54 - 90
μg/L) [1]. This number represents eons of evolution. Migratory patterns over the
past century have further compromised the validity of 20 - 30 ng/mL (50 - 75
nmoles/L) as sufficient.
This discussion will be a more complete look at magnesium and Long Covid,
including the impact of our deteriorating nutrition, biological individuality, and
related physiology. It will combine the clinical with the technical, absent in pre-
vious attempts to discern the nature of Long Covid. The goal is to incentivize all
who suffer from Long Covid to include vitamin D and magnesium in their the-
rapeutic regimen.
The link between vitamin D deficiency and rickets was first discovered in the
1920s. It was not until 50 years later, in the 1970s, that the entity, magnesium
deficient, vitamin D resistant rickets, was realized. In 1971 Jean Durlach founded
the Society for the Development and Research on Magnesium (SDRM). But de-
spite two excellent books on the topic, The Magnesium Factor (2003) by Mildred
Seelig/Andrea Rosanoff and The Magnesium Miracle (2006 first ed., 2017 second
ed.) by Carolyn Dean, research has languished (Figure 1).
Magnesium metabolism and requirements are inextricably entwined with vi-
tamin D. One cannot discuss vitamin D without discussing magnesium. Similarly,
Figure 1. The number of basic and clinical research papers published (Y-axis) on Fe, Ca, and Mg [2].
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one cannot correct a vitamin D deficiency-associated problem without magne-
sium sufficiency (Figure 2).
However, sudden increases in vitamin D intake in the presence of magnesium
deficiency can be problematic. Existing free Mg2+ could be triaged from low
priority functions, e.g., neuromuscular, to servicing the added D3/25(OH)D3.
These can manifest as signs and/or symptoms of magnesium deficiency, e.g.,
Figure 2. Magnesium is not only required for the synthesis of active vitamin D [1,25(OH)2D] but is also required for the synthesis
and secretion of PTH by the parathyroid glands. Synthesis of 7-dehydrocholesterol is also Mg2+ dependent.
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worsening constipation or increase in palpitations. It is noteworthy that replet-
ing D alone will deplete Mg2+. This has tarnished the value of vitamin D supple-
mentation in many who are also magnesium deficient. In many, the double defi-
ciency persists and future supplementation is then shunned.
2. Hypothesis
Magnesium deficiency is intimately involved in the brain fog, fatigue, post-exertional
malaise, headache, dizziness, myalgia and asthma of Long Covid or Post Acute
Coronavirus Syndrome (PACS) also known as Post Acute Sequelae of COVID-19
(PASC).
3. Discussion
3.1. Is Magnesium Deficiency Related to Vitamin D Deficiency?
A recent study demonstrated that dietary magnesium intake is inversely related
to serum parathormone (PTH) concentration in the overweight and obese, espe-
cially in response to raising serum 25(OH)D concentration [3].
Based on dietary magnesium intake, three groups over-weight or obese (n =
57) were identified: low Mg intake group (mean 131 mg/day); intermediate in-
take group (mean 216.9 mg/day); high intake group (mean 376 mg/day). (RDA
for magnesium is 310 to 320 for women and 400 to 420 for men). The magne-
sium intake in the group reporting benefit (lower PTH) approached that rec-
ommended by the RDA. The median body mass index (BMI) for all three groups
was 27.7 - 29.0, less than the mean American BMI, which is greater than 29, ac-
cording to the most recent NHANES survey (2016).
The study subjects in the three groups had 25(OH)D levels between 24.6 and
27.1 ng/mL,
i.e.
, all were magnesium deficient. However, according to Figure 3,
any value less than 50 ng/mL implies deficiency, since the PTH/25(OH)D rela-
tionship is still suboptimal below that amount. Gastrointestinal absorption and
renal resorption of Mg2+ (and Ca2+) are influenced by vitamin D, which responds
inversely to PTH. The latter is predominantly controlled by circulating ionized
calcium (Ca2+) and Mg2+ to a lesser extent.
The flattening of the curve at serum 25(OH)D concentrations above 50 ng/mL
seems to imply an optimum balance between calcium, magnesium, PTH (and
calcitonin) above this set point. In the study serum 25(OH)D concentration was
inversely associated with PTH only in the high Mg2+ intake group. Data from
that study have several implications.
1) In the low magnesium intake group all the magnesium is consumed by
bone needs and the PTH is inappropriately low. This paradox suggests insuffi-
cient Mg2+ to meet PTH synthesis needs.
2) Magnesium is consumed by bone needs and PTH synthesis in the interme-
diate magnesium intake group, since the PTH was elevated (indicating the pres-
ence of some degree of secondary hyperparathyroidism and perhaps, overactive
osteoclastic activity), with little magnesium left to synthesize 1,25(OH)2D to address
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Figure 3. This curve represents the natural/physiological relationship between two hor-
mones with plateauing of the curve when serum 25(OH)D concentration is approximate-
ly 50 ng/mL. The dashed lines represent 95% confidence limits. Data is from the 2003-2006
NHANES.
the osteoporosis. PTH (mean 76.3 pg/ml) and Ca:Mg (mean 3.12) were elevated
in this intermediate group. Ironically any increase in magnesium intake could
precipitate symptoms of magnesium deficiency due to increased PTH induced
suppression of both Vitamin D synthesis and magnesium absorption/resorption.
3) In the high intake group not all the magnesium is consumed by bone needs
and PTH synthesis. The surplus is directed to vitamin D synthesis (Figure 2).
The Ca:Mg plummets, as relatively more Mg2+ than Ca2+ is absorbed, depressing
PTH. Note: At least in the renal tubular cells, PTH enhances the conversion of
25(OH)D into 1,25(OH)2D (magnesium is a required cofactor), which in turn
decreases PTH secretion (Figure 2).
All were vitamin D deficient (<30 ng/mL). But the study demonstrates that
the minimum should be 50 ng/mL (not 50 nmoles/L) 25(OH)D. Viatamin D re-
quirement for the obese is 2 to 3 times greater than that for those of normal av-
erage weight [4]. The curve in Figure 3 from a 2019 study of 15000 with a mean
BMI of 26.9 should be shifted to the right. The mean BMI in 2019 was over 29.
One can appreciate the importance of magnesium and the complexity of its
physiology, especially when known and unknown feedback loops, polymor-
phisms (genes), nutrition, lifestyles, etc., are considered. Randomized clinical
trials (RCTs) are rarely comparable; some incorporate controversial assump-
tions, are expensive, and are time-consuming.
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This 50 ng/mL is not a serum concentration recommended by most meta-
analyses or some prospective NIH-funded-study, but one ordained by Mother
Nature through human evolution. The production of vitamin D3 (cholecalcife-
rol) in the skin from sunlight is essentially limited to four hours between 10 am
and 2 pm. This benefit is also seasonal and needs are directly proportional to
BMI. Generally, with the current lifestyles, solar exposure is rarely sufficient and
supplementation is rarely adequate. Both routes to the active form are magne-
sium-dependent (Figure 2).
Once the minimum serum concentration of 50 ng/mL is established, evaluat-
ing magnesium status becomes easier. Unfortunately, biologic individuality, e.g.,
genes or single nucleotide polymorphisms (SNPs), and the complex nature of
measuring free intracellular Mg2+ make accurate evaluation difficult. Unlike vi-
tamin D, there are no simple laboratory tests that are reliable in this regard. This
makes evaluation of symptoms or a bottom-up approach superior to a top-down
one (evaluation of lab results).
In 2006 Bruce Ames [5] posited that when micronutrient availability is li-
mited, those functions required for short-term survival take precedence over
those less urgent. In the case of magnesium, it appears that skeletal needs for
magnesium supersede those needed to produce active vitamin D. After all vita-
min D deficient rickets was described in the 1920s. However, magnesium-deficient
vitamin D-resistant rickets was not recognized until the 1970s.
The recommended serum 25(OH)D 30 ng/mL is sufficient to avoid rickets in
the presence of magnesium sufficiency but is inadequate to avoid secondary
hyperparathyroidism and osteoporosis. Furthermore, the minimum magnesium
intake for any individual should be that necessary to maintain a 25(OH)D level
above 50 ng/mL. Nevertheless, there is no measure estimating whether this
amount of magnesium is sufficient to address magnesium needs for a healthy
immune system.
Based on the higher incidence of osteoporosis and the lower incidence of
COVID-19 in Northern Europe versus the opposite in Southern Europe, any
magnesium shortfall is triaged first to bone needs. In second place are Vitamin
D synthesis needs, which supersede those of immunomodulation. The high die-
tary calcium and 25(OH)D levels in Northern Europe create a magnesium
shortfall by suppressing PTH. PTH down-regulates vitamin D, decreasing mag-
nesium intestinal absorption and renal resorption, decreasing blood levels of
magnesium (innocent bystander), and aggravating osteoporosis. Clearly, ade-
quate vitamin D is more critical to immunomodulation than adequate magne-
sium, given the low incidence of COVID-19 in Northern Europe.
On the other hand, their Southern cousins have sufficient magnesium to avoid
osteoporosis, but not enough to avoid a greater risk of COVID-19. Their
25(OH)D3 levels are lower and SARS CoV2 is more often severe. There is no
significant osteoporosis => vitamin D, calcium, and magnesium needs are in
balance,
i.e.
, healthy bone needs for calcium and magnesium have been satisfied,
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as have magnesium needs for synthesis of active vitamin D. However, there is a
problem with immunomodulation compared to their northern neighbors. This
confirms that magnesium needs for immunomodulation are subservient to
magnesium for healthy bone and vitamin D synthesis (demonstrated in the
South) and that vitamin D is more critical to immune function than any solo
role in this for magnesium (demonstrated in the North).
Since neuromuscular needs are probably in the runt position, we can only as-
sure sufficient magnesium to fulfill any immunomodulation needs by addressing
neuromuscular symptoms often associated with insufficiency, via magnesium
supplementation. The contribution of magnesium to immune function inde-
pendent of vitamin D is vastly under appreciated.
3.2. Why Is Magnesium Deficiency Increasing?
It is decreasing because the quality of our food has decreased (Figure 4).
Furthermore, an increasingly sedentary lifestyle, now with work at home vid-
eo-conferencing, precludes adequate sun exposure, aggravating many health is-
sues and compromising vitamin D status. Inflammatory conditions deplete the
already low storage of other vital vitamins and minerals, e.g., selenium, vitamin
C, zinc….
Humans in Western countries are consuming four times more calcium than
magnesium versus the recommended 2:1 ratio. This is one of the reasons why
osteoporosis is so high in those on diets high in dairy. The pharmaceutical in-
dustry has been conveniently available to address any symptoms due to a mag-
nesium shortfall and/or any associated pain and suffering with a growing menu
of helpful medications. Many of these exacerbate magnesium deficiency. A more
recent (Mar 2022) and more relevant assessment of this ratio reveals it to be 6.93
in those dying of Covid versus 4.93 males/3.93 females in the general population
[6].
Figure 4. The average mineral content of calcium, magnesium, and iron in cabbage, let-
tuce, tomatoes, and spinach has dropped 80% - 90% between 1914 and 2018 [1].
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Dehydration is at the center of muscle cramps and headaches, commonly seen
in magnesium deficiency. Aldosterone triggers renal resorption of Na+ and wa-
ter, but at the expense of K+ and Mg2+, which are excreted to maintain electrical
neutrality. Stress is also a major player. The hormone cortisol from the adrenal
cortex exerts aldosterone-like activity.
3.3. What Is the Role of Magnesium outside Bone Health and
Vitamin D Synthesis?
Magnesium is a critical mineral in the human body and is involved in ~80% of
known metabolic functions. Currently 60% of adults do not achieve the average
dietary intake (ADI) and 45% of Americans are magnesium deficient [2]. Mag-
nesium is a required cofactor for about 600 enzymatic reactions (many require
vitamin B6) and serves as an activator for perhaps an additional 200 [7] (many if
not all of these involve ATP).
The most significant of these is its role (as an activator) storing and releasing
energy generated by ATP (Figure 5). In green plants it is also involved in gene-
rating ATP through chlorophyll in photosynthesis. Eating leafy greens is healthy.
Chlorophyll is identical to hemoglobin but with Mg2+ instead of Fe2+.
Magnesium is vital to the conduction of electrical impulses in nerves and
muscles. There are three types of musclessmooth, skeletal, and cardiac. Ma-
nifestations of magnesium deficiency in smooth muscle include constipation,
bronchial asthma, and vasospasms (migraine headaches and even Prinzmetal
angina due to coronary vasospasm). In skeletal muscle, it’s cramps and twitches
(fasciculations). In heart muscle it’s palpitations (premature atrial contractions)
and even atrial fibrillation. Any of these symptoms should put a magnesium
shortfall on the radar.
In the immune system, the role of vitamin D is well known but poorly em-
braced. Vitamin D supplementation offers 10 times the efficacy of the flu shot.
Figure 5. ATP and energy generation cannot proceed without magnesium (from The
Magnesium Factor by Seelig and Rosanoff).
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Magnesium (independent of vitamin D) is required for many disparate func-
tions. But the role of magnesium in immune function is poorly understood and
relatively unexplored.
Some well known natural antioxidants, e.g., glutathione and melatonin, re-
quire a magnesium cofactor for their synthesis. Melatonin, which decreases with
age, also balances Th1 and Th2 cytokine responses, mimicking the benefits of
vitamin D [8]. However, the role of magnesium as a receptor activator via ATP
in immune function is especially intriguing. These are called receptor tyrosine
kinases (RTKs) and include all the interferon receptors [9]. These ATP/Mg de-
pendent RTKs include JAKs and TYK2 (Janus kinases 1, 2, 3, tyrosine kinase 2)
and spotlight a very pertinent role for magnesium in immunomodulation.
3.4. Might Any Particular Cytokine Connect Magnesium Deficiency
to Long Covid?
CD4+ and CD8+ T cell proliferation and activation are greatly reduced in
Mg-deficient conditions [10]. These same cells are primarily responsible for the
production of types I, II, III interferons.
Secretion of type I interferons (INF-
α
, IFN-
β
) and type III interferons (IFN-
λ
),
which are innate immune cytokines (early), are induced directly by invading vi-
ruses (primary release, no interferon receptors required, STAT independent). At
the same time, type II interferon gamma (IFN-
γ
) is predominantly an adaptive
immune cytokine (secondary release, interferon receptors required, STAT de-
pendent), induced by NK (natural killer) cells (innate) and CD4+/CD8+ T cells
(adaptive) via IFNGRs (IFN-
γ
receptors) [11].
JAKs1,2, TYK2, STATs1,2 are ATP/Mg dependent, as are all protein kinases.
So one can appreciate the overwhelming role of ATP/Mg in not only interferon
production, especially IFN-
γ
, but also the cells (CD4+/CD8+ T cells) that secrete
them (Figure 6, Figure 7).
Accordingly, a magnesium shortfall might contribute to a decrease in IFN-
γ
and adaptive immunity. IFN-
γ
in particular is fundamental to understanding the
symptoms of Long Covid and an alphabet soup of chronic inflammatory condi-
tions (ME/CFS, FM, EBV, CMV) and autoimmune diseases (MS, SLE, RA,
DM…). These CD4+/CD8+ T cells are the PBMCs (peripheral blood mononuc-
lear cells) that are exhausted during prolonged COVID-19 (lymphopenia).
Plasma levels of IFN-
γ
were significantly reduced in Covid ICU patients [11]
[13] [14]. IFN-
γ
is a Th1 pro-inflammatory cytokine. But it has several beneficial
effects, including blocking differentiation of naive CD4+ T (Th0) cells into Th17
cells and enhancing synthesis of the inhibitor of C1 (C1-INH) of the CCP (Clas-
sic Complement Pathway).
3.5. What Causes Long Covid?
The diagnosis of Long Covid or PACS has become a bit of a mixed bag that can
include those that never recovered from the primary infection, those that were
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Figure 6. Note the extensive involvement of Mg2+ [9].
Figure 7. This demonstrates the primary and secondary releases of interferons. Note the orange Ps, which indicate ATP/Mg dependency.
JAK1, 2 and TYK2 are also similarly dependent [12] (P not shown). The primary release of IFN-
α
/
β
is triggered by the virus (STAT inde-
pendent), while the secondary release of IFN-
α
/
β
and primary release of IFN-
γ
are triggered by IFN-
α
/
β
and are STAT dependent.
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never infected but developed similar symptoms during the prolonged quaran-
tining and social isolation, those that recovered but developed unrelated but at-
tributed symptoms…. This complicates rational analysis. Accordingly, discus-
sion is directed primarily toward those never hospitalized for COVID-19 that
developed cognitive dysfunction or brain fog. Those in the ICU that developed
Long Covid more than 12 weeks after discharge appear to be a separate smaller
group (see Summary), probably mediated by TGF beta (transforming growth
factor) and treatable by angiotensin receptor blockers (in addition to vitamin D
and magnesium).
PACS or Long Covid exhibits a unique immunoglobulin signature (decreased
IgM and IgG3) [15]. Ironically IgG3 and IFN-
γ
are proportionately elevated in
both mild and severe COVID-19 cases [16]. IFN-
γ
actually induces IgG3 secre-
tion [17]. Only IgG1 and IgG3 can activate CCP and only the CCP crosstalks
with the KKS (Kallikrein Kinin System). Development of Long Covid may be
suspected in those with indeterminate (low) IGRA (IFN-
γ
release assay) results
[18] [19]. Low IgG3 levels have also been linked to chronic fatigue syndrome
(CFS) [20] [21], which suggests IFN-
γ
may also be lower in CFS. IFN
γ
enhances
synthesis of C1-INH in PBMCs and the liver [22] [23], suppressing over-activation
of the CCP. So low IgG3 and low IFN-
γ
in Long Covid and CFS translate to less
C1-INH and more C1 activation (Figure 10). Once C1 has been activated, the
CCP begins crosstalk with the KKS [24]. The lectin complement pathway (LCP)
and the alternative complement pathway do not cross talk with the KKS, because
neither activates C1q.
There are two types of asthma, allergic and non-allergic. Vitamin D was ade-
quate (25(OH)D > 30 ng/mL) in only 15% of pediatric asthmatics v 80% of healthy
controls [26]. This suggests that the majority of asthmatics are non-allergic. The
risk of severe disease in COVID-19 is increased in non-allergic asthma [27] [28].
On the other hand allergic asthma (defined by the presence of eosinophilia) pro-
vides protection against COVID-19 [29]. Might much of this non-allergic asth-
ma be due to magnesium deficiency causing bronchial smooth muscle spasm
[30]? Might this group of asthmatics be at greater risk of Long Covid (and Mul-
tisystem Inflammatory Syndrome in Children or MIS-C) [15]?
This is the same pediatric sub-population (asthmatic and vitamin D deficient)
that develops MIS-C. So, asthma in these children and adults (MIS-A) may be a
marker for magnesium deficiency. Unfortunately in those at risk for MIS-C (and
Long Covid) a sudden increase in vitamin D intake without simultaneously
adding magnesium could further exacerbate symptoms due to triage. In addition
to vitamin D (Figure 8), melatonin also helps balance the Th1/Th2 response [8].
But magnesium is a required cofactor for the synthesis of serotonin, the precur-
sor to melatonin. Melatonin and asthma seem to connect magnesium to Long
Covid.
Low IFN
γ
in COVID-19 is also associated with lung fibrosis [31] => post ex-
ertional malaise, breathlessness, fatigue in Long Covid. Toxoplasma gondii,
Cryptosporidium, Blastocyst, and Giardia infections downgraded COVID-19
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Figure 8. Vitamin D operates in both the innate and adaptive immunity phases, pro-
motes anti-inflammatory cytokines, and balances the Th1/Th2 immune response [25].
severity via elevation of IFN-
γ
[32]. This speaks to the beneficial C1 inhibiting
properties of IFN-
γ
,
i.e.
, inhibition of CCP with inhibition of crosstalk to the
KKS. Therefore, depleted IFN-
γ
seems to translate to an acquired angioedema
type clinical condition. Long Covid brain fog, fatigue, and breathlessness may be
a function of low IFN-
γ
, causing lung fibrosis, mild angioedema, and less C1
INH (more C1) due to activation of the CCP and crosstalk with the KKS.
Due to the extensive ATP/Mg requirements for activation of naïve CD4+ T
(Th0) cells and their release of interferons, magnesium deficiency could easily
result in low IFN
γ
levels/low melatonin levels and mimic or exacerbate Long
Covid [33]. Indeed one could probably expand this to include CFS, FM, EBV
(chronic phase), and CMV (chronic phase) in combination with magnesium de-
ficiency. All vitamin D receptors (VDRs) require zinc. Zinc deficiency could also
masquerade as vitamin D deficiency and Long Covid [34].
MIS-C [35] (and probably Kawasaki’s Disease), MIS-A, and Long Covid seem
to be products of the classical complement pathway (antibody mediated (ex-
hausted IgG3)) and the KKS. Not surprisingly Long Covid can frequently make a
delayed appearance in MIS-C (10% - 30%) [36]. Asthma is the only reported
pre-existing medical condition in pediatric Long Covid [37].
In summary low levels of IFN-
γ
(due to exhausted CD4+ and CD8+ T cells)
with commensurately low levels of C1-INH result in activation of C1 and the
CCP with crosstalk to the KKS. This creates an acquired angioedema clinically in
those with increased Th1/Th2 and decreased IFN-
γ
,
i.e.
, those that are vitamin
D/Mg deficient and/or T cell exhausted => Long Covid.
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3.6. What Population Does Long Covid Target?
If we approach the question from the perspective of an activated KKS, then bra-
dykinin (BKN) should be the starting point.
ACE is the main enzyme responsible for BKN and LYS-BKN degradation
[39]. The half-life of BKN is age independent. In men it is shorter than in wom-
en, because estrogen down-regulates ACE levels (vitamin D down-regulates es-
trogen) [40]. This means that Long Covid is more likely in women [39]. BKN
operates via BKN2Rs and causes vascular leakage (Figure 9). Loose endothelial
intercellular junctions are associated with brain fog [41] [42].
ACE levels for the ACE DD haplotype are up to 70% higher [43] [44]. The
ACE DD haplotype is more common in African-Americans, which means that
they are less likely to develop Long Covid, unless they were in the ICU (see
Summary). The evolutionary pressure of falciparum malaria favors the DD hap-
lotype [45] and provides protection against both Covid brain fog and childhood
cerebral malaria [45] [46]. This explains the mild pulmonary angioedema seen in
many hypertensive African Americans on angiotensin converting enzyme inhi-
bitors (ACEIs) [47]. So both the ACE DD haplotype and COVID-19 enhance
ACE and RAS activity but reduce BKN and KKS activity. The incidence of the
ACE DD haplotype is greater in power sport athletes. On the other hand, a high
kinin ACE II haplotype has been associated with enhanced endurance perfor-
mance at an Olympic level, especially in triathlons [48].
According to a recent study, females appear to be more susceptible to Covid
brain fog, 63% v 37% [46], the reverse of the COVID-19 gender breakdown. Age
(median 43) and BMI (median 26) had no impact on cognitive function between
those PCR+ and those PCR− (non-hospitalized) long haulers, first seen for brain
fog 5 - 6 months after onset of COVID-19 symptoms [46]. Covid brain fog seems
to prefer Caucasians (88%) over African Americans (6%) [46]. BKN can increase
Figure 9. BKN (1-9), BKN (1-8), Kallidin (1-10) or LYS-BKN, and Kallidin (1-9) are all vasoactive peptides. BKN/Kallidin
trigger B2 receptors and BKN (1-8)/Kallidin (1-9) trigger B1 receptors. The green boxes are inactive metabolites [38].
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the permeability of the blood brain barrier [46] and the blood-gas barrier (lungs).
ACE/ACE2 provides a balance between angiotensin II and BKN with respect
to thrombosis on the one hand and vascular permeability on the other. Too
much ACE produces thrombotic microangiopathy (TMA). Too much BKN re-
sults in vascular leakage and angioedema. Therefore, Long Covid seems to prefer
premenopausal/perimenopausal females with the ACE II haplotype. The in-
crease in osteoporosis risk at menopause may enhance the magnesium shortage
due to triage. Severe COVID-19 prefers males with the ACE DD haplotype (and
those that live at altitude) [49]. Those that survive the ICU can also develop
Long Covid (see Summary). This is a much smaller subset of Long Covid.
The immunological differences between COVID-19 and Long Covid are:
1) Severe COVID-19 represents a problematic immune response, in which
Th1 > Th2 in responding to an invading pathogen, e.g., antibody independent. It
involves mannose binding lectins (MBLs), MBL associated serine protease
(MASP2), and the LCP [50] with activation of C2,4. Although it is strongly asso-
ciated with vitamin D/magnesium deficiency, the KKS is uninvolved and not ac-
tivated by the LCP (no crosstalk).
2) Long Covid and MIS-C/MIS-A represent a problematic immune response,
in which Th1 > Th2 in responding to Ag-Ab or immune complex,
i.e.
, antibody
dependent. This is a secondary response after mild to moderate primary expo-
sure and recovery. It involves the classical complement pathway [50], activates
the KKS via C1 activation of the CCP with crosstalk (Figure 10), and is strongly
associated with vitamin D/magnesium deficiency.
3.7. Is Long Covid One of the Faces of Magnesium Deficiency?
Frequent symptoms of magnesium deficiency
Fatigue
Migraines
Sleeplessness
Stress
Depression and anxiety
Hyperalgesia
Asthma
Frequent symptoms of Long Covid
Breathlessness
Fatigue
Brain fog
Hyperalgesia
Sleeplessness
Headaches
Asthma
3.8. What Other Faces Does Magnesium Deficiency Wear?
An alphabet soup of chronic inflammatory diseases seem to reflect a vitamin D/
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Figure 10. If IFN-
γ
is decreased and C1-INH with it, both complement and the KKS are activated. If ACE2 is decreased, B1Rs are
also activated (Figure 9) [51].
magnesium deficiency through decreased IFN-
γ
expression [52]. IFN-
γ
signal-
ing seems to be at the heart of many chronic inflammatory conditions, including
EBV, CMV, Fibromyalgia, CFS/ME, and Long Covid [53] [54] [55] [56]. Initially
IFN-
γ
levels are high, but then the CD4+/CD8+ T cells producing the IFN-
γ
be-
come exhausted with decreased IFN-
γ
. Although IFN-
γ
plays a prominent role in
autoimmune disease, some findings are contradictory [57]. But what is clear is that
vitamin D deficiency is involved in the pathogenesis of autoimmune disease [58]
[59]. Th17 cells and their IL17 cytokine, markers for COVID-19 severity and au-
toimmune disease [60], are unchallenged (see Figure 8).
3.9. How to Address Long Covid?
Whether Long Covid is due to a smoldering viral infection and/or sterile in-
flammation and/or exhaustion of T cells and/or consumption of magnesium is
unclear. But biologic individuality dictates a bottom up approach to magnesium
with attention to neuromuscular symptoms (“runt” symptoms) to assure cover-
age of immunomodulation needs.
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Upon initiation of vitamin D supplementation magnesium (and vitamin K2)
must be included [61] or one risks an exacerbation of magnesium deficiency
symptoms (and ectopic calcifications) due to triage, e.g., sleeplessness [62].
Sleeplessness can occur, because magnesium (and vitamin B6) is required for the
conversion of glutamate (excitatory) to GABA (calming); both are neurotrans-
mitters. Magnesium also blocks access of glutamate to excitatory NMDA recep-
tors. Others have reported palpitations, constipation, and/or muscle cramps that
disappeared after cessation of vitamin D supplementation.
Magnesium supplementation itself must also be approached carefully. Most
have a laxative effect, especially magnesium citrate. Exceeding bowel tolerance
results in loss of magnesium and potassium. Magnesium in chelated form to
malate, taurate, threonate, glycinate, or another amino acid is recommended. An
increase in palpitations has been reported with magnesium glutamate and mag-
nesium aspartate. Magnesium oxide is poorly absorbable. Aqueous magnesium
(Mg2+) was previously considered highly absorbable, but the size of the hydrated
cation compromises passive ion channel passage, which is otherwise responsible
for the vast majority of small bowel absorption [2]. Furthermore absorption via
active transport requires ATP and is magnesium dependent. If supplementing, it
is also important to differentiate the magnesium content by weight per tablet
(“elemental Mg” or “Mg as …”) versus total tablet weight and to note how many
tablets per serving. Furthermore, do not overlook the transdermal approach
(MgCl2, MgSO4 can be absorbed through hair follicles) Avoid any oral route-related
adverse reactions like laxative effect.
4. Summary
If 25(OH)D3 blood level is less than 50 ng/ml, one is not only vitamin D defi-
cient but also magnesium deficient. A vitamin D problem cannot be fixed in the
face of a magnesium problem, e.g., vitamin D resistant magnesium deficient
rickets. Modern osteoporosis seems to reflect a vitamin D resistant magnesium
deficient entity. Surely this implies the existence of vitamin D resistant magne-
sium deficient immune dysfunction.
Asthma paradoxically reduces the risk for COVID-19 but increases it for
MIS-C/MIS-A and Long Covid. But the separation of allergic asthma from non-
allergic asthma provides clarification. The eosinophils in the former and the
smooth muscle bronchospasm in the latter shed light on this.
Magnesium deficiency compromises both CD4+/CD8+ T cell activation/pro-
liferation and interferon production, especially IFN-
γ
(adaptive immunity).
IFN-
γ
normally signals B lymphocytes to produce IgG3, which may be decreased
due to a magnesium shortfall. This decrease in IFN-
γ
is assisted by exhaustion of
CD4+/CD8+ T cells, which are responsible for its production. In those who de-
velop PASC IFN-
γ
, TNF-alpha, and IL-6 are elevated in early recovery (<90
days) but only IL-6 is persistently elevated in late recovery (>90 days) [63]. The
domino effect of low IFN-
γ
leads to low C1-INH. A decrease in the latter pro-
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motes activation of the CCP which “crosstalks” with the KKS. The ACE II hap-
lotype and estrogen then can explain the demographics of Long Covid.
IFN-
γ
links Long Covid with many other chronic inflammatory diseases. In-
deed it links magnesium deficiency to dysfunctional immunomodulation. Vita-
min D deficiency has been strongly linked to autoimmune disease [58], but for
pleiotropic IFN-
γ
much of the research has yielded paradoxical resultspro-
inflammatory in one circumstance yet anti-inflammatory in another [64] [65]
[66]. IFN-
γ
can also promote tumor progression in one instance but regression
in another [67]. Nonetheless, despite our lack of understanding of this, efforts
toward achieving adequate vitamin D and magnesium seem prudent.
This article is more speculative in some ways than definitive but is based on
the latest research. There are other opinions on the pathogenesis of Long Covid.
For example, EBV inhibits IFN-
γ
signaling and Long Covid may represent reac-
tivation of EBV, which has remarkably similar symptoms [68] [69]. Or EBV
could be reactivated by elevated TGF beta [70].
The discussion has been limited to Long Covid in the non-hospitalized. But
there appear to be two kinds of Long Covid, both vitamin D/magnesium defi-
cientwhite middle-aged women (and children) who contracted COVID-19 but
were never hospitalized and those with comorbidities who were.
Those that developed Long Covid more than 12 weeks after discharge from
the ICU (severe not mild COVID-19) appear to be different (a smaller subset).
In addition to low IFN-
γ
, TGF beta (transforming growth factor) is elevated [71].
TGF beta inhibits IFN-
γ
[72] and is elevated in diabetics, especially those with
nephropathy [73], hypertensives [74], and the obese [75]. SARS-CoV-2 in severe
COVID-19 induces a TGF-
β
-dominated chronic immune response [76].
TGF beta is also elevated in POTS, which shares some dysautonomic features
with Long Covid [77] and is treated with losartan [78]. Vitamin D deficiency has
also been implicated in autonomic dysfunction [79]. Elevated TGF beta also
connects CFS/ME with Long Covid [80] [81]. High levels of TGF beta are asso-
ciated with hard-to-treat asthma attacks, fibrosis in organs such as the liv-
er/kidney/lungs [82], and autoimmunity. The elevated TGF beta in CIRS (Chronic
Inflammatory Response Syndrome), which overlaps with Long Covid symptoms,
can be lowered with losartan [83].
Ang II induces TGF-
β
expression via AT1Rs [84] and is treatable by angioten-
sin receptor blockers [85] [86] (in addition to vitamin D/magnesium). Pulmo-
nary fibrosis through activation of the RAS can be seen in chronic vitamin D de-
ficiency [87].
Indeed an elevated TGF-beta/IFN-gamma ratio post-COVID-19 might pre-
dict those most likely to develop PACS in both those never been hospitalized
and those that survive the ICU. Perhaps some future meta-analysis or RCT will
answer this question.
The role of magnesium in human health cannot be underestimated and its
solo role in immune function is complex. This discussion only scratches the sur-
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face. Genetic and epigenetic considerations that control Th1 and Th2 responses
are in large measure a black box [88].
Ironically the Frontline Covid Critical Care Alliance (FLCCC) makes no men-
tion of magnesium in any of its protocolsgeneral prevention, hospitalized
treatment, long haul prevention. In fact, only three items appear in all three
protocolsvitamin D, vitamin C, and melatonin. Two of these require magne-
sium for their synthesis. Perhaps that is why they are on all three protocols. Al-
most everyone is short magnesium.
5. Conclusion
The involvement of magnesium in human physiology is so comprehensive as to
be almost beyond comprehension. Its role in preventing Long Covid is but a
sliver, albeit a hot one at this time. Vaccination status is irrelevant. Whether or
not you are taking vitamin D, you should consider adding magnesium to your
regimen. It might ameliorate some of your Long Covid-like symptoms and that
list is long.
Acknowledgements
The author greatly appreciates the input of Dr. Sunil Wimalawansa.
Conflicts of Interest
The author declares no conflicts of interest.
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... TGFβ inhibits IFN-γ and downregulates NK cell cytotoxicity [79]. This IFN-γ inhibition leads to loss of its inhibitory effect on C1 of the classic complement pathway (CCP) [80]. TGFβ inhibits IFN-γ expression on CD4+ T cells [81]. ...
... TGFβ inhibits IFN-γ expression on CD4+ T cells [81]. Activation of C1 and the CCP initiates crosstalk with the KKS (Kallikrein Kinin Systems) [80] and seemingly brain fog type of Long Covid. Vitamin D modulates IFN-γ production by PBMCs [82]. ...
... Chronic vitamin D deficiency induces lung fibrosis through activation of the RAS [115]. Ang II induces TGF-β expression via AT1Rs [80] and is treatable by angiotensin receptor blockers [116]. ...
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The calcium to magnesium ratio plus adequate vitamin D greatly determine success or not in the immune battle against pathogens and cancer, not to mention cardiovascular disease. Ionized calcium and magnesium in normal, healthy individuals can be calculated and a ratio determined from serum levels. Using widely accepted laboratory reference range values and NHANES data, the recommended daily allowances from the Institute of Medicine of the National Academy of Sciences for calcium, magnesium, and D3 (cholecalci-ferol) are objectively refuted mathematically and physiologically. Midrange values for both cations, despite RDA sufficiency, are shown to be unattainable without secondary hyperparathyroidism (high parathormone (PTH), low D) or hypoparathyroidism (low PTH, high iCa:iMg) at the officially designated level of 25(OH)D sufficiency (30 ng/mL). Calcium and magnesium utilize the same calcium sensing receptor (CaSR) not only on cell membranes but also on organelle membranes. Intra-mitochondrial hydroxylation of cholecalcife-rol can become compromised. An imbalanced intake of calcium and magnesium can impact the efficacy of vitamin D supplementation. Several pertinent articles underscoring these conclusions are analyzed in detail. The impact of an imbalanced Ca:Mg ratio on Covid-19, Long Covid and vaccination is also discussed.
... TGFβ inhibits IFN-γ and downregulates NK cell cytotoxicity (79). This IFN-γ inhibition leads to loss of its C1 (of the classic complement pathway (CCP) inhibiting capabilities (80). TGFβ inhibits IFN-γ expression on CD4+ T cells (81). ...
... Chronic vitamin D de ciency induces lung brosis through activation of the RAS [115]. Ang II induces TGF-β expression via AT1Rs [80] and is treatable by angiotensin receptor blockers [116]. ...
Preprint
Full-text available
The calcium to magnesium ratio plus adequate vitamin D largely determine success or not in the immune battle against pathogens and cancer, not to mention cardiovascular disease. Ionized calcium and magnesium in normal, healthy individuals can be calculated and a ratio determined from serum levels. Using widely accepted laboratory reference range values and NHANES data, the recommended daily allowances from the Institute of Medicine of the National Academy of Sciences for calcium, magnesium, and D3 are objectively refuted mathematically and physiologically. Midrange values for both cations, despite RDA su ciency, are shown to be unattainable without secondary hyperparathyroidism (high parathormone (PTH), low D) or hypoparathyroidism (low PTH, high iCa:iMg) at the o cially designated level of 25(OH)D su ciency (30 ng/mL). Calcium and magnesium utilize the same calcium sensing receptor (CaSR) not only on cell membranes but also on organelle membranes. Intra-mitochondrial hydroxylation of cholecalciferol can become compromised. An imbalanced intake of calcium and magnesium can impact the e cacy of vitamin D supplementation. Several pertinent articles underscoring these conclusions are analyzed in detail. The impact of an imbalanced Ca:Mg ratio on Covid-19, Long Covid and vaccination is also discussed. Subject Areas Pathology
... Open Access Library Journal no KKS crosstalk with either the alternative complement pathway or the lectin complement pathway [9]. BKN (bradykinin) is the principal hormone of the KKS as angiotensin II is the principal hormone of the RAS. ...
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Background: The clinical and epidemiological implications of abnormal immune responses in COVID-19 for latent tuberculosis infection (LTBI) screening are unclear. Methods: We reviewed QuantiFERON TB Gold Plus (QFT-Plus) results (36,709 patients) from July 2016 until October 2021 in Asturias (Spain). We also studied a cohort of ninety hospitalized patients with suspected/confirmed COVID-19 pneumonia and a group of elderly hospitalized patients with COVID-19 who underwent serial QFT-Plus and immune profiling testing. Results: The indeterminate QFT-Plus results rate went from 1.4% (July 2016 to November 2019) to 4.2% during the COVID-19 pandemic. The evolution of the number of cases with low/very low interferon-gamma (IFN-gamma) response in the mitogen tube paralleled the disease activity and number of deaths during the pandemic waves in our region (from March 2020 to October 2021). The percentages of positive QFT-plus patients did not significantly change before and during the pandemic (13.9% vs. 12.2%). Forty-nine patients from the suspected/confirmed COVID-19 pneumonia cohort (54.4%) had low/very low IFN-gamma response to mitogen, 22 of them (24.4%) had severe and critical pneumonia. None received immunosuppressants prior to testing. Abnormal radiological findings (P=0.01) but not COVID-19 severity was associated with low mitogen response. Immune profiling showed a reduction of CD8+ T cells and a direct correlation between the number of EMRA CD8+ T-cells and IFN-gamma response to mitogen (P=0.03). Conclusion: Low IFN-gamma responses in mitogen tube of QFT-Plus often occur in COVID-19 pneumonia, which is associated with a low number of an effector CD8+ T-cell subset and does not seem to affect LTBI screening; however, this abnormality seems to parallel the dynamics of COVID-19 at the population level and its mortality.
Article
Background: Acute neurological complications from COVID-19 have been reported in both pediatric and adult populations. Chronic symptoms after recovery have been reported in adults and can include neuropsychiatric and sleep symptoms. Persistent symptoms in children with the multisystem inflammatory syndrome in children (MIS-C) have not been studied. Methods: We conducted a single-center retrospective chart review and cross-sectional survey of patients diagnosed with MIS-C. Patients and parents were surveyed on symptoms before the COVID-19 pandemic, upon admission, and 23 weeks (interquartile range 20-26 weeks) after discharge. Age and gender-matched patients requiring intensive care unit (ICU) care for status asthmaticus were surveyed as a control group. Results: In this cohort of 47 patients, 77% reported neurological, 60% psychiatric, and 77% sleep symptoms during hospitalization. Prior to hospitalization, 15% reported neurological, 0% psychiatric, and 7% sleep symptoms. Eighteen (50%) of the 36 patients who had neurological symptoms during hospitalization continued to have symptoms on follow-up (odds ratio [OR] = ∞, p = .003]). Similarly, 16 (57%) of 28 patients with psychiatric symptoms reported persistence at follow-up (OR = 5.00; p = .02). Fifteen (42%) of the 18 patients reporting sleep disturbance during hospitalization had persistence on follow-up (OR = 1.9; p = .49). The aggregate of neurological, psychiatric, and sleep symptoms during admission and at follow-up was significantly higher for MIS-C patients requiring ICU care when compared to the control group ( p = .01). Conclusions: In this cohort of patients with MIS-C, a majority of patients reported new-onset neuropsychiatric and sleep symptoms. Almost half of these patients had persistent symptoms on a follow-up survey.