Long Covid Part 9: Management

Dr Graham Exelby Revised June 2023

Management described below does not include the specialized programs in the severely impaired patients. It is geared primarily towards the common fatigue and cognitive impairment, but also includes those with the marked autonomic instability that characterizes Postural Orthostatic Tachycardia Syndrome (POTS.) The recognized programs as described in the RACGP Guidelines(182) should be followed, and the suggestions based on DNA findings by Dr Vittone and ongoing research in POTS could be added where considered appropriate.

This clinic has been researching POTS for around a decade, and given the clear association between POTS and Long COVID, has given us a “head start” in management protocols.

Figure 1: Timeline of post-acute COVID-19.

Source: Euro Heart J Suppl, Vol 23, Issue Supplement E, October 2021. https://doi.ord/10.1093/eurheartj/suab080

Acute COVID usually lasts until 4 weeks from onset of symptoms, beyond which replication-competent virus has not been isolated. Post-acute COVID-19 is defined as symptoms and/or delayed or long-term complications beyond 4 weeks from onset of symptoms. Common symptoms are summarized.(22)

Summary:

COVID is a microembolic and inflammatory disease that also may amyloid to the fibrin clot that is associated with increased neurovascular damage. There is an increased risk of Alzheimer’s, Parkinsons diseases and neurodegenerative disorder in infants

One out of five reported continued fatigue and/or muscle weakness, while 17 per cent said they were still experiencing sleep difficulties. Just over one in four reported suffering anxiety or depression.

There is a poor prognosis in obesity, diabetes, hypertension, and atherosclerosis Over 65- 60+% increased cardiovascular or cerebrovascular event in next 12 months

High incidence new diabetes (30% increase)

Infection may be co-related with aggressive malignancy (Natural Killer cell and Interferon 1 dysfunction), although there are no definitive studies as only observational reports are currently available. People with cancer are at a higher risk if they contract COVID

Common problems in Long COVID:

• Fatigue, brain fog and shortness of breath

• Increased cardiovascular or cerebrovascular event in next 12 months, as well as dementia, especially in the over 65's

• Change in microbiome

• High incidence diabetes

• Increased incidence of autoimmune diseas

• Neural sensitisation with autonomic dysfunction, triggering multiple problems including Postural Orthostatic Tachycardia Syndrome (POTS.)

Overview of Long Covid and Mast Cell Activation

From the DNA studies by Dr Valerio Vittone, the mutations in the mast cell membrane and in Dao enzyme function are major contributors to the pathogenesis of Long COVID, and when combined with his other findings, clear paths are emerging to reduce the severity of COVID infections and in the management of Long COVID. Using a technique called genetic imputation, it is now possible to use the ~750,000 SNPs on a chip into up to 83 million additional SNP variants with an accuracy rate of 98%.

More than 400 genes are differentially expressed in long covid patients. Primary problems from our DNA appear to be in the following, and dealt with in more detail in “DNA Mutations that Underpin POTS and Long COVID.”): Ongoing DNA assays in Long COVID that confirm similar findings warrant further investigation in a broader cohort of Long COVID subtypes.

There is increasing DNA evidence that multiple mutations in the Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual problems being caused by Covid. These are common and look to provide directions for management in patients not responding to the first line mast cell blockade. The TLR2 and TLR4 mutations are currently being investigated.

The TLR4 mutations may explain the effectiveness of Low Dose Naltrexone in chronic fatigue and cognitive impairment. The TLR4 mutations appear to be potentially one of the critical “molecular connections” associated with the abnormally low “biomarkers” used to measure the inflammatory responses seen in many Covid patients. These patients have often “fallen below the radar” while in fact have an impaired immune response. Nigella Sativa (black cumin or black seed oil) is currently being looked at in the management of this with its role in modulating the TLR4 response.

Arguably the most important when looking at recovering Long Covid patients, there are mutations in mast cell function Dr Vittone has discovered- one on the membrane. Furthermore, Dr Vittone, correlated additional mutations of two critical enzymes (namely DAO & HNMT) involved in clearing Histamines in different tissues in the body.

The Dao enzyme (Diamine oxidase) is involved in the metabolism, oxidation, and inactivation of histamine and other polyamines such as putrescine or spermidine. DAO is produced in kidneys, thymus and intestinal lining that breaks down excess histamine in the body, particularly in the gut.

HNMT Histamine N-methyltransferase) catalyzes the methylation of histamine in the presence of S-adenosylmethionine (SAM-e) forming N-methylhistamine. HNMT is involved in metabolism of intracellular histamine, mainly in kidneys and liver, but also in bronchi, large intestine, ovary, prostate, spinal cord, spleen, trachea. and peripheral tissue.

Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual problems being caused by Covid.

NLRP3 mutations look to play a major role in this neurodegenerative/inflammatory process as University of Qld researchers Woodruff et al demonstrated that SARS drives NLRP3 inflammasome activation in human microglia through spike protein.

Mast cell mutations that affect body’s ability to respond to mast cell activation and threats mediated through mast cells. These are major mutations in POTS and thus far in Long Covid. The primary ones are on the mast cell membranes and in the function of Dao and HNMT enzyme. The mast cell is a potent immune cell known for its functions in host defence responses and diseases, such as asthma and allergies. “Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury. An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts.)

There is increasing DNA evidence that multiple mutations in the Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual problems being caused by Covid.

COMT mutations (= reduced ability to process catecholamines and oestrogen with implications in malignancy, rheumatoid arthritis and SLE) Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade catecholamines eg dopamine, adrenaline, nor-adrenaline, catecholestrogens and various drugs. COMT introduces a methyl group to the catecholamines which is donated by S-adenosylmethionine (SAM).(116)Therefore you need adequate SAM for COMT to work. Having too little SAM and too much SAH (s-adenosylhomocysteine) from undermethylation results in COMT inhibition as well.(117) For this reason, MTHFR SNPs that cause undermethylation and COMT SNPs that lower COMT levels are a bad combination.(118)

• COMT gene production is itself influenced by methylation.(119) Usually, methylation shuts down gene production. The association of COMT mutations with malignancy and auto-immune disease is discussed in another paper currently being updated

• Oestrogen also signals mast cells to release histamines via its ER receptor on Mast cells. This is a critical mutation in POTS. COMT gene production is itself influenced by methylation (in the presence of SAMe a product of the methylation cycle), which in turn is affected by multiple mutations, some very common such as the MTHFR genes.

• There is an association between COMT mutations with malignancy especially breast cancer, and also endometriosis and auto-immune disease. Then there are various oxidative stress and inflammatory mutations. These combinations are amenable to epigenetic modification Dr Vittone can provide with a personalized protocol based on individual genetics.

Oxidative stress and mitochondrial mutations- eg eNOS, SOD2. NO metabolism- associated with the development of FMS and pain sensitization, and a likely problem in Long Covid.

Inflammatory mutations- various mutations in interleukins.

Methylation mutations (especially MTHFR) the 677 MTHFR mutation typically is associated with increased homocysteine, and affects collagen function via SAMe and other molecules as well as increased thrombotic risk and plaque formation in different tissues.

Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. It is thought that PEMT gene polymorphisms are associated with non-alcoholic fatty liver disease (NAFLD).(255) Fatigue is a common symptom of PEMT mutations and its associated mitochondrial dysfunction.

The CHKA gene codes for the choline kinase alpha enzyme, which is involved in the pathway of reactions that coverts choline into phosphatidylcholine needed for cell membranes.

• PEMT and similar mutations may provide the missing link to the non-resolving elevated D-Dimer measurements for microemboli, as well as persisting cognitive impairment despite mast cell blockade. There are no tests currently available to test for this except DNA, and even then a decision needs to be made about long term supplementation, as this mutation is associated with neurodegeneration, as with APO E4. The addition of SPECT scanning of the brain is being used to assess hypo-and hyperperfusion in Long Covid, and is of value in managing these patients.

• BHMT, PEMT and CHKA are connected to MTHFR and the folate and methylarion cycle so mutations in genes like MTR and MTFHR indirectly affect them too, eg methyl folate is used by BHMT to convert betaine into methionine.

TRP mutations- TRPM3 appears critical in NK (Natural Killer) immune cell function, with implications for Ca2+ signalling and cell function.(113) The transient receptor potential melastatin subfamily 3 (TRPM3) is one of the most primitive receptors in the body, activated by a wide variety of agents, from bacteria and viruses to temperature and environmental factors such as perfumes. This diversity made it a logical suspect for a condition like CFS that has so many different triggers in different people.

• Prof Sonya Marshall-Gradisnik and the Griffith University Chronic Fatigue team working with TRPM3 function in the research into chronic fatigue at Griffith University(63)(113)(114) have linked mutations in this pathway with “glymphatic” function with consequent reduced clearance of waste solutes from the brain with production of fatigue and brain fog and the therapeutic benefit of Low Dose Naltrexone

• TRPA1 is a key ion channel that detects oxidative stress and a range of endogenous and exogenous chemicals (smoke, solvents, cold air).

• TRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.(113)(114)

Lipoprotein a (LPa): High levels of LPa, found in 20% of European descent, increases the inflammatory response and thrombotic risk in COVID-19.(159)

APO E4 - The Apolipoprotein E allele 4 is a major genetic risk factor for Alzheimer's disease, as this lipid carrier is important for maintaining homeostasis necessary for a healthy environment of the brain. This mutation is seen in around 15 to 20% of the general population, with 2-3% being homozygous with the increased risks that are associated. This is emerging as a significant mutation in resistant cognitive impairment. Of note there has been research into the use of ARB medication candesartan and telmisartan in reducing risk- this is the subject under close scrutiny, particularly with increasing evidence of neuroprotection afforded by telmisartan.

• APO E is particularly concentrated in astrocytic processes at the pial surface and around the blood vessels. In addition, the choroid plexus and tanycytes in the wall of the third ventricle also produce Apolipoprotein E. Thus, Apolipoprotein E production is co-localized with CSF production sites and transport pathways suggesting that lipids are transported by the glymphatic system.

• The glymphatic system is thought to play a central role in macroscopic distribution of lipids in the brain and that medium to large lipid soluble molecules might require carrier particles in order to be delivered via the CSF. Astrocytes thus play a key role in lipid synthesis and lipid distribution by releasing lipid carrier proteins, such as Apolipoprotein E, and in maintaining the highway for distribution, the glymphatic system.

• APO E4 mutation also affects arteries, significantly increasing coronary artery disease risk ,decreased mitochondrial function, decreased insulin sensitivity, increased insulin resistance, fatty liver and progression to cirrhosis (APO E4 contributing to altered VLDL metabolism and increased atherosclerosis).(120)Mast cells- membrane and Dao enzyme (Dr Vittone research)(44)with consequent aberrant immune response by mast cells and the underlying cause we believe of the cytokine storm, the exaggerated inflammatory and microembolic response which then causes microglial inflammation, small fibre neuropathy and autonomic instability.

The SARS-CoV-2 virus is transmitted via respiratory droplets and aerosols from person to person. The Spike- S glycoproteins on the SARS‐CoV‐2 envelope bind to angiotensin‐converting enzyme 2 (ACE2) and the virus enters inside the cells.(30)

After the virus enters the airways, it starts to replicate and the immune response begins with activation of macrophage and dendritic cells via Toll-Like (TLRs) and NOD-Like (NLRs) against the production of inflammatory cytokines and reactive oxygen species (ROS).(88)

The exaggerated inflammatory process, the “cytokine storm” is marked by the over-expression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumoral necrosis factor-alpha (TNF-α), products of the Toll-Like receptors 4 (TLR4) pathway.

The cytokine storm is from aberrant activation of the mast cells by our immune system gate keepers, the threat receptors, or Toll-Like Receptors (TLRs), 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). IL-8, triggered by IL-1a, IL-1b and TNFa, is produced early in the inflammatory response and controls activity of neutrophils, and persists for weeks once released.

·IL-8 showed remarkable increases in the blood, the broncho-alveolar lavage fluid, and the lungs of COVID-19 patients, and exhibited a notable compartmentalised response within the lungs, consistent with its well-established role in the recruitment of neutrophils to the lungs during acute pulmonary inflammation(204)

The major cause of morbidity and mortality in COVID patients is from the “cytokine storm.”(12)

Petrovic et al (9) describe “approximately 15 to 20% of COVID-infected patients suffer a severe form of the acute infection, characterised by activation of mast cells leading to histamine release and hyper-inflammatory cytokine storms causing far more damage than from any direct viral toxicity.”(9)

Peddapalli et al(6) report that “nearly 20% of COVID-19 patients develop serious complications due to excess immune response of the human immune system, resulting in pneumonitis, Acute Respiratory DistressSyndrome (ARDS), encephalopathy, hypercoagulability, pulmonary embolism, deep vein thrombosis, ischaemic stroke, myocardial infarction, systemic arterial embolism, disseminated intravascular coagulation, virus-activated cytokine storm syndrome, fulminant myocarditis, septic shock, mimicry of vasculitis, endothelium damage, and multiple organ failure in humans.”(6)

Complicating this has been the addition of amyloid in these clots by virtue of the intensity of the inflammatory reaction in some people- amyloid better known for its association with Alzheimers disease.(72)(73)(74)

Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for 10% to 15% of all cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defence in the CNS.(135)

Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19: 42% are affected, and another 15% have microclots in brain tissue.(105

Dong et al(109) demonstrated that brain inflammation plays a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells, rather than microglia, are the "first responders" to brain injury. They showed that site-directed injection of a “mast-cell degranulator” compound in the hypothalamus initiated the acute inflammatory response by inducing mast-cell degranulation, activating microglia, and triggering the production of inflammatory factors. The complex nature of the immune response and mast cell activation in now an integral part of Long COVID pathogenesis.

Dong et al continue “The mast-cell stabiliser disodium cromoglycate (cromolyn) inhibited this effect: decreasing the production of inflammatory cytokines, reducing microglial activation, inhibiting the MAPK and AKT pathways, and repressing the expression of H1, H4, protease-activated receptor 2 (PAR2), and toll-like receptor 4 (TLR4) in microglia. These results demonstrated that in the brain, activation of mast cells triggers activation of microglia, whereas stabilisation of mast cells inhibits the CNS inflammation that would otherwise result from activation of microglia. Thus, interactions between mast cells and microglia could constitute a new and unique therapeutic target for diseases that result from CNS inflammation.”(109)

The microglial activation results in Small Fibre Neuropathy and neuropathic pain, and from this small fibre neuropathy comes the sensitisation and characteristic autonomic chaos that is POTS and POTS-like Long COVID, and this includes random symptoms such as the eye pain in Covid.

• POTS or Postural Orthostatic Tachycardia Syndrome is orthostatic intolerance or the inability to remain upright without symptoms associated with tachycardia exceeding 120 beats per minute or an increase in the heart rate of 30 beats per minute when changing posture from a lying to standing position. It is commonly associated symptoms such as headache, nausea, tremors, sweating, palpitations and near -syncope. 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)Skin biopsies in patients with Hashimotos disease, fibromyalgia, Lupus, Bipolar disorder, schizophrenia and even PTSD demonstrate this similar neuropathy, and it is felt that the processes that have been uncovered could potentially be the same.

Fatigue is the most common symptom in Long COVID, often totally incapacitating. The mitochondria are the energy sources of our cells and Covid affects the mitochondria and it is correlated to reactivation of other viruses especially glandular fever -viruses that are resident still and affect mitochondrial function.

Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation.(28)

Mitochondrial dysfunction and oxidative stress are the major culprits in most of the Long COVID patients treated at our clinic. The main areas we have assessed:

• Mitochondrial dysfunction /oxidative stress. DNA testing with Dr Vittone provides clarity on mitochondrial and inflammatory deleterious bad gene variants that are critical to Mitochondrial dysfunction and the exaggerated immune response caused by Covid

• Direct cardiac damage (eg pericarditis, myocarditis, reduced EF%)

• Pulmonary damage- embolic, inflammatory

• Small fibre neuropathy inflammatory and very common (again IL-6 and TNFa)

• Autonomic instability- “POTS” symptoms

• Impaired cardiac function

• Microglial damage in brain -link to Glymphatic research and impaired function

Fatigue, thus, can also be from direct inflammatory or embolic damage to the heart, kidneys, liver, brain and lungs etc as well as mitochondrial dysfunction and oxidative stress. And it can be impaired autonomic function from the IL-6 and TNFa driven small fibre neuropathy affecting heart function or microglial damage in the brain. These have to be patiently sorted out to have any hope of correcting the problems we are being confronted with.

D-Dimer is an important test we use for blood clots, especially pulmonary emboli and is a major tool to watch for the progression of Long COVID, despite the lack of clear guidelines from medical authorities.

• Chest pain and shortness of breath are so common, as are mild elevations of D-Dimer.

• Large increases in D-Dimer are investigated with scans for pulmonary emboli, but these scans don’t show the microemboli damage, so is the elevation can only be assumed to be microembolic as at this point, there is no definitive proof. The levels are also increased in malignancy, obesity and prolonged immobilization, all of which increased embolic risk.

• When the D-Dimer is normal, it is a logical assumption that it is the inflammatory pathway and mitochondrial dysfunction that drive the symptoms, giving us a pathway for management.

• There have been many where there is persistent D-Dimer elevation despite apparent recovery from major symptoms. Rauchet al(249) found phosphatidylserine was associated with increased thrombo-inflammation and vascular complications. PEMT mutations appear to be a constant finding in those with DNA testing with this which provides a possible answer and solution. This work continues.

There are different subtypes of Long COVID, and Long COVID is not a homogeneous illness and each patient has to be personalized. Canas et al at King’s College UK (110)(111) identified distinct profiles of symptoms for post-COVID syndrome within and across variants.

• The largest group was characterised by a cluster of neurological symptoms such as fatigue, brain-fog, headache, anosmia/dysosmia, depression, and delirium.

• A second group experienced cardiorespiratory symptoms, including chest pain and severe shortness of breath. This was the largest cluster in the wild-type period when the population was unvaccinated, and "may reflect lung damage", commented the authors.

• The third common cluster, present in all variants, was distinguished by systemic/inflammatory symptoms, abdominal symptoms, myalgias, and changes in skin and hair

• While these three subtypes were evident in all variants, additional symptom clusters were also identified which were subtly different between variants.

Xie et al(42) described a magnified risk in the over 65 year old group. With potential dysfunctional immune responses there are early warning signals, such as lymphopenia, troponin release, elevated BNP, rising inflammatory markers such as CRP, IL-1β and IL-6. He advocates that these aging patients should be followed closely and monitored for early evidence of organ failure, with efforts made to restore immunosenescence and cellular-mediated response.(42)

Immunocompromised patients are unable to clear the virus. In a hospital situation management includes anti-viral treatments and IV immunoglobulins, as well as the supportive treatment such as intubation when shortness of breath is severe.

The prevalence of Mast Cell Activation Syndrome (MCAS) is similar to that of severe cases in the COVID- infected population, and much of the Covid hyperinflammation is remarkably similar to mast cell-driven inflammatory processes. The wide range of symptoms seen in post-COVID conditions are those seen in POTS and its auto-immune co-morbidities.(7)(8)

The DNA findings in POTS and Long COVID patients studied implicate Mast cell DNA mutations, on the mast cell membranes and Dao and HNMT enzyme (Dr Vittone research)(44) with consequent aberrant immune response by mast cells and a large part of the underlying causes we believe of the cytokine storm, the exaggerated inflammatory and microembolic response which then causes microglial inflammation, small fibre neuropathy and autonomic instability. There are multiple mutations, but the response to the DNA findings in the mast cells correlate well with the work from Afrin et al. (7)(15)(16)

Drugs with activity against mast cells or their mediators have been shown to be helpful in management of COVID patients. Afrin’s group (7) describes how none of his treated MCAS patients with COVID-19 suffered a severe course of the infection and he conjectures this is because their dysfunctional mast cells were at least under partial control during the acute infections.

Weinstock’s group(10) have seen improvement in their “Long COVID Clinics” using a varying combination of mast cell-directed therapies including antihistamines, cromolyn, flavonoids (quercetin and lutein), low dose naltrexone, montelukast and vitamins C and D.

Studies have reported that H1 as well as H2 receptor antagonists, are associated with a reduced risk of infection and deterioration leading to intubation or death from COVID-19. These agents are considered to improve pulmonary symptoms of Covid-19 infection by blocking the histamine-mediated cytokine storm. (125)

The use of H1 + H2 blockade has been expanded in our clinic, using usually fexofenadine or cetirizine for H1 blockade twice daily and famotidine for H2 blockade up to 160 mg daily, and occasionally more subject to tolerance and QT changes, adding H4 blockade subject to response. Low Dose Naltrexone (LDN) is a H4 blocker, and TLR4 modulator, reducing the cytokine response from TLR4 as well as having positive results with chronic fatigue. It must be emphasized that the results obtained with high dose Famotidine are beyond normal recommended doses, and that any patient using these doses are aware they are used without backup from therapeutic guidelines, as all work is still at a research level.

Nigella Sativa (TLR4 modulator with anti-viral and anti-thrombotic qualities)and Omega 3 are being trialled to augment these protocols, especially when D-Dimers remain elevated, or when LDN is not tolerated.

Brennan et al (272) reported in 2022 that using 80mg three times daily (240 mg/day) Famotidine was found to be safe and well-tolerated, reducing symptoms by 50% after 8 days. They also showed that H2 blockade caused early recovery from elevated interferon alpha, presumably by modulating inflammation in organ tissues.

Repurposed old medications Doxycycline and Metformin have shown to have potential value in management of Covid. Doxycycline in particular is proving to be helpful in the resistant “Long Covids.” In particular its ability to block TLR4 and reduce cytokines IL-6 and TNFa makes this a potentially valuable tool in Long Covid as well as acute Covid management, especially when combined with Zinc. Details in Doxycycline and Metformin in Covid Management- repurposing old medication.

The glymphatic system is a recently discovered macroscopic system for waste clearance in the brain. It uses a system of perivascular channels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the CNS. Besides eliminating waste, the glymphatic system may also distribute non-waste compounds, such as glucose, lipids, amino acids, and neurotransmitters, as well as permitting the flow of fluid through the brain (see Part 12 The Glymphatic System with loss of Cervical Lordosis and association with Thoracic Outlet and Jugular Outlet Syndromes.)

Intriguingly, the glymphatic system functions mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of inactivity that enables elimination of potentially neurotoxic waste products, including β-amyloid.”(122) The relevance of this becomes important in Long COVID as the inflammatory process can produce microemboli containing amyloid.

Natural Killer Cells (NK) are lymphocytes of the immune system that monitor surface of autologous cells and allows NK cells to distinguish malignant from health cells.(234) NK cell function is impaired in people with TRP mutations.

Type I and III interferons (IFNs) are innate cytokines important in the first line defence against SARS-CoV-2. SARS-Co-2 though has evolved mechanisms to evade the antiviral function of Interferon-1.(235)(236) Studies of SARS-CoV-2 patients showed limited IFN-1 responses, while there was an increased expression of IL-6, TNFa and other chemokines.(236) The possible implications of this are in increased malignancy rate, and severity of malignancy at presentation following SARS- CoV-2 infection.

The ongoing research into glymphatics could shed light on POTS and long COVID. Professors Sonya Marshall-Gradisnik Natalie Eaton-Fitch teams discovered mutations in an important TRP pathway (TRPM3 ion channel dysfunction)(181) that affects the function of the glymphatics and a product called Low Dose Naltrexone that improves function, a valuable tool in management of the cognitive changes and chronic fatigue by improving glymphatic flow as well as being a Histamine or H4 blocker.

In an editorial in Frontiers in Pharmacology, “Cytokine Release Syndrome in COVID-19: Mechanisms and Management,” Tao Hue(204) discussed favourable management of “Cytokine Release Syndrome” by suppressing hyper-inflammatory responses. This was initially with toxilumab blocking IL-6. Other agents, monoclonal antibodies against IL-8 are being trialled. He also described the use of 17a hydroxyprogesterone caproate in multiple cytokines, and SSRIs “including paroxetine, fluoxetine, fluvoxamine, sertraline and escitalopram, in the inhibition on IL-6 production in various immune cells. Fluoxetine was identified as the most promising candidate as an anti-inflammatory drug to mitigate hyper-inflammatory responses and to treat cytokine release syndrome, given its potent efficacy and low cytotoxicity among five SSRIs”.(204)

As described in 2022 Pathology Tests Explained (208), “Angiotensin converting enzyme (ACE) is an enzyme produced by vascular endothelial cells to help regulate blood pressure. It catalyses the conversion of angiotensin I (an inactive protein ) to angiotensin II.

• Angiotensin II functions as a strong vasopressor - it causes arteries to contract, making them temporarily narrower and increasing the pressure of the blood flowing through them.

• ACE is produced throughout the body, but is especially concentrated in the lungs. It is normally found in high levels in the blood in those less than 20 years of age, but then drops to a relatively stable lower level in healthy adults.

• Increased amounts of ACE are sometimes secreted by cells found at the margins (outside borders) of granulomas. Granulomas are small tumour-like masses of immune and inflammatory cells and fibrous tissue that create bumps under the skin and throughout the body. They are a classic feature of sarcoidosis, a systemic disorder of unknown cause that often affects the lungs but may also affect many other body organs including the eyes, skin, nerves, liver and heart.

• ACE levels often increase when granulomas develop. About 50-80% of patients with active sarcoidosis will have elevated levels of ACE; levels that will rise and fall with disease activity.”(208)

• Elevated Se ACE is felt to play an important role in the response to SARS-CoV-2 infection.(209)

Red Flags: symptoms requiring medical attention: It needs to be remembered that a deterioration in symptoms can also reflect a new COVID or other infection.

• Lack of response to mast cell blockade

• New, increasing or severe shortness of breath

• Arrhythmias

• Unexplained chest pain

• Syncope

• Confusion

• New neurological symptoms

• Increasing D-Dimer/ HS-CRP and other markers (occult malignancy needs to be excluded)

As described previously, managing mast cell activation is crucial to successful management. The knowledge of the DNA mutations that underpin the primary problems has confirmed the importance of this. Frequently lifestyle change, especially with diet and addition of mast cell blockade, initially with H1 and H2 blockade has resulted in major improvements in almost all fatigue and cognitive impairment. Just as the mast cell researchers found when their patients were not affected severely by COVID, the blockade may turn off the ongoing inflammatory processes.

Some of the symptoms attributed to mast cell activation are in my opinion, mechanically-driven, as in our POTS research we seek the answers to the impaired intracranial vascular flow and resultant “brain fog.” The work here can be seen in the “POTS” as well as the “Cervical spine with loss of lordosis and impeded glymphatics and association with Thoracic Outlet and Jugular Outlet Syndromes” documents on the website.

Research is ongoing as information is available. The plethora of research into COVID and Long-COVID is slowly unravelling the underlying causes of these and so many other diseases. It is our hope that these management programs can be utilized by your health providers as they see fit to help you recover.

Recommendations for managing arrhythmias are similar to those for non-COVID patients, including electrolyte optimization, avoidance of triggers, and medication modification. Concomitant ECG monitoring for patients who have long QTc or taking medications known to prolong the QTc interval is required.(145) Cardiac arrest was reported in 11% of COVID-19 patients with ECG evidence of ST elevation in a case series from New York(145). Ketotifen can be a useful product as a H1 blocker when QT prolongation is present, as it does not affect the QT interval.

Our clinic has been actively involved with QT prolongation for some years as it is a common finding in POTS. Generally speaking, we have found this can be controlled with “Kiiko Matsumoto” acupuncture which reduced sympathetic overactivity in an as-yet unpublished study of 50 POTS patients. Watching the QT interval we believe is an important component on managing Long-COVID cardiac complications, especially when medications are added that may affect the QT interval. There is inconsistent data on QT prolongation from famotidine use.We have found arrythmias are not uncommon but early data would suggest closer attention is needed to electrolytes and magnesium levels for better management.

Mast Cell Blockade

Mast cells are programmed to site themselves at environmental interfaces- lungs, gut, skin, bladder, nose and sinuses etc, so there can be a wide range of pathology in aberrant mast cell activation. Mast cell activation syndrome is known to permanently escalate its baseline level of dysfunction of the affected mast cells shortly after a major stressor, likely due, Afrin believes, to complex interactions between epigenetic abnormalities and the stressor’s induced cytokine storm- of additional mutations by the mutated stem cells from which the mutated /dysfunctional mast cells are derived.)(7)

In a similar fashion, Afrin et al(7) describe post-infectious multisystem inflammatory syndromes, eg from Ebstein-Barr virus and tick-borne infections, are suspected to be rooted in initiation of mutations of normal stem cells leading to aberrant controller genes.

Current reviews have sought to explain COVID-19 clinical and pathologic findings based on standard models of antiviral innate and adaptive immune responses which do not consider the potential role of mast cell activation and degranulation. Reviews have emphasized the inflammatory cell response cascade associated with monocytes, macrophages and adaptive T and B cell helper and effector responses. These types of immune responses are also invoked to explain the novel microvascular pulmonary intravascular coagulopathy associated with COVID-19. (8)

Malone et al propose an alternative paradigm;COVID-19 infection- induced mast cell activation could account for some of the core pathologic cascade and much of the unusual symptomatology associated with COVID-19 pharmacologic findings suggesting potential benefits of histamine H2 receptor blockade using famotidine. This model is also supported by the significant overlap in the clinical signs and symptoms of the initial phase of COVID-19 disease and those of mast cell activation syndrome (MCAS), as well similarities to Dengue haemorrhagic fever and shock syndrome (including T cell depletion) during the later phase of COVID-19.(8)

The DNA findings from Dr Vittone confirm the importance of mast cell management in the treatment of Long COVID, coupled with the successful use of histamine blockade in our clinic appears to confirm the accuracy of Malone’s hypothesis as medication with activity against mast cells or their mediators have been shown to be helpful in management of COVID patients. The findings of the DNA mutations warrants extensive study into the different Long COVID subgroups.

Afrin’s group (7) describes how none of his treated MCAS patients with COVID-19 suffered a severe course of the infection and he conjectures this is because their dysfunctional mast cells were at least under partial control during the acute infections. Weinstock’s group(7) have seen improvement in their “Long COVID Clinics” using a varying combination of mast cell-directed therapies including antihistamines, cromolyn, flavonoids (quercetin and lutein), low dose naltrexone, montelukast and vitamins C and D.

Famotidine in Covid-19

Mukherjee et al(78) reported that dsRNA virus activated mast cells also trigger innate immune signalling through TLR3, which causes activation of IRF3 and synthesis of interferons.(78) “Deregulation of mast cells contributes to the inflammatory response leading to a pulmonary cytokine storm that is seen in severe COVID-19 infections. Upon activation, mast cells release proinflammatory cytokines and chemokines (IL-1, IL-6, IL-33, TNF, CCL2, MCP-1), histamine, prostaglandins, and leukotrienes. Increase in systemic histamine levels in combination with IL-1 causes inflammation-induced lung damage in SARS-CoV-2 infection.”(78)

In humans, the TLR family comprises ten members (TLR1– TLR10), which are expressed in innate immune cells including macrophages, epithelial cells, and MCs. TLRs are pattern recognition receptors that recognize several pathogen associated molecular patterns (PAMPs) present in bacteria, viruses, and other pathogens. TLRs on activation produce inflammatory cytokines, type I IFN, and other mediators. TLR3-mediated signalling is an important antiviral signalling pathway that is activated in coronavirus infections.

TLRs can be localized either on the cell surface (TLR-1, -2, -4, -5, -6, -10) or in endosomes (TLR-3, -7, -8, -9). SARS-CoV-2 enters the cell through the endosomal pathway and hence activates the endosomal TLRs. TLR activation via MyD88-dependent and TRIF-dependent pathways causes nuclear translocation of the transcription factors NF-κB, IRF-3, and IRF-7, with production of innate proinflammatory cytokines (IL-1, IL- 6,TNF-α) and type I IFN-α/β, which are essential for antiviral responses.

Though TLR3 is beneficial in the initial viral clearance, hyperactivation may contribute to hyperinflammation and cause cytokine storms characteristic of COVID-19. Studies showed that on infection, famotidine does not affect the viral life cycle and replication, but affects host cells by histamine-induced signalling processes.

Famotidine is a histamine H₂ receptor antagonist medications that decreases stomach acid production. Over decades, (the original, cimetidine released commercially in 1971) they have been used to treat peptic ulcer disease, gastroesophageal reflux disease, as well as helicobacter pylori infections. While these have fallen out of favour in favour of the more potent protein pump inhibitors, they have found a very important vital role in the management of COVID-19 and Post-COVID Syndrome.

Brennan et al (272) reported in 2022 that using 80mg three times daily (240 mg/day) Famotidine was found to be safe and well-tolerated, reducing symptoms by 50% after 8 days. They also showed that H2 blockade provided early recovery from elevated interferon alpha, presumably by modulating inflammation in organ tissues.

Malone et al(8) propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.(8)

Mukherjee et al (78) demonstrated “while famotidine has no direct effect on viral replication or viral protease activity it inhibits histamine-induced expression of Toll-like receptor (TLR3) in COVID-19 and reduces TLR3 dependent signalling processes leading to activation of Interferon Regulating Factor 3 (IRF3) and the NF-kB pathway, subsequently controlling antiviral and inflammatory responses.”

SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19.(78) Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19.

Famotidine reduces the risk of intubation and death in hospitalized COVID-19 patients. It has also been suggested to reduce respiratory symptoms in non-hospitalized patients. In combination with a H1-receptor antagonist, it has been shown to reduce pulmonary distress in hospitalized COVID-19 patients. These studies confirmed that famotidine has a beneficial role in managing COVID-19 disease symptoms.(78)

Mukherjee et al described the histamine H2 receptor targeted by famotidine is not limited to the stomach, but is also found in the brain, the endocrine and exocrine glands, the pulmonary system, and the cardiovascular system. H2 receptors are also present on mast cells, which are deregulated in viral infections including those caused by coronaviruses. Studies show that famotidine (unlike cimetidine) reaches systemic concentrations that are sufficient to antagonize H2 receptors on other cell types such as those on mast cells and neutrophils.(78)

Long COVID Management

Management can be very complex, depending on the symptoms. Some problems eg fatigue, shortness of breath, chest pain are obvious, but others are more subtle. Unfortunately even mild infections can cause significant risks, especially in the obese, diabetics, those over 65. The increased cardiovascular risk is present long after the initial infection.

Critical points in management is identification of “risk” factors, and detailed histories and family histories are needed, especially if there is a poor response to H1 and H2 blockade. The Long COVID with POTS-like symptoms will have a history that will lead to areas that will need to be managed, eg IBS, Ehlers-Danloss Syndrome, loss of cervical lordosis, migraine, thoracic outlet syndrome, Nutcracker and pelvic congestion syndromes. These “drivers” may be from the gut, or mechanical commonly affecting the sympathetic chain or vagus, and their identification allows a targeted program which includes management of MCAS to be prepared for each POTS or Long-Covid patient.

Pulmonary complications:

Respiratory symptoms can be embolic, inflammatory, and these are often hard to distinguish from each other, especially when the emboli are microscopic so may not be seen in the CTPa scan used to look for pulmonary emboli. COVID can cause fibrosis in the lungs as well as heart, inflammatory pneumonitis and pneumonia-like changes. CTs of lungs look for “ground glass changes.” The corticosteroid inhalers are often very helpful. Sometimes oral corticosteroids are needed. Fluid build up (effusions) may need drainage. CT angiography changes representing pulmonary emboli require blood thinners, most effectively Clexane as it does appear to contain the fibrin clots that contain amyloid, giving an opportunity to wind back the inflammatory changes with things like histamine blockade. The amyloid may cause changes that are similar to amyloidosis, and checked with D-Dimer and Se ACE.

Bubble EPAP (positive expiratory airways pressure) is a device to assist recovery: it enables alveoli or bronchioles that may have collapsed (atelectasis) to be forced to open up by the extra air pressure when blowing out against the pressure of water via a tube that ends below the water level. This reduces the ventilation/perfusion mismatch in the affected lungs. This improves the ability of the lungs to exchange oxygen and carbon dioxide and decreases the work of breathing. Surfactant in the alveoli lowers surface tension and helps alveoli from collapsing. Atelectasis is a known trigger for pulmonary fibrosis, where the affected lungs are permanently scarred.

The following sites provide information on breathing techniques to aid respiratory recovery: devices are available commercially eg Therabubble, or can be made as a home made device. Suggestions provided by an affected physician advises that Bubble EPAP may theoretically be more beneficial than AirPhysio for treating post_COVID atelectasis, starting Bubble EPAP at around 10 to 12 cm pressure, then raised or lowered as required. The advice is also that AirPhysio may be better for clearing mucous than recruiting atelectic alveoli. The Breathwork program is in use at Mt Sinai Hospital in their Long Covid Clinic.

1. https://www.mountsinai.org/health-library/selfcare-instructions/how-to-breathe-when-you-are-short-of-breath

2. https://www.stasis.life/

3. https://therabubble.com.au/#

4. https://airphysioaustralia.com.au/

Cardiovascular complications:

Cardiovascular changes include myocarditis, pericarditis, tachycardia (inflammatory effect on the autonomic nervous system that may cause POTS, where heart rate increases by 30 from lying to standing, and frequently shortness of breath and syncope (fainting.) We utilize echocardiograms, holter monitors and ECGs (lying and standing) as important tools, along with checking the inflammatory, mast cell response and other levels (including HS-CRP measuring IL-6, Se ACE, and Se Tryptase which measures mast cell response.)

As the research into POTS “drivers” following the activating of the syndrome through Mast Cell Activation continues, it is identification of the ongoing “drivers” that provides the best likely long term solutions. A genetic predisposition is unquestionable seen both in family clusters and the simple fact that most people who have the recognized “drivers” that have been found simply have no symptoms.

Deconditioning

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. In many POTS patients, reconditioning programs can lead to improvement, but rarely to complete resolution of symptoms, and the same has been found in post-COVID syndrome. (29)

Fatigue

Fatigue, while usually from the mitochondrial dysfunction/ oxidative stress, it can also be part of the secondary effects of the cytokine storm. Areas that must be considered in management:

• Mitochondrial dysfunction /oxidative stress/metabolic damage. ( DNA testing with Dr Valerio Vittone can provide clarity on mitochondrial and inflammatory deleterious bad gene variants that are critical to Mitochondrial dysfunction and the exaggerated immune response caused by COVID

• Reactivation of EBV and similar viruses

• Metabolic changes eg phosphatidycholine and phosphatidylserine

• Direct cardiac damage (eg pericarditis, myocarditis)

• Pulmonary damage- embolic, inflammatory

• Small fibre neuropathy inflammatory and very common (again IL-6 and TNFa). -accompanying exaggerated neuropathy, rheumatoid arthritis, reactive arthritis, PMR strongly suggestive of TLR4 mutations

• Autonomic instability- “POTS” symptoms

• Impaired cardiac function

• Microglial damage in brain -link to Glymphatic research at Griffith Uni

Monitoring Long COVID

Many of the tests are just above normal and hard traditionally to interpret in the Post-acute phase. When the D-Dimer, which gives a good idea of the clotting situation is abnormal, consideration is needed for a CTPa scan. A lung function test is used to differentiate those with serious damage, and those with minor that we can observe, while turning off the COVID inflammation.

Ketso describes: "D-Dimer is a product of clot breakdown, released upon degradation of polymerized, cross-linked fibrin. Elevated plasma D-Dimer levels indicate that coagulation has been formed and clot degradation has occurred. There are many causes of elevated D-Dimer; identification of the underlying cause requires correlation with other findings."

Causes include:

• Thromboembolism- arterial, venous and Disseminated Intravascular Coagulopathy

• Inflammation eg COVID, sepsis and other severe infections, through activation of the acute inflammatory response and coagulation pathway

• Surgery and trauma through tissue ischaemia and necrosis

• Liver disease, with reduced clearance of fibrin degradation products

• Kidney disease, through multiple causes including renal vein thrombosis and nephrotic syndrome

• Vascular malformations (and sickle cell disease vaso-occlusion)- Intravascular thrombosis and fibrinolysis

• Malignancy- multiple causes including microvascular thrombosis

• Thrombolytic therapy

• Normal pregnancy - Physiologic changes in coagulation system

• Pre-eclampsia and eclampsia- Microvascular thrombosis and fibrin deposition.

Source: Kelso, J.(Ed): COVID-19: Allergic reactions to SARS-CoV-2 vaccines. 2021. https://www.uptodate.com/contents/covid-19-allergic-reactions-to-sars-cov-2-vaccines?

Monitoring progress in Long-COVID is difficult, given limitations of using D-Dimer (with High-sensitivity CRP with FBC and routine biochemistry and other markers discussed below. Many of the tests are just above normal and hard traditionally to interpret in the Post-acute phase. When the D-Dimer, which gives what appears to be reasonable idea of the clotting situation is abnormal, consideration is needed for a CTPa scan. These are frequently normal, reflecting microembolic cascades rather than the large pulmonary emboli. A VQ Scan will sometimes show perfusion abnormalities more reflective of the microembolic cascade. A lung function test is used to differentiate those with serious damage, and those with minor that we can observe, while turning off the COVID inflammation.

Although Sakr et al (165) believe D-dimer levels may not be a reliable predictor of VTE but rather a marker of poor overall outcome, it appears to provide one of the few biomarkers to watch progression of the syndrome. Leonard-Lorant et al.(179) showed that D-dimer greater than 2660 μg/L is highly sensitive but not specific measure to detect PE in COVID-19 patients. In their opinion, routine screening for VTE based on elevated D-dimer levels was not recommended (180) in the most recent guidelines of the ISTH.(165) The guidelines have simply not been able to develop to a level where accuracy can be guaranteed, so it takes clinical assessments as well as using assays that may be considered non-standard.

In his editorial in Frontiers in Pharmacology, “Cytokine Release Syndrome in COVID-19: Mechanisms and Management,” Tao Hue(204) discussed IL-8 as a “biomarker and prognostic factor in modulating the hyper-inflammatory state in acute respiratory distress syndrome (ARDS). IL-8 showed remarkable increases in the blood, the bronchoalveolar lavage fluid, and the lungs of COVID-19 patients, and exhibited a notable compartmentalized response within the lungs, consistent with its well-established role in the recruitment of neutrophils to the lungs during acute pulmonary inflammation respiratory distress syndrome associated with SARS-CoV-2 infection.”(204)

Details of the investigations employed at this clinic are detailed in https://www.mcmc-research.com/post/long-covid-part-10-the-protocol

RACGP Recommended Management Guidelines(182) “The most common scenario: Non-specific multisystem post-viral symptoms

Common symptoms include:

• fatigue

• dyspnoea

• joint pain

• chest pain

• cough

• change in sense of smell or taste

• cognitive disturbances

• hoarse voice

Less common symptoms include:

• insomnia

• low-grade fevers

• headaches

• neurocognitive difficulties

• myalgia and weakness

• gastrointestinal symptoms

• rash

• depression”

The guidelines describe “Management of these presentations will usually be pragmatic and symptomatic. Management should be guided by the patient’s specific clinical circumstances and be evidence based. Specialist referral should be undertaken, as required.

• Support your patient to maximise their personal wellbeing through diet, exercise and sleep.

• Consider and exclude serious complications and possible alternative causes of ongoing symptoms, such as anaemia.

• Investigate new or worsening symptoms that could indicate delayed sequelae, such as venous thromboembolism (VTE), cardiac complications or pneumonia.

• Where possible, optimise the management of the patient’s other chronic conditions.

• Identify other social factors that could intersect with their personal health and wellbeing, including smoking, alcohol intake, drug use, risk of mental health issues, risk of family and intimate partner violence, and risk of social isolation.

• Consider current recommendations for management of specific symptoms

Breathlessness:

• Optimise management of pre-existing respiratory conditions

• Recommend respiratory muscle conditioning (pulmonary rehabilitation)

• Consider chest X-ray at 12 weeks for patients who have had significant respiratory illness

• Corticosteroids could be considered for inflammatory lung disease on the advice of a respiratory physician

• Recommend gradual commencement or return to symptom-limited exercise guided by tertiary-trained exercise professionals

• Referral to a speech pathologist for management of chronic cough, hoarse voice or dysphagia

• Consider home pulse oximetry measurement

• Referral to an Accredited Practising Dietitian if symptoms interfere with nutrition, and speech pathology if dysphagia is present

Fatigue:

• Maximise self-care, sleep, relaxation and nutrition

• Recommend that patients pace and be selective when prioritising daily activities

• Recommend caution with return to exercise (reduce if there is any increase in symptoms)

• A monitored return to exercise can be supported by an exercise physiology, physiotherapy or rehabilitation referral

• If fatigue is causing difficulty with activities of daily living (ADLs), recommend energy conservation techniques and home visits by an occupational therapist or rehabilitation service

Chest pain:

• Exclude acute coronary syndrome, myocarditis, pericarditis, pulmonary effusion or pulmonary embolism, and arrhythmia

• Provide education regarding symptoms of concern

• Patients who have had myocarditis or pericarditis as a component of their acute illness should abstain from vigorous exercise for 3–6 months, and athletes should have cardiology supervision for return to training

• Refer for graded increase in low-to-moderate activity to increase mobility, exercise capacity and quality of life; this should be facilitated by a physiotherapist or exercise physiologist, or cardiac rehabilitation program

Headaches, low-grade fevers and myalgia:

• Exclude COVID-19 reinfection or recrudescence

• Prescribe simple supportive measures and analgesia or antipyretics, as needed

• Check for secondary infections and prescribe antibiotics, as appropriate

Neurocognitive difficulty:

• Provide supportive management

• If severe enough to cause difficulty with ADLs, consider cognitive testing, occupational therapy support and speech pathology support for cognitive communication impairment

Depression/anxiety:

• Provide information about post–COVID-19 recovery

• Use existing standardised screening tools

• Address multifactorial contributors that might require assistance with pain management, independence with ADLs, financial and other social supports, and loneliness

• Facilitate access to mental health services or online support if patient is unwilling to access face-to-face counselling

• Encourage individualised moderate-intensity exercise initiated and supervised by a tertiary trained exercise professional

• Refer to an Accredited Practising Dietitian for nutrition support and access to food services

Thrombosis risk and contraceptive choice:

• COVID-19 causes a hypercoagulable state in some people, which might worsen the VTE risk associated with combined hormonal contraception. The incidence of VTE in biological females of reproductive age with COVID-19 infection is currently not known

• Patients should be advised of this risk to allow informed choice of contraceptive option

• For biological females who have had mild or moderate COVID-19 and stopped oral menopausal hormone therapy, also known as hormone replacement therapy, if recommencing, consider using a transdermal preparation

• For biological females who have had COVID-19 and who are taking oestrogen-containing contraception, manage these medications as per usual care

• For biological females who have stopped or suspended contraception when they have contracted COVID-19, contraception can be restarted when acute symptoms have resolved(182)”

Traditional management of POTS

Traditional management, while sound and proven, unfortunately is limited in its effectiveness as it is based on symptom-management.

1. Established conservative/lifestyle measures

• ·Avoid situations that can exacerbate symptoms

• Large heavy meals

• Alcohol intake

• Heat exposure

• Liberal intake of salt and water

• Sleep with head of bed elevated—bed head raised 10 cm

• Use of compression garments

• Hose to top of abdomen

• Abdominal binder

• Physical counter manoeuvres

• Leg crossing

• Squatting

• Drinking water before getting up in the morning

• Strategies to avoid upright exercise

• Seated rower

• Swimming

• Recumbent bike

2. Established therapeutics

• Fludrocortisone (mineralocorticoid/aldosterone analogue- 100- 200 mcg mane

• Midodrine (a1 agonist)- 2.5 to 10 mg tds

• b blockers in hyperadrenergic state (metoprolol or propranolol)

• Pyridostigmine (acetylcholinesterase inhibitor – cholinergic agonist)- 30- 60 mg tds

• Clonidine (central sympatholytic)- useful in hyperadrenergic POTS or hypertensive response- 100 mcg twice daily

• Ivabradine (IST and POTS)- 2.5- 10 mg bd

Management based on current research at Mermaid Beach for Long Covid POTS patients- detailed in Part 10 MCMC Management Protocol

Our work supports a general approach that leads to individualised solutions:

• Control the inflammatory and microembolic cascade if present

• Control the sensitisation that separates these patients from other people with similar mechanical issues. Initial management with mast cell blockade or TLR4 modulation depending on history

• Control the immune, inflammatory, and dysautonomic responses (Kiiko acupuncture invaluable).

• Identify and (if possible) address the underlying mechanical problems that we have found present in all Long COVID patients with POTS.

• Improve mitochondrial functioning (eg low histamine diet and NMN/ NAD+)

• Encourage DNA testing if not responding to identify individual metabolic pathway abnormalities

Initial management involves a detailed history from birth, as well as detailed family history to provide the clues for treatment and appropriate investigations undertaken. This looks for where the mast-cell activation started, what activated the POTS, the origin of the sensitisation, and what drives the POTS. Past history and family history are very important.

Then, a management plan is started. So far, most of the patients with long COVID have a pattern of previous injury or minor symptomatology that is similar to that in other POTS patients.

POTS and Long COVID are very similar. DNA may be recommended. Dr Valerio Vittone (39) has decoded the DNA pathways in POTS and this does appear to be the same in Long Covid. His nutritional advice based on history, and supplemented by DNA provides a valuable tool in dealing with the various problems.

As studies unlock the association of COVID-19 with POTS the research take us closer to the causes and treatment of POTS. It will aid the linking of the various research pathways, looking at cause, rather than the current approach of pharmacological intervention that will provide the ability to treat POTS.

It seems most likely that it is the sensitization of the ANS especially the sympathetic chain by mast cell activation (from multiple possible sources) and cytokine storm that underpins the autonomic instability of POTS and its co-morbidities, especially fibromyalgia, which is known to be IL-6 and IL-8 generated glial cell hypersensitivity. (49)

As the research into POTS “drivers” following the activating of the syndrome through Mast Cell Activation continues, it is identification of the ongoing “drivers” that provides the best likely long term solutions. A genetic predisposition is unquestionable seen both in family clusters and the simple fact that most people who have the recognized “drivers” that have been found simply have no symptoms.

These “drivers” may be from the gut, or mechanical commonly affecting the sympathetic chain or vagus, and their identification allows a targeted program which includes management of MCAS to be prepared for each POTS or Long-Covid patient.

Ultimately, our approach is simple: work out the drivers (especially in the spine and vascular compression), sort out dietary triggers; look at lifestyle, posture, occupational causes, commence mast cell blockade, supplement where necessary, and heal what has been damaged, if this is possible. Dr Vittone can provide the DNA/artificial intelligence assessment for each patient, providing the way to treat the affected metabolic pathways. DNA assessment is very helpful in the complex patients that appear to fail to management plans, This is particularly so in Long COVID.

Specific Management

A good starting point can be to add H1 and H2 blockade as soon as Tryptase (and sometimes Chromogranin in hyperadrenergic states) have been checked. Ideally heart rate variability assessed (a number of commercially available Holter monitors have this facility, or smart phone applications.) As described by Afrin, “normal” are incorrect. To reduce the histamine response and sensitization, we are using H1 blockade with fexofenadine or cetirizine (occasionally others) along with dietary change as a first-line treatment. Ketotifen is useful when QT prolongation is present.

Famotidine (H2 blockade) is then rapidly added, especially if there is any sign of continuing COVID activity in the long-COVID POTS patients. Even is apparent “past” infections, if symptoms of eg fatigue persist, blockade is usually very helpful, often in only a few weeks. Doses used usually are twice daily. To be effective, famotidine may need to be increased to 160mg daily, with patient acknowledgement that these are research-based doses and greater than recommended doses. There is a group of patients who are intolerant of this management. DNA profiling is likely to be needed in them.

The research from Professors Marshall-Gradisnik and Smith’s team from Griffith University discovered mutations in an important TRP pathway (TRPM3 ion channel dysfunction)(181) found Low Dose Naltrexone (LDN) of great assistance, and as it improves glymphatic function the various research pathways start to merge. APO E4 , PEMT and similar potentially neurodegenerative disease mutations mutation appears to be a significant addition to risk.

Low dose naltrexone needs to be started at low dose, and increased slowly. Our starting dose is usually 0.5 mg daily in a compounded form, increasing weekly. We usually use 4 .5 mg daily as maximum dose, but benefits usually occur around 2 to 3 mg.

The combination of histamine blockade, attention to diet usually improves patients’ well-being, the acupuncture can be added to control the autonomic instability, then the vascular and mechanical drivers need to be attended to.

Many POTS patients are easily fatigued while sitting at a computer, or reading on their phones, or driving and may even suffer panic attacks while driving. The role of the spine is obvious after whiplash or other spinal injury; but spinal problems can be occupational (e.g., in hairdressers, dentists, and nurses, who work with a rotated spine). This problem is likely to become more common, as people become more dependent on their computers and tablets without attending to their posture.

Shoulder pain is just so common. Often, it is not improved or is even made worse by normal shoulder treatments. Yet as one retraces the history of the injuries, there is often a thread implicating an injury to the thoracic outlet rather than to the shoulder itself. But as the rotator cuff wears anyway, the patient ends up as a diagnosis of rotator cuff syndrome or subacromial bursitis, as scans show worn rotator cuffs. Thus, the real problem is missed, and the patient’s treatment fails. An easy clue to TOS is the frozen shoulder, which appears to be a localised autonomic response, although there is no objective proof.

Cytokine-induced central sensitisation is the key to understanding why patients with POTS and long COVID are so ill whereas many people with similar mechanical issues (e.g., TOS) have few if any symptoms. Once the cytokine-induced sensitisation is controlled, symptom control may be seemingly simple (e.g., correction of posture during computer use, avoidance of the use of backpacks, correction of rotated thoracic spine or sustained neck flexion, especially at an angle affecting C2/3 that triggers a cascade of symptoms which are quite difficult to explain). Misguided physiotherapy and manipulation are common problems here.

We try to “turn off” the sensitisation before adding “Kiiko Matsumoto” acupuncture (which targets the ANS, to stabilise the autonomic instability) and appropriate physiotherapy to deal with the mechanical factors that can be corrected.

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. Deconditioning alone, however, does not explain the many other symptoms present in POTS, including cognitive impairment, gastrointestinal upset, sleep disturbances, and neuropathic pain. In many POTS patients, reconditioning programmes can lead to improvement, but they rarely lead to complete resolution of symptoms. The same has been found in post-COVID syndrome.(51)

Addressing the patient’s deconditioning is a major part of managing POTS, regardless of the cause of the POTS, and usually requires a skilled exercise physiologist or physiotherapist. Experience has shown the older concepts of pushing exercise even though it increases symptoms is counterproductive. The programme must be tailored for each patient and must be graded very slowly.

So many POTS patients have migraine frequently with PFO’s. The brain MRI brain is so important for spotting hyperintensities that can reflect microembolic damage resulting from microemboli passing into the cerebral circulation via the PFO. The initial assessment is with a Trans-Cranial Doppler Bubble Test but confirmation of the PFO usually requires transoesophageal echocardiography. Standard echocardiography seldom see these although clues such as left atrial dilatation may be present. POTS patients usually have improved significantly after closure of the PFO,(11) so if closure doesn’t control symptoms it requires a more detailed look for possible causes.

Patients with arterial Thoracic Outlet Syndrome (TOS) we believe should be referred to vascular surgeons for assessment—for formal MRI angiography and other imaging and possible surgery. Patients with venous and neurogenic TOS generally go to our physiotherapists for assessment. Our programme is evolving, as there is no one-size-fits-all. Diagnosis is difficult in patients with EDS, hypermobility, C0/1/2/3/4 neck trauma, or other spine injuries, especially in the sacrococcygeal area. Kjetil Larsen’s advice (3) about musculoskeletal management has, and is continuing to help in the development of our programme.

Management of the Intra-abdominal compression syndrome is complex and difficult. Symptoms are often quite pronounced, just as they are in electrophysiology studies. Surgeons appear interested only in the direct vascular compression, ignoring the autonomic pathways that are also affected. Coeliac plexus blocks may be useful, and their possible use as a diagnostic tool and management protocol is being explored, although finding specialists interested in exploring this has been very challenging.

The typical Median Arcuate Ligament Syndrome (MALS) patient is a thin hypermobile person usually diagnosed with an eating disorder. These patients often vomit after eating and are often in pain, sometimes just from bending forward. So when the diagnosis of MALS is confirmed, it questions the credibility of the eating disorder diagnosis, especially if the patient has suffered from this problem for an extended period.(18) Our latest studies combining EP with radiology implicates direct compression of the sympathetic and parasympathetic pathways in the compression area. Many of these patients respond well to psoas treatment by skilled therapists.

An interesting paper by Weber et al (273) in MALS showed the usefulness of a simple yoga exercise “Upward Dog” in reducing symptoms. This is described in: https://www.mcmc-research.com/post/median-arcuate-ligament-syndrome This may be of major importance, especially where patients were asymptomatic before having COVID, and all we need is reduction of symptoms until the autonomic instability can be overcome.

Pelvic congestion, usually from nutcracker variants, is often treatable, and there seems to be 2 components in symptoms: likely the direct nerve compression around the SMA/renal vein where the renal vein compression is, but also the vagal effect from the venous congestion affecting the pelvic plexuses.

Mitochondrial repair

Diet change can produce major improvement in symptoms, especially pain and fatigue. While criticized by many dieticians, the change to a low histamine ketogenic diet has sound scientific research backing. Ketosis yields ATP through the catabolism of ketone bodies. During ketosis, ketone bodies undergo catabolism to produce energy, generating twenty-two ATP molecules and two GTP molecules per acetoacetate molecule that becomes oxidized in the mitochondria.(80)

Ana Belén Crujeiras, from the Health Research Instituteof Santiago de Compostela-Galician Health Service (IDIS-SERGAS) Group of Epigenomics in Endocrinology and Nutrition and the Biomedical Research Networking Center for Obesityand Nutrition Physiopathology (CIBEROBN) commented, "Nutritional ketosis has gained great interest in recent years because it is shown to have beneficial properties for health and promotes healthy aging, increasing longevity. Furthermore, in the case of obesity, we have more and more evidence that it is an effective treatment, mainly because to achieve this metabolic state (ketosis), routes that require the combustion of fats are activated, and this induces body weight loss."(62)

Nicotinamide mononucleotide (NMN) is a molecule naturally occurring in all life forms. At the molecular level, it is a ribo-nucleotide, which is a basic structural unit of the nucleic acid RNA. NMN is the direct precursor of the essential molecule nicotinamide adenine dinucleotide (NAD+) which is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, and cell growth.(240)

NAD+ is an essential coenzyme required for life and cellular functions. Enzymes are catalysts that make biochemical reactions possible. Coenzymes are ‘helper’ molecules that enzymes need in order to function. NAD+ is the most abundant molecule in the body besides water, and without it, an organism would die. NAD+ is used by many proteins throughout the body, such as the sirtuins, which repair damaged DNA. It is also important for mitochondria, which are the powerhouses of the cell and generate the chemical energy that our bodies use. (240)

NAD+ plays an especially active role in metabolic processes, such as glycolysis, the TCA Cycle (AKA Krebs Cycle or Citric Acid cycle), and the electron transport chain, which occurs in our mitochondria and is how we obtain cellular energy. (240)

In its role as a ligand, NAD+ binds to enzymes and transfers electrons between molecules. Electrons are the atomic basis for cellular energy and by transferring them from one molecule to the next, NAD+ acts through a cellular mechanism similar to recharging a battery. A battery is depleted when electrons are expended to provide energy. Those electrons can’t return to their starting point without a boost. In cells, NAD+ serves as that booster. In this way, NAD+ can decrease or increase enzyme activity, gene expression, and cell signalling. (240)

NAD+ Helps Control DNA Damage

As organisms grow older, they accrue DNA damage due to environmental factors such as radiation, pollution, and imprecise DNA replication. According to the current aging theory, the accumulation of DNA damage is the main cause of aging. Almost all cells contain the ‘molecular machinery’ to repair this damage. This machinery consumes NAD+ and energy molecules. Therefore, excessive DNA damage can drain valuable cellular resources. (240)

One important DNA repair protein, PARP (Poly (ADP-ribose) polymerase), depends on NAD+ to function. Older people have decreased levels of NAD+. The accumulation of DNA damage as a result of the normal aging process leads to increased PARP, which causes decreased NAD+ concentration. This depletion is exacerbated by any further DNA damage in the mitochondria. (240)

Enhances Maintenance of DNA Repair- PARP1 is ‘Middleman’ of DNA Repair

The NAD+ made from NMN activates a group of proteins called sirtuins. Sirtuins are a family of enzymes, participating in cellular stress responses and damage repair, and play a key role in maintaining DNA integrity, which is constantly being bombarded by DNA altering substances (mutagens) like UV radiation. The sirtuins play a vital role in maintaining cellular health. They’re also involved in insulin secretion, and the aging processes and aging-related health conditions, such as neurodegenerative diseases and diabetes. The activation of sirtuins requires NAD+. (240)

Telomere Repair

Each time our cells divide, the DNA at the very ends of our chromosomes, the telomeres grows a tiny bit shorter. At a certain point, this begins to damage our genes. Sirtuins slow this process by stabilizing these. As David Sinclair, a Harvard geneticist and NAD researcher says we lose NAD+ as we age “and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.” He believes that increasing NAD+ levels naturally while aging may slow or reverse certain aging processes. (240)

The cell uses up NAD+ during the fight against COVID-19, weakening our body, according to a recent study that has not been peer-reviewed. NAD+ is essential for innate immune defence against viruses. The researchers of the study are trying to assess whether NAD+ boosters can help humans beat the pandemic. (240)

Improved Mitochondrial Function

Mitochondria are the powerhouses of the cell, and are critical for metabolism, converting molecules from the food we eat into the energy that our cells use. (240)

The chronic fatigue that is rampant in our society is largely caused by mitochondrial dysfunction from a wide variety of causes. The ongoing research in COVID-19 has confirmed the virus causing mitochondrial dysfunction as one of the primary causes of the fatigue in Long Covid.

At the very core of metabolism is NAD+. Without NAD+, mitochondria cannot metabolize and cells will be left without energy, resulting in their death. In fact, mitochondrial anomalies caused by the loss of NAD+ may even impact degenerative neurological disorders eg Alzheimers disease.(244)

NAD+ Levels and Immune Function Drop With Age

Many aspects of immunity decline with age, and NK (Natural Killer Cells) immune cell function is no exception to this phenomenon. The age-related deterioration of immune function with age is linked to levels of nicotinamide adenine dinucleotide (NAD+), which also declines with age. Boosting NAD+ levels has been shown to improve immune function in mice. (240)

The NAD+ precursor NMN helps with age-related disorders like insulin insensitivity and metabolic impairments like obesity in aged mice. Also, since boosting NAD+ levels have been shown to work against tumours in mice, it may also potentially enhance anti-tumour NK cell activity. Figuring out whether NMN has these immunity-restoring effects in NK cells is critical for determining if it is the compound we’ve been looking for to restore their cytotoxicity. (240)

Weiss (238) found NMN increases natural killer cell capabilities to destroy cancer cells (cytotoxicity) without increasing immune cell numbers. This study supports that taking NMN may be a way to rejuvenate natural killer immune cell activation to preserve tissue health during aging.(238)

Studies show that boosting NAD+ levels can extend life span in yeast, worms and mice and improving several aspects of health. Raising levels of the molecule in old mice appears to rejuvenate mitochondria —the cell’s energy factories, which falter over time. Other mouse studies have demonstrated benefits such as improved cardiovascular function, enhanced muscle regeneration and better glucose metabolism with NAD+ supplementation.(240)

A study released in 2023 by Bramante, Buse, Liebovitz, et al (300) showed that Metformin (Diabex) lowers the risk of getting Covid by 40%, and if this was started less than 4 days after Covid symptoms started, the risk of Long Covid was decreased by 63%. Metformin (Diabex) activates AMPK , a central regulator of energy homeostasis, acts as a signal integration platform to maintain mitochondrial health. Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. AMP-activated protein kinase (AMPK) is a highly conserved sensor of low intracellular ATP levels that is rapidly activated after nearly all mitochondrial stresses, even those that do not disrupt the mitochondrial membrane potential.(301)

Figure 2: Regulation and Function of AMPK in Physiology and Diseases

Metabolic functions of AMPK. A schematic summarizing the mechanisms underlying AMPK-induced regulation of diverse metabolic pathways. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).(302)

Source: Jeon, SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48, e245 (2016). https://doi.org/10.1038/emm.2016.81 (302)

More details regarding the POTS management can be found in: https://www.mcmc-research.com/post/postural-orthostatic-tachycardia-syndrome-pots and https://www.mcmc-research.com/post/pots-part-2