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  • Writer's pictureGraham Exelby

Long Covid Part 10: MCMC Management Protocol

Revised June 2023


This protocol has been developed at our clinic at Mermaid Beach. It is designed to be used in association with normal guidelines as described in “RACGP. Caring for patients with post-COVID-19 conditions. 2021”(182) . This has evolved over 10 years of research into POTS and now the association with Long COVID. It is not a replacement for evidence-based management. It does not support using the listed tests as screening, but suggestions that may be useful in individual management.

Covid enters the body via ACE2 receptors- triggers the cytokine storm after activation of the mast cells by Toll-Like Receptors, releasing cytokines, which are small proteins involved in cell signalling, as well as other inflammatory products, in particular Interleukins 6 and 8 (or IL-6 and IL-8) and Tissue Necrosis Factor alpha (or TNF). The inflammatory response can lead to lung oedema, fibrosis, inflammation that affects heart, kidneys, liver, brain etc etc, and microthromboses.

Mukherjee et(78) al found these emboli are a result of histamine receptor 1 (H1) induced fibrinogen.(78) Increased TLR expression and TLR-mediated platelet activation during COVID -19 appears to enhance vascular and coronary thrombosis.(75)

The most common brain pathology found post-mortem has been cytokine activation of microglial cells and damage by microclots, which are themselves a result of inflammatory or cytokine changes in our blood and can be found in almost any affected organ. Complicating this has been the incorporation of amyloid in some of these clots by virtue of the intensity of the inflammatory reaction in some people- amyloid better known for its association with Alzheimers disease- and makes these clots resistant to clot lysis.

Microglia account for 10% to 15% of all cells found within the brain, and as the resident macrophage cells, they act as the first and main form of active immune defence in the CNS. 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.

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 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.(109)

The neuroinflammatory response “sensitises” the glial cells with consequent small-fibre neuropathy and from this small fibre neuropathy it is believed comes the characteristic autonomic chaos that is POTS and POTS-like Long Covid, and this includes random symptoms such as the eye pain in Covid, and the anosmia.(191)(192)

The various neurodegenerative mutations involved in Long Covid by and large have no biomarkers to measure the level of danger. Persistent inflammation can destroy brain cells. Combining MRI brain with brain SPECT scan reveals whether the impaired patient has inflammatory (hyperperfusion) or damage (hypoperfusion).

SARS-CoV-2 (is a similar way to EBV, CMV, and other viruses) affects the mitochondria, causing mitochondrial dysfunction. Mitochondria are the powerhouses of our cells and are vital to maintaining the health and even survival of cells and play a key role in maintaining homeostasis and cell-mediated immunity.

From this the PACS/ Long Covid patients have chronic fatigue, aggravated by:

  • Direct cardiac damage (eg pericarditis, myocarditis)

  • Pulmonary damage

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

  • Autonomic instability- “POTS” symptoms

  • Impaired cardiac function

  • Reactivation of EBV and similar viruses

  • Metabolic damage eg to phosphatidylserine and phosphatidylcholine pathways

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

Around 30% to 45% of patients continue to report an array of persistent symptoms after infection, with recent studies confirming these changes up to 2 years and ongoing in roughly 1 in 8. Commonly reported symptoms range from fatigue and dyspnoea to “brain fog” with ongoing disability and disruption of work, social, and home lives.

Long Covid is not one condition. Canas et al at King’s College UK (110)(111) identified distinct profiles of symptoms for post-COVID syndrome within and across variants. They found that people with symptoms for 12 weeks or more fell into three main groups based on the types of symptoms they were experiencing.

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

  2. 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.

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

Major Points

  1. Long Covid is not one condition.

  2. The Covid infection may continue to be active /reactive months after contact (sustained inflammation for at least 8 months, esp if unvaccinated

  3. It is a microembolic and inflammatory disease that may also add amyloid to fibrin with increased risk Alzheimers, Parkinsons, neurodegenerative disorder in infants

  4. Microemboli is thought to be the result of histamine receptor 1 (H1) induced fibrinogen. (78) Increased TLR expression and TLR-mediated platelet activation during COVID -19 appears to enhance vascular and coronary thrombosis

  5. Rauchet al(249) found phosphatidylserine was associated with increased thrombo-inflammation and vascular complications, and increasingly PEMT and similar DNA mutations may be relevant in persisting elevated D-Dimer. PEMT mutations are also associated with persisting fatigue. There are no biomarkers for PEMT, and persisting D Dimer elevation should be offered DNA from Dr Vittone. Nigella sativa as an anti-thrombotic agent should be considered on top of the H1/H2 blockade and TLR4 modulation

  6. Microglial activation 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.

  7. Cytokine-induced central sensitisation (inflammatory activation of glial/microglial cells and neuropathic inflammation) is the key driver of the autonomic and inflammatory instability in POTS and the POTS-type of PACS patients. People with cancer are at a higher risk if they contract COVID.

  8. 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.

  9. The TLR4 mutations may explain the effectiveness of Low Dose Naltrexone in chronic fatigue and cognitive impairment. LDN is both a TLR4 modulator and mast cell stabilizer.

  10. 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.

  11. Covid may reactivate earlier problems eg EBV, shingles, HSV and stay in cell nuclei

  12. It appears to be co-related with aggressive malignancy (thought to be Interferon 1 and NK cell dysfunction) -no formal data as yet available, but recent DNA studies from Dr Vittone confirm The increased malignancy rate following Covid-related disease is still not formally published. It can however be seen through the DNA pathways already uncovered- eg TLR4/ RAGE/STAT3 and TLR4/COMT. The direct effect of Covid on natural Killer cells (NK cells) looks also to be critical as this cell’s function is vital in controlling malignancy.

  13. There is a poor prognosis in obesity, diabetes, hypertension, and atherosclerosis

  14. Increased cardiovascular or cerebrovascular event in next 12 months

  15. There is an increased risk of dementia in over 65’s of 50 to 80%

  16. High incidence new diabetes -around 30%

  17. All the POTS-type PACS patients have underlying conditions eg TOS/ neck pathology/ MALS/ Nutcracker. You can't just supplement your way out of POTS/Long Covid.

  18. All Long Covid POTS have impaired cerebral blood flow and brainstem hypoperfusion with tilt/NASA Lean testing

Common problems in Long COVID:

  • Fatigue, brain fog and shortness of breath

  • Over 65- 60+% increased cardiovascular or cerebrovascular event in next 12 months, and around 50 to 80% increased risk of dementia

  • Change in microbiome

  • High incidence diabetes

  • Increased incidence of autoimmune disease

  • Neural sensitisation with autonomic dysfunction, triggering multiple problems including Postural Orthostatic Tachycardia Syndrome (POTS.) Over 70% of Long-COVID have cardiovascular autonomic disorder, 30% of these with POTS (Postural Orthostatic Tachycardia Syndrome)(271). Other researchers have found POTS to be associated with impaired middle cerebral artery flow and brainstem hypoperfusion in SPECT scans when challenged in NASA Lean Testing.

Red Flags:

  • Unresponsive to mast cell blockade + TLR4 modulation after 4 weeks

  • New, increasing or severe shortness of breath

  • Arrhythmias

  • Unexplained chest pain

  • Syncope

  • Confusion

  • New neurological symptoms

  • Increasing/ non-resolving elevated D-Dimer levels


1. Biomarkers utilized at this clinic:

Pathology which could be utilized depending on symptoms. This is not a screening profile, but a list of tests commonly used.

  • FBC, E’s & LFTS- high incidence liver pathology, again IL-6 driven, watch for renal dysfunction

  • HS-CRP (watch for low response). Low CRP falls under the radar

  • D-Dimer (add APTT if elevated)- elevated in around 15% for 3 months. Clear guidelines are not available. Concerns if prolonged immobilisation, previous venous thromboembolism, hormonal therapy, body weight >120 kg or BMI >35 kg/m², or in patients with an ongoing malignancy. Malignancy a possible concern in a D Dimer not improving

  • Complement C3, C4 (low C3 major prognostic value). Low complement C3 with low HS-CRP is thought to signal the impaired immune response, and appears to be a marker for TLR4 dysfunction. Commonly comorbidities that are driven by TLR4 signalling are also found

  • Se Ferritin / Fe studies

  • Lymphocyte subpopulations: (CD8+ lymphopaenia major prognostic value)

  • ANA, TSH, Thyroid abs (80% develop auto-immune activation- drops to 2% within 12 months

  • Tryptase -measure of mast cell degranulation

  • Se ACE if cardiac and pulmonary symptoms

  • Se Troponin as appropriate

  • Homocysteine- reflects oxidative stress, as increases over 15 (ideal <8) - increasing thrombotic risk – usually MTHFR mutation, if elevated, and not responding to methylated B12 may needs SAMe- there are a large number of DNA mutations involved and if not responding should have DNA profiling. B12 (normal range probably too low, ideally probably 400+), Zn, Vit D if homocysteine over 10 (“normal” of <15 not correct as increased CV risk over 9

  • B2Microglobulin- consider if atypical lymphocyte subpopulations, FBC

  • Se Lipase if abdominal pain (if normal, often sensitized vagal compression by SMA, coeliac artery or variant, and gastroparesis can be from this or brainstem)

  • APO E4- major prognostic value if cognitive impairment (marked increased risk Alzheimer’s disease, coronary artery disease and fatty liver) Not covered by Medicare, but is in full DNA if being done. Look for aneurysms, non-alcoholic fatty liver, FH early CV disease, dementia

  • Lipoprotein a is increasingly recognized as a prognostic factor in NASH and CV disease and may be relevant

2. Other studies that may be useful:

  • ECG lying and standing- picks up autonomic dysregulation with changing HR (watch for short PR and long QT)

  • Kubo et al(190)demonstrated changes of up to 9 msec when standing (Bazett’s formula), and up to 14 msec in Framingham’s formula.

  • The PR interval is the time for the electrical impulse generated in the sinus node to travel through the atria and across the AV node to the ventricles. Normal range is 0.12 to 0.20 seconds. The PR interval can be altered by changing sympathetic and parasympathetic activity. Beta blockers antagonize beta-1 and beta-2 receptors, the usual targets of the sympathetic nervous system, and can lengthen the PR interval with resultant first-degree heart block.(193)

  • Postural assessment

  • NASA Lean test if autonomic instability in lieu of tilt testing. Should be considered in all patients with autonomic dysfunction.

  • ROOS test may reproduce symptoms in thoracic outlet syndrome (should be done in all POTS-like patients given very high association)

  • Thoracic outlet scans (if positive ROOS test) Dynamic doppler needed to pick up the positional changes in Roos and Wright’s positions, and generally not seen on static MR (MRA) scans.

  • CXR (any SOB)- may need HS-CT if elevated ACE. Use Spectral CT if available as much higher pickup of pathology.

  • CTPA- chest pain and elevated D-Dimer (low pickup in microembolic cascades but reduces medico-legal risk)

  • VQ scan in recurring chest pain and elevated D-Dimer with normal CTPA -heterogeneous pattern reflecting microembolic damage may be present. Spectral CT more accurate

  • Echocardiogram -watch for subtle changes and EF. If LA dilatation and migraine check for PFO (Transcranial Doppler Bubble Test is gold standard)

  • Cardiac MRI

  • SPECT scan brain

  • Holter, ideally with heart rate variability (R-R interval) if any suggestion of dysautonomia or changes on ECGs.

  • RFT for any SOB

  • MRI (xray or CT) cervical spine in POTS-type -watch for loss of lordosis, C2/3 dysfunction especially where hypermobility is present.

  • MRI brain in cognitive impairment- best done with cervical spine together. Medicare compliant only with chronic headache. Look for:

MRI Brain

  • Hyperintensities > age-associated

  • Perivascular spaces

  • Empty/partially empty pituitary sella

  • Ventricular asymmetry > expected

  • Optic nerve changes

  • Microhaemorrhages > age expected

MRa brain or CTa may be considered if seizures, severe headache, CVA presentation for rare cerebral infarction or less common haemorrhage, the most common site the Superior Sagittal Sinus.

The various neurodegenerative mutations involved in Long Covid by and large have no biomarkers to measure the level of danger. Persistent inflammation can destroy brain cells. Combining MRI brain with brain SPECT scan reveals whether the impaired patient has inflammatory (hyperperfusion) or damage (hypoperfusion) and treatments tailored appropriately

Common Specific Problems

1. Fatigue:

  • POTS patients have chronic fatigue, aggravated by the dysfunctional autonomic responses.

  • In Covid there are other factors especially the microembolic processes which too are inflammatory.

  • Amyloid can also be part of the fibrin clots (Covid) when the inflammation is particularly severe and the process becomes even more dangerous

  • Mitochondria are the powerhouses of our cells and are vital to maintaining the health and even survival of cells and play a key role in maintaining homeostasis and cell-mediated immunity. Mitochondrial dysfunction/ oxidative stress /metabolic damage ( DNA testing with Dr Valerio 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).

  • Reactivation of EBV and similar viruses esp in Covid

  • Direct cardiac damage (eg pericarditis, myocarditis in Covid)

  • Pulmonary damage- embolic, inflammatory (common in Covid, rare in other POTS, but re-examination of CFS patients has revealed elevated D-Dimers, but numbers uncertain)

  • Impaired glymphatic function (NK cells and TRMP3)

  • Other organ damage, including malignancy

  • Small fibre neuropathy inflammatory -very common (again IL-6 and TNFa) -accompanying exaggerated neuropathy, auto-immune activation eg rheumatoid arthritis, reactive arthritis, PMR strongly suggestive of TLR4 mutations esp in Covid. Dr Vittone has clarified the pathways to many of these mutations.

  • Autonomic instability

  • Impaired cardiac function

  • Microglial dysfunction in brain

  • Impaired craniovascular function

  • Glymphatic dysfunction

2. Dysautonomia / POTS pattern

  • Dysfunctional TLR4 signalling and microglial activation causing sensitization at the root of the symptoms.

  • All (so far) have history of other problems, but dysregulated by Covid-related sensitization, most common is neck injury, but once sensitized, computers, phones, poor posture very important

  • Recommend lying and standing ECGs, Holter monitor (for HRV pattern and QT). Sympathetic pattern best controlled by “Kiiko Matsumoto” acupuncture and with diet change- keto/low histamine and base treatment with H1/H2 blockade to get them started.

  • DNA mutations include mast cell receptor and DAO metabolism- HNMT histamine metabolism, COMT, PEMT, oxidative stress, MTHFR, frequent APO E4, IL-6 and others. Clues in detailed history, especially endometriosis, migraine, syncope.

  • The POTS type ALL have mechanical components, mostly (85%) from neck and thoracic outlet (see “Assembling the Pieces in POTS” article in website). The intra-abdominal drivers are hard to assess as we can only image the arteries and veins, not the vagal compression, and unless significant enough to interest surgeons, require management of sensitization and symptoms often settle (until reactivated)

3. Brain Fog/cognitive impairment

  • Glymphatic flow is very important when fatigue and cognitive impairment are present (see separate article “Cervical spine with loss of lordosis and impeded glymphatics and association with Thoracic Outlet and Jugular Outlet Syndromes”) This usually improves with good posture, TOS management, LDN.

  • Variability in brain fog – intra-arterial pressure change (ref Lau, Wells et al(164))- often improves with diet change, sometimes H1/H2 blockade, LDN most effective (with care). Watch for “pressure” as research is currently looking for increased intracranial perfusion as well as the impaired flow documented by Wells et al.

  • Covid-related- inflammatory + can be microembolic – in Covid amyloid may be present but not measurable- depends on radiologist skill in interpretation

  • APO E4 mutations and elevated lipoprotein a (impaired glymphatic function)

  • Other neurodegenerative mutations eg PEMT

  • Amyloid at present not measurable- depends on radiologist skill in interpretation -if risk contact radiology for formal Alzheimers study as may need specialist referral

  • Retinal arterial photography if camera adequate can give a clear picture of cerebral vasculature , significant intracranial hypertension, and venous congestion, sometimes amyloid can be seen

Persistent elevation D-Dimer

Failure of improvement in D Dimer elevation is suspicious of underlying malignancy. It can also be related to mutations in PEMT (Phosphatidylethanolamine.)(253)


This is a personal management protocol. Use as possible suggestions in association with RACGP Guidelines. There are no Cochrane Guidelines at this point, and all treatments are based on research from around the world. Patients need to be made aware of this.

As the DNA studies reap more information the first response TLR 2 and TLR4 mutations are likely to be critical in the individual patient response. A decision whether to modulate the TLR4 or microglial sensitization needs to be made.

If QT prolongation is present, acupuncture should be considered early. Nigella sativa has demonstrated that it can oppose the spike proteins -may be of benefit in early COVID. Ketotifen may be useful when QT prolongation is present to modulate the mast cell response.

Desensitization and TLR4 Modulation

Individually H1 and H2 blockade have reasonable reductions in symptoms, but work extremely well in combination

H1 blockade -mast cell stabilization.

o Fexofenadine 180 bd or Cetrizazine 10mg bd or equivalents, used in combination with H2 blockade with famotidine has provided best results

o Ketotifen (see below)

H2 blockade:

o Famotidine 40 bd, but may need to be increased to 80mg bd. Famotidine is limited by arrythmias and QT prolongation. Extra magnesium may counter these. Famotidine interferes with inflammatory signalling, reducing inflammatory mediators CCL-2 and IL-6 that trigger the cytokine release by regulating TLR3 expression by H2 receptors on immune cells.(78)

TLR4 modulation -Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune system, recognizing pathogen-associated molecular patterns and initiating inflammatory responses.

When TLR4 is overactivated, it can contribute to excessive inflammation and the development of various inflammatory and autoimmune diseases. Modulating TLR4 signalling can have significant effects on immune responses and inflammation.

  • Low Dose Naltrexone -improves glymphatic function (and probably Natural Killer cell function). If H1/H2 not tolerated, caution with Low Dose Naltrexone. A study by Wang et al. (296) demonstrated that naltrexone could attenuate TLR4 signalling in glial cells, leading to reduced neuroinflammation

  • Nigella Sativa contains several active compounds, in particular thymoquinone, that have been found to modulate TLR4 signalling. Studies have shown that thymoquinone can down-regulate TLR4 expression and inhibit TLR4-mediated signalling pathways, reducing inflammation and oxidative stress. It increasingly looks to be a reasonable adjunct to above treatments, especially when D-Dimer remains elevated as it has anti-thrombotic activity, and may be a reasonable replacement when LDN is not tolerated.

  • Curcumin- Turmeric is widely studied for its health-promoting properties. It has been used in Traditional Chinese Medicine, as well as Ayurvedic medicine, for more than 2,000 years. Curcumin is turmeric’s most active component and provides numerous health benefits, including support for joint function and mobility, liver and gut health, cardiovascular function. Curcumin is also a potent antioxidant and has been found to modulate TLR4 signalling.

  • PPARg agonists eg pioglitazone and rosiglitazone, have been shown to inhibit TLR4 expression and signalling in various cell types

Other products that can influence TLR signalling include:

  • 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.

  • Glutathione indirectly by regulating redox state and mitigating oxidative stress (298)

  • Nicotinamide mononucleotide (NMN) appears to indirectly influence TLR4 signalling and inflammation by increasing NAD+ levels and promoting sirtuin activation. Sirtuins especially SIRT1 and SIRT6 can modulate TLR signalling and related inflammation (299)

  • Amitriptyline is a tricyclic antidepressant (TCA) commonly used to treat depression, neuropathic pain, and other chronic pain conditions. While the primary mechanism of action of amitriptyline is the inhibition of serotonin and norepinephrine reuptake, it has also been shown to have other effects, including anti-inflammatory and immunomodulatory properties. While there is no direct evidence of amitriptyline acting as a TLR4 modulator, it appears to have anti-inflammatory and immunomodulatory effects that could be indirectly related to TLR4 signalling. (294)(295)

In the POTS patients, especially when it has been triggered by COVID, we have found there is a high percentage that have QT prolongation shown in lying and standing ECGs. This makes the use of H1/H2 blockade with antihistamines and famotidine potentially risky until the prolongation can be controlled (which can be with sympathetic overactivity control with Japanese [Kiiko-Matsumoto in our studies] style acupuncture. In this situation consideration should be given to TLR4 modulation and/or oral ketotifen (H1 blockade)

Mitochondrial Dysfunction

Deal with the mitochondrial dysfunction largely responsible for fatigue, cognitive impairment, low energy and memory loss

  • `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) /low histamine diet (low histamine major importance if has HNMT,Dao enzyme defect)

  • Nicotinamide adenine dinucleotide (NAD+) or precursor Nicotinamide mononucleotide (NMN) is a crucial coenzyme involved in cellular processes including energy metabolism, DNA repair, and regulation of cellular aging. While there is no direct evidence that NMN specifically modulates Toll-like receptor 4 (TLR4), it may have indirect effects on TLR4 signalling and inflammation

  • The phytochemical sulforaphane (in nature seen in cruciferous vegetables), eg EnduraCell is being utilized to activate Nrf2 (nuclear factor erythroid 2-related factor 2,) seen as an activator of cellular defence mechanisms to induce the expression of a battery of cytoprotective genes and help repair mitochondria, induce mitochondrial biogenesis and activate Beta oxidation in the mitochondria to clear and transform fatty acids into ketone. Ketones like BHB beta hydroxybutyrate are a critical signal in the brain that upregulates Brain-derived neurotrophic factor, critical for neuroplasticity and brain health.

Support associated psychological damage

Deal with underlying metabolic damage- all the above ideally consider DNA analysis from Dr Valerio Vittone (PH.D) DNA of great importance in non-resolving symptoms.

Underlying DNA causes to be identified and dealt with- seldom only 1 mutation. More than 400 genes differentially expressed in long covid patients. Platelet and megakaryocyte gene sets seen in fatigue. Primary problems from our DNA appear to be in:

  • 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.

  • 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 cells- membrane, HNMT, Dao enzyme function

  • TRPM3 appears critical in NK (Natural Killer) immune cell function (Griffith CIFS research) and glymphatic function

  • COMT (impaired processing of catecholamines, 2 types, fast and slow COMT- clue is family history breast cancer, autism, ADHD, POTS/dysautonomia)

  • MTHFR, PEMT, CHKA and other methylation mutations

  • Oxidative stress and mitochondrial mutations eg eNOS

  • IL-6 and other Interleukins

  • APO E4, (and LPa also appears likely)

Consider IV protocol for severe fatigue and possible addition of NMN or NAD for mitochondrial repair

o IV Vitamin C 15g with IV B dose in 100 ml Saline 1-3 times per week

o Glutathione 500 mgs in 10 mls in 100ml saline bag weekly- Glutathione infusions- powerful antioxidant provides significant immune system support.

o B12 can be added in these periodically depending on the homocysteine (ideal below 7-8) and B12 (ideal 400+) levels

With IVs, if/when they plateau after a few weeks, until proficient chasing these -consider refer to Valerio for DNA. Valerio Vittone advice: “when the IV is most critical to do as a “reset” depending on the genetics so when they see Mitochondrial dysfunction of even “intermediate” nature they should consider DNA to validate IV with the genetics when possible”

LDN -for fatigue, TLR4 stabilisation, reducing small fibre neuropathy.(personal experience)

o When effective, in combination with H1/H2 blockade, fatigue and brain fog usually lift at around 3 mg on average.

o A significant percentage are having reactions, mostly sleep disorders but I have seen a serotonin syndrome when used with a tricyclic antidepressant- cause ultimately an adrenal adenoma. With a dramatic deterioration it can be another Covid infection.

o A clue to potential poor responders so far are those that react adversely to antidepressants or H1/H2 blockade.

o Start low 0.5 mg, maximum 4.5 mg, taken once daily, increasing weekly. Cease immediately if any side effects-common is insomnia- it may increase and hold or reduce dose. Sometimes change timing. Can reduce dose to 0.1 mg and go slower.

o I cannot find anything more than observational studies on LDN, and it is being used liberally with few safeguards. —Information sheet for patients on website.

  • Beware of supplements they are taking esp SAMe – danger with anti-depressants, although it can be extremely beneficial and psychiatrists use it liberally in addition to other psychotropic agents.

  • Use with caution in bipolar disorder.

  • Consider referral to Dr Valerio Vittone who understands the complex interplay and how it potentially affects the body.

  • SAMe may have positive benefits, but I believe should not be used unless skilled in its use. best I can find is imported Klaire Labs SAMe 200mg (needs script in Australia and hard to source, but no script needed if imported)

If neuropathy present, TLR4 mutations are probably very significant. Early results for nigella sativa (2 gm/day are very encouraging).

Diet is very important, then DNA to source the underlying metabolic defects. Assess traditional pathways –NAD/NMN, LDN and SAMe may be helpful.

Some improvements with H1/H2 blockade as above. At this stage hard to quantify what gives best relief, but my impression is that it is the H2 blockade with famotidine. Best results occur when H1 and H2 are used in combination


  • Red flags includes lack of response within 4 weeks of mast cell blockade- look for other factors, especially for autonomic instability. POTS has mechanical drivers that require sorting. If watching an elevated D Dimer that will not settle, check for inflammatory problems elsewhere driving this

  • Occult malignancy. Observational reports are of increased malignancy but as yet no published data

  • Sustained stress

  • Mechanical factors – may need to assess for POTS (ECG instability /NASA lean test).

  • Metabolic damage/ DNA mutations

Particularly when POTS / dysautonomia predominate my management starts with:

Desensitizing the “sensitization” that characterizes the underlying microglial activation -Link to protocol- this is an inexpensive regime based on the use of H1 + H2 blockade as used by Lawrence Afrin and cohorts, and this has been expanded in our clinic, using usually fexofenadine or cetirizine for H1 blockade twice daily and famotidine for H2 blockade at higher than normal doses, often up to 4 daily, adding H4 blockade subject to response.

  1. Low Dose Naltrexone modulates TLR4 as well as having positive results with chronic fatigue. If pericarditis or other processes are occurring, the treatments are continued until the inflammatory response is subdued.

  2. Nigella Sativa has around a 30% significant improvement in symptoms when used alone, but best appears to be when used as an addition. Nigella sativa has demonstrated that it can oppose the spike proteins -may be of benefit in early COVID. The active ingredient, thymoquinone, though is not specific for TLR4, and has a host of other modulation sites which may or may not be useful to a particular patient. LDN appears to be more specific for microglial TLR4 blockade.

Calming the autonomic instability (usually with acupuncture although some medication may be needed. 70% of Long COVID had autonomic dysfunction, and 30% of these have POTS, mostly undiagnosed (271)

Assessing persisting problems, eg most POTS have an underlying problem with their upper cervical spine, often with a thoracic outlet syndrome, or a MALS, and control these until desensitization is completed. Fatigue is the predominant problem but using mitochondrial “support” and appropriate supplementation, almost all can be recovered.- link to protocol

Recovery program. This is vital and needs to be paced to individual patients. Poor posture is a significant problem for most, aligned with phone and increased laptop use and deconditioning. This includes attention to diet and mitochondrial repair.

When using this simple mast cell blockade, either to prevent Covid-related disease, or to treat the fatigue and cognitive impairment, it comes with a warning that lack of improvement may represent more serious damage, and should be actively pursued.

As mentioned earlier, personalized DNA provides a pathway that helps in the management of those Long Covid patients that do not fully respond to the management protocols that we have put in place.

Physical Rehabilitation (RACGP Guidelines)

All post-COVID needs a progressive return to physical activity and exercise as deconditioning causes deterioration- start assessment at 6 to 8 weeks post infection. Same as POTS deconditioning program -needs good exercise physiologist if there is significant impairment

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