Introduction to Long Covid
Dr Graham Exelby MB BS Uni of Qld
Dr Valerio Vittone PhD Medicine (SYD 2008) BSc Hons (UNSW): Topic: Virology and Molecular Biology.
June 2023 Update
This website is intended to summarise our current research on the aetiology and management of Long COVID. It is our hope that these findings may enable physicians to “join the dots,” to help their patients now, often with conservative measures such as physical therapy, dietary change, and medications that have a well-established safety profile and are often available without a prescription.
The most important part of our work has been the use of TLR4 modulators (TLR4 is a "first responder to threats, and mutations appears to provide the answer as to whether symptoms of Long Covid occur.) Mast cell responses are vital in the pathways, histamine blockers to counter the overactivity of “mast cells”triggered by the SARS-Co-2 virus. Fexofenadine (or cetirizine) and famotidine (H1 and H2 blockers) usually provide excellent protection against disease severity as well as treatment of the common inflammatory problems of Long Covid. Low dose naltrexone, itself a H4 blocker, as well as TLR 4 modulator, has been shown to have major benefits in management of chronic fatigue.
It is though, like opening Pandora’s Box. The information in these documents is based on research from around the world coupled with Dr Vittone’s DNA findings, 15 years of personal research into Postural Orthostatic Tachycardia Syndrome (POTS,) Fibromyalgia, and the linking to co-morbidities eg migraine and accumulating data from our Long Covid Clinic. It utilizes work especially from Griffith University into Chronic Fatigue, from Lawrence Afrin and cohorts in Mast Cell Activation Syndrome, Kjetil Larsen in Thoracic Outlet Syndrome, with assistance from a multitude of colleagues, mostly based on the Gold Coast.
A Long COVID Management Team was established in May 2022 to examine directions for management, and individually these specialists are continuing to provide assistance. These papers discuss overall underlying pathology as we approach the increasing health burden on Long Covid, and how the problems can be managed.
Current guidelines Australian doctors are expected to follow remain based on a rehabilitation program with physios and psychiatric or psychological support, and no other medical treatments unless there are respiratory deficits are recommended, and even more forcefully that doctors should not operate outside these guidelines.
This update summarizes the changes and improvements to our management protocols, but a reminder that the treatments are research-based, and not on recommended guidelines, and these treatments based on the evolving findings from our DNA studies. Funding for the research arms, especially DNA, has not be able to be obtained so it has been individual patients funding this that has allowed the progression in management.
Summary of February 23 update:
Increasing 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 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.
High dose famotidine for H2 receptor blockade combined with H1 blockade and low histamine diet has proven to be very effective in most Long-Covid, and forms the backbone of initial treatment. Individually, the response is not as effective
High dose famotidine (up to 160mg/day) has potential risks with increasing an electrical pathway in the heart, causing QT prolongation, and needs to be watched carefully, especially if there are any arrythmias. It is thought to be caused by its effect on Magnesium levels. Higher doses have been trialled safely, and the medication is inherently very safe.
Kiiko acupuncture appears to control this problem, and formal studies have been started
Microembolic formation in Covid has been attributed to histamine. The lack of response to histamine blockade when testing persistent elevation D-Dimer continues to require more investigation, and again the close association with DNA mutations that affect both liver and brain are being examined, as well as the associated with amyloid a. Two products that will be investigated for this includes Nigella Sativa and Krill oil. Retrospective studies of ME/CFS patients has shown similar elevated D-Dimer levels. As it can also signal an underlying malignancy careful medical assessment is required.
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).
Persisting fatigue generally is part of mitochondrial dysfunction, which is also seen as part of the neurodegenerative process
Persisting cognitive impairment looks to be of mixed cause with mitochondrial dysfunction and microglial activation /inflammation which can progress to neuronal damage. In over 65’s, increased dementia risk is increased between 50 to 80%.
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.
Nigella Sativa (especially thymoquinone or TQ) has been shown to have antiviral, anti-inflammatory as well as immunomodulating effects on the SARS spike protein potentially making this a weapon against the virus itself, downregulating the over-expression of the threat receptors (TLRs) responsible for the cytokine storm, and the development of neurodegenerative diseases
Breaking Through in Long Covid and POTS management
Research in COVID-19 has answered many of the questions that kept popping up in POTS, Fibromyalgia and similar conditions- how a virus (or trauma, mould, parasites, sustained stress) can activate threat receptors (Toll-like receptors, or TLRs) which then activate Mast Cells that are responsible for the cytokine storm that is what happens in COVID.
The inflammatory cytokines, especially Interleukins 6 (IL-6) and Tissue Necrosis Factor alpha (TNFa) cause microglial activation that is responsible for the characteristic Small Fibre Neuropathy (SFN) (and the characteristic pain of Fibromyalgia) and from this the autonomic instability of dysautonomia, POTS and Long COVID.
"Mast cell blockade” with H1, H2 and often H4 blockers, is usually, but not universally effective, and lack of improvement signals a need for deeper level of assessment of the patient, and hopefully this DNA breakthrough will enable clinicians to target the underlying problems rather than just recommending “acceptance” of the disease. The mast cell responses are vital in our immune system, so looking at whether the response is aberrant- inadequate or excess becomes part of the management. At present there is no simple way of assessing this.
It has been the “decoding” of the DNA assessments by Dr Valerio Vittone, https://www.drvaleriovittone.com/ that revealed common threads of DNA mutations that has allowed us to develop a simple, cheap management program that may improve the fatigue and cognitive impairment for Long Covid sufferers anywhere. The program has been developed utilizing methods from researchers such as Lawrence Afrin, Kjetil Larsen, and especially Griffith University Gold Coast, and used successfully in our clinic at Mermaid.
Dr Vittone uses a technique called genetic imputation, utilizing the ~750,000 SNPs on a chip in a sequencing machine in Germany and use this information to predict with over 99% accuracy level the patient's genetic variances. Once this process is completed the patients variances are then further analyzed against 83 million additional SNP variants.
These findings make it possible to recover most patients if not too badly damaged by the inflammatory and microembolic cascades that are typical of a SARS infection.
Valerio and I have chosen to share this information, in the hope we can help the millions of people afflicted by Long Covid symptoms. This discussion document gives a very brief description of what is contained on this website. It will be difficult reading for which I apologize, as it was meant to assist my fellow clinicians.
The typical fatigue and cognitive impairment of Long Covid can in most people be managed with simple, cheap old medication, based on controlling the “histamine pathways,” along with a paced recovery program. The DNA research has been hampered by lack of funding, and given the subtypes we are finding, patient funded DNA studies from Dr Vittone are still needed to overcome some of the very difficult ones. The main DNA mutations are briefly:
TLR4 mutations- mutations in the "first responders" and likely to be the critical point which decides whether you have Long Covid or not.
Mast cell mutation- mast cell membrane and Dao and HNMT function
COMT- processing of catecholamines
TRMP3- critical in Natural Killer Cell and glymphatic function
Apo E4- a known major risk for Alzheimers, and affects lipid transport in the brain
Methylation mutations
PEMT and STAT3 and similar involved in vascular complications, neuro-degeneration and thrombo-inflammation, plus fatty liverOxidative stress and mitochondrial mutations
Other inflammatory mutations
These, and the protocols we are employing, are described in more detail in the Long Covid articles.
So What is Happening
Mast cell histamine is a regulator of proinflammatory, fibrotic, and thrombogenic processes, and exerts its biological actions through four types of histamine receptors H 1,2,3 and 4.
In the immune system, histamine is mainly stored in cytoplasmic granules of mast cells and basophils and is released upon triggering along with other mediators such as serotonin and tryptase.
Inflammatory microglial activation by IL-6 and TNFα is the most common brain pathology found in patients who died of COVID-19.
But it is the TLR2 and TLR4 threat receptors on Natural Killer cells rather than microglia, which are the "first responders" to brain injury. Most importantly, activation of mast cells has been shown to activate microglia, whereas stabilization of mast cells inhibits the CNS inflammation that would otherwise result from activation of microglia.
The microglial activation results in Small Fibre Neuropathy and neuropathic pain, and from this small fibre neuropathy it is believed comes the sensitization and characteristic autonomic chaos that is POTS and POTS-like Long Covid, and this includes random symptoms such as the eye pain and anosmia in Covid.
Then there are various COMT mutations with their reduced ability to process catecholamines. 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 Valerio can provide.
Natural Killer Cells distinguish malignant from healthy cells, while type I and III interferons (IFNs) are innate cytokines important in the first line defence against SARS.
The TRP mutations found at Griffith affect Natural Killer cell function. Complicating this, SARS has evolved mechanisms to evade the antiviral function of Interferon-1 and SARS patients show limited Interferon-1 responses, while there was an increased expression of IL-6, TNFα and other chemokines.
Possible implications of this are in an increased malignancy rate, and severity of malignancy at presentation following SARS infections. But there is a glimmer of hope from this as well, as modern research into malignancy is targeting these very same TLRs.
The Glymphatic System
“The glymphatic systems in the brain and eye export fluid and solutes from metabolically active neural tissue. Fluids from both the brain and the eye drain via the cervical lymph vessels, which empty into the venous system at the level of the subclavian veins.” Source: Mogensen et al. The Glymphatic System (en)during Inflammation
The Glymphatic System was discovered in 2013. It is basically the sewer of the brain, and dysfunction and obstruction to its flow is a major part of evolving work, not only in brain fog in POTS and Long Covid, but also in migraine, Parkinsons and Alzheimers Diseases.
The TRP mutations also affect glymphatic function, with a consequent reduced clearance of waste solutes from the brain causing fatigue and brain fog. Low dose naltrexone, a H4 blocker, and TLR4 modulator provides a therapeutic benefit here, but it is not a universal panacea, and at times hard to use.
Controlling mast cell activation is the first step to recovering a Long COVID, or a POTS and many other “obscure” neurological disorders. Management usually starts with H1 and H2 blockers- this alone significantly improves most fatigue in 4 to 5 weeks.
Attention to TLR4 modulation with the H4 blocker low dose naltrexone or nigella sativa may be added.
Diet is an important part of improving the mitochondrial dysfunction which is also critical in exacerbating fatigue and brain fog. Low histamine keto-based diets are important to re-establish good mitochondrial functions essential for energy productions and cognitive functions that COVID undermine during infection.
Lack of response to histamine blockade is a reason to look more deeply into a patient’s history, including mechanical causes as described in the POTS and fibromyalgia articles.
Our current research has been to continue looking at the various DNA subtypes and mechanical causes that can impact adversely on Glymphatic flow causing craniovascular perfusion dysfunction as well as directly impacting on arterial and venous flow to the brain.
Patients not significantly improving require a more detailed assessment, as there are a number of other potential contributing causes. These may be mechanical, especially postural as with the fatigue, deconditioning becomes an issue, so recovery programs are important. By taking a preventative approach in all facets of a person’s life, by taking a thorough family history, and using appropriate investigations, and using appropriate investigations including DNA testing where appropriate, POTS, Long-COVID, Fibromyalgia have a greater capacity for control.
Acknowledgements:
1. Dr Valerio Vittone, PH.D (biochemistry, molecular biology and virology) for his ongoing research into the underlying DNA and metabolic pathways that underpin POTS and long COVID. https://www.drvaleriovittone.com/
2. Special thanks to Prof Jon Jenkins, retired infectious diseases physician, for his invaluable and ongoing assistance working through the complex issues pertaining to the Covid infection, to his providing peer review in an area where there are few medical guidelines, and chairing a Long COVID Management Team on the Gold Coast to look at management from various Medical Specialists in May 2022.
3. Special thanks to Prof Pete Smith, allergist, for his guidance when there are “roadblocks” to overcome, in particular with his assistance with the emerging Glyphatic information and the DNA mutations that affect the function.
4. Special thanks to Mr David Haynes, acupuncturist who has been working in combination to demonstrate effective control of autonomic instability, especially the hyper-adrenergic type, with “Kiiko Matsumoto” style acupuncture. Using heart rate variability studies, and the ability to reduce the autonomic instability with his “Kiiko” style acupuncture, he demonstrated the ability to reduce QT prolongation.
5. QScan Radiology for assistance in research and interpretation of MRI cerebral hyperintensities.
6. Mermaid Beach Radiology for developing programs using Spectral CTs and 3T MRI with Sy capability.
7. QXRay for providing dedicated sonographers for various dynamic ultrasound scans, and MRI neurological changes
8. Absolute Ultrasound for providing sonographers for the multiple dynamic doppler ultrasounds to investigate the mechanical “drivers”
9. Mermaid Molecular Imaging for the assistance with SPECT scanning to determine whether the apparent brain damage is inflammatory (hyperperfused) or damaged (hypoperfused)
10. Ms Holly Charlton, dietician who has spent the time to train in the dietary management of these very difficult problems.
11. Thoracic Outlet Syndrome has been produced with a large contribution by Kjetil Larsen. His work is reproduced with his permission, and as a source of information in the developing work including Jugular Outlet Compression. Details of the impact of posture and management are seen on his website: https://mskneurology.com/how-truly-treat-thoracic-outlet-syndrome/
12. The author wishes to thank the invaluable assistance of QML Laboratories for providing access to multiple holter monitors that have been calibrated to measure R-R intervals to provide an assay of HRV over 24 hours, Dr Rebecca Ryan, Gastroenterologist for her assistance in mast cells, Dr Sahan Bandara, Respiratory Physician, Dr Zane Sherif at Mermaid Beach Radiology, and Dr Charles Appleton, pathologist from QML for his patience when we find pathology issues that are not apparent in the literature.
13. Then the team of physiotherapists who have been assisting developing a program to treat the POTS and now Long COVID patients- Adam Antoniolli, Tom Atkins, Brendan McLeod, Tiele Santos, Stuart Stephenson (DMA Pilates), Melanie Roberts (Watson Therapy), Drew Singleton, Liz Fong (Connect Therapy) and recently Roger O'Toole for his research into Trigeminocervical Sensitisation.
14. The ever- patient and enthusiastic Craig Phillips (DMA Pilates), who has provided 13 years of assistance looking at the mechanical forces at play in POTS, fibromyalgia, migraine and their co-morbidities, and continues to be involved in the emerging research.
Dedication:
1. To my wife Robyn for her patience and understanding - my first teacher
2. To Dr Merv Garrett, the pioneer allergist, my second real teacher
3. To Dr Ken Johnson, another pioneer, sadly missed.