Dr Graham Exelby, Dr Valerio Vittone. Updated June 2023
Introduction
Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21st century. Its causative agent, Severe Acute Respiratory Syndrome (ARDS) coronavirus 2 (SARS-CoV-2), is an enveloped single stranded positive-sense ribonucleic acid virus that enters cells via the angiotensin converting enzyme 2 receptor or several other receptors. While COVID-19 primarily affects the respiratory system, other organs including the brain can be involved.(1)
Figure 1: Timeline of post-acute COVID-19. 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)
Source: Euro Heart J Suppl, Vol 23, Issue Supplement E, October 2021. https://doi.ord/10.1093/eurheartj/suab080
Around 30% (and higher in other studies) of patients continue to report an array of persistent symptoms after infection, with recent studies (3) confirming these changes up to 2 years and ongoing. Commonly reported symptoms range from fatigue and dyspnoea (shortness of breath) to “brain fog” with ongoing disability and disruption of work, social, and home lives. The array of symptoms lasting 4 or more weeks after COVID-19 infection has been labelled as a Post-COVID Condition, PASC, or Chronic Post-Covid, or Long Haul COVID, or Long COVID. (2)
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. The analysis adds to emerging evidence that long COVID is not a homogenous illness and should have personalised treatment and care.
The discovery by Dr Vittone of the underlying DNA mutations in Postural Orthostatic Tachycardia Syndrome (POTS) has led to a combination of therapies that have been amalgamated with the Mast Cell work by Afrin(7)(15)(16)and others, Glymphatic, Chronic Fatigue Syndrome and ion channel research at Griffith University by Sonya Marshall-Gradisnik and her team(63) (113)(114), and mechanical contributors through the work by Kjetil Larsen.(112)
Common problems in Long COVID:
Fatigue, brain fog and shortness of breath
Increased risk cardiovascular or cerebrovascular event as well as dementia in next 12 months
Change in microbiome
High incidence diabetes (30% increase)
Increased incidence of autoimmune disease
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
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)
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 and HNMT 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.”):
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.
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, Dao enzyme and HNMT function (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
COMT – affects ability to process catecholamines and oestrogen.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.
Methylation mutations- 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. PEMT and similar mutations are involved in vascular complications, neurodegeneration and thromboinflammation. In Covid infections amyloid may be to the fibrin clot making the plaques become very dangerous. The pathways are extremely complex and are best assessed with detailed DNA analysis, especially as there are no formal tests for PEMT.
Oxidative stress and mitochondrial mutations
IL-6 and other inflammatory mutations
APO E4 -a major genetic risk factor for Alzheimers disease as this lipid carrier is important for maintaining homeostasis necessary for a healthy environment of the brain. LPa is emerging as an increasing risk factor
TRPM3 appears critical in NK (Natural Killer) immune cell function, CIFS and “Glymphatic” function. (Griffith CIFS research)(63)(113)(114)(181)
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 major cause of morbidity and mortality in Covid-19 patients is from the “cytokine storm”.(12) Approximately 15–20% of Covid-19-infected patients suffer a severe form of the acute infection, characterized by activation of mast cells leading to histamine release and hyperinflammatory cytokine storms causing far more morbidity and mortality than from any direct viral cytotoxicity.(9)
The exaggerated inflammatory process, the “cytokine storm” is marked by the overexpression 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.
Nearly 20% of COVID-19 patients develop serious complications due to excess immune response of the human immune system, resulting in pneumonitis, Acute Respiratory Distress Syndrome (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)
Not all emboli and microemboli are venous, as some are arterial, and in some there is bleeding. Mukherjee et(78) al found these emboli are a result of histamine receptor 1 (H1) induced fibrinogen.(78) Rauchet al(249) found phosphatidylserine was associated with increased thromboinflammation and vascular complications. Increased TLR expression and TLR-mediated platelet activation during COVID -19 appears to enhance vascular and coronary thrombosis.(75)
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 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 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 and anosmia in Covid.(191)(192)
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 and Brain fog are the most common symptoms in Long Covid, often totally incapacitating.
Fatigue:
Long Covid 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 in Covid when the inflammation is particularly severe and the process becomes even more dangerous and difficult to control
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. Dysfunctional mitochondria are associated with defective immunological response to viral infections and chronic inflammation.(28)
Mitochondrial activation- 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).
Impaired Glymphatic function
Reactivation of EBV and similar viruses especially in Covid
Other organ damage, including malignancy (especially 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)
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 especially 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
11. Brain Fog/cognitive impairment
Glymphatic flow is very important when fatigue and cognitive impairment are present (This usually improves with good posture, TOS management, LDN.)
Variability in brain fog – intra-arterial pressure change Middle Cerebral Artery (ref Lau, Wells et al- effect looks to be from dysfunctional sympathetic function, but often mechanical component eg loss of cervical lordosis (4)
Covid-related- inflammatory + can be microembolic – in Covid amyloid may be present but not measurable- very difficult to assess, although research with a new MRI assessment- Synthetic MRI Volumatic reporting as an MRI brain add-on, especially combined with SPECT scanning should provide this information, to enable us to differentiate inflammatory from microembolic damage.
APO E4 mutations and elevated lipoprotein a (impaired glymphatic function)
Other neurodegenerative mutations eg PEMT
Retinal arterial photography if camera adequate (figure 2) can give a clear picture of cerebral vasculature, significant intracranial hypertension, and venous congestion, sometimes amyloid can be seen
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
Other organ damage
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 and impaired function
Figure 2: Retinal Photograph demonstrating amyloid plaque in arteries
Courtesy Alan Ming.
Fatigue, thus, can also be from reactivation of Ebstein-Barr and similar viruses, direct inflammatory or embolic damage to the heart, kidneys, liver, brain and lungs etc as well as mitochondrial dysfunction, metabolic 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
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. Rauchet al(249)found phosphatidylserine was associated with increased thromboinflammation and vascular complications, and can trigger the blood coagulation cascade, the complement system, inflammation and reside on activated immune cells.
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. Increasing levels require a systematic assessment of possible causes.
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 that is not embolic.
Within the clinic patients, there are many whose elevated D-Dimer does not improve with the mast cell blockade, and current investigations are centered on the PEMT and similar mutations, and trials with omega 3, nigella sativa (black cumin) and turmeric to complement the mast cell blockade.
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.
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 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 recommendation from Kelso(121) in “UptoDate” for patients who suffered mild reactions to mRNA COVID-19 vaccines is the use of H1 blockers, or non-sedating antihistamines before the second dose.
The use of H1 + H2 blockade has been expanded in our clinic, using usually fexofenadine or cetirizine for H1 blockade twice daily (and sometimes higher) and famotidine for H2 blockade twice daily), adding H4 blockade subject to response. The famotidine dose needed is usually higher than those normally used, up to 4 daily. Low Dose Naltrexone is a TLR4 modulator and H4 blocker, and clinically appears to reduce the cytokine response from TLR4 as well as having positive results with chronic fatigue. Increasingly research here has found the association may be more in keeping with improved “glymphatic” function.
A study released in 2023 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%.
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 https://www.mcmc-research.com/post/long-covid-part-12-the-glymphatic-system-with-loss-of-cervical-lordosis-and-association-with-thoraci
Figure 1: 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
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.
The ongoing research into glymphatics could shed light on POTS and long COVID. Professors Marshall-Gradisnik and Smith’s team discovered mutations in an important TRP pathway that affects the function of the Natural Killer Cells and glymphatics (the brain’s sewer.) Low Dose Naltrexone 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.
Natural Killer Cells (NK) monitor surface of autologous cells and allows NK cells to distinguish malignant from healthy cells.(234) Griffith University discovered 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 associated with SARS-Co-2.
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 or increased symptoms on mast cell blockade
New, increasing or severe shortness of breath
Arrhythmias (includes with increasing medication)
Unexplained chest pain
Syncope
Confusion
New neurological symptoms