Long Covid and Mast Cell Activation

A Perspective on Inflammation that May Open Treatment Options

We don’t fully understand the Long Covid syndrome, but one existing diagnosis that seems to fit most Covid long-haulers is MCAS: Mast Cell Activation Syndrome. There is fairly good evidence that covid-19 can trigger persistent mast cell activation, and this may be a big part of many of the symptoms that people suffer from. And it raises possibilities that the treatments for MCAS may reduce suffering and accelerate healing in people with Long-Covid.

The best research outlining mast cell issues in Long-Covid is a paper titled “Mast cell activation symptoms are prevalent in Long-COVID.” There is a link to that paper below in the sources section. The top-level summary of that paper: as a group, people with Long-Covid look like they have mast cell activation syndrome or MCAS.

The study first looked at chemical markers of MCAS in the blood. The normal, healthy people had an average marker score of 9.7 (a higher number indicates more mast cell activity). Patients diagnosed with MCAS had a score of 20.1 when they were diagnosed (but before being treated for MCAS)- their score was basically twice as high as the normal control group. The Long Covid group had a marker score of 21.1 - slightly higher than the MCAS patients, but the study found that statistically, they were basically the same.

Then the study asked the normal, MCAS, and Long Covid groups about the type of symptoms and intensity. Again, there was a clear difference between the normal group and the MCAS group. The Long Covid group reported even more fatigue than the MCAS group, and the Long Covid group had a lower quality of life. A ten-dimensional spider plot was created to index symptoms for each group, and the MCAS and Long Covid groups looked very similar to each other - and very different from the healthy group.

My interpretation is not that Long Covid and MCAS are identical, but that the Long Covid group does contains a lot of MCAS, or an “MCAS-like” disorder. Long Covid is likely to contain other types of injury that is not present in the MCAS group … we know that covid can cause very specific types of lung injury, blood clotting, unusual nerve and heart issues and other maladies, and these are probably not common in the average person with MCAS. But the similarities strongly suggest that there is something like MCAS at work, and that many long-haulers might benefit from being treated as if they have MCAS. Indeed, there are some reports in the medical literature that the MCAS therapies are useful in improving how people with LC function and feel.

So What Are Mast Cells?

Mast cells are white blood cells that are part of the immune system. They can circulate in the body via the blood, and they can dig-in and take up residence in places where there are signs of infection, cancer, or inflammation. They produce and release little packets of chemicals that fight invaders. One familiar mast cell chemical is histamine, which increases blood flow in areas where there is an immune battle - and histamine also causes redness, itching and irritation. Another mast cell chemical is tryptase, an enzyme which chews up protein. If tryptase is released right onto a bacteria or virus, it might tear apart that microbe and take it out of commission. But when there is too much tryptase everywhere, it can interfere with cells that are normal and otherwise healthy. Other ‘mediators’ released by mast cells stimulate other types of immune cells to gear up for a fight.

Some Chemicals Released by Mast Cells

• Histamine - familiar allergic response

• Tryptase, Chymase - protein destroying enzymes

• Prostaglandins D2 and F2-alpha - increases several types of inflammation

• Leukotriene E4 - constricts airways, stimulates other immune cells

• Thromboxanes - vasoconstrictors, pro-clotting agents

• Heparin - anti-clotting agent

• Tumor Necrosis Factor (”TNF”) - fever, apoptosis (cell death),

• Reactive Oxygen compounds - free radical/pro-oxidative compounds (“bleach”)

What are mast cell activation disorders?

Mast cell disorders (MCDs) are conditions where the mast cells are hyperactive. Mastocytosis is a relatively rare condition where there are too many mast cells and/or the mast cells show an unusual shape under the microscope. Mast Cells Activation Syndrome (MCAS) is more common, and it typically does not involve an increase in mast cell numbers (and the shape of these cells is normal) - but in MCAS these cells are over-active and release too many inflammatory signaling molecules.

Mastocytosis is easier to spot and diagnose, while many people with MCAS are undiagnosed and do not have a name put on their condition.

The general process at work in MCAS is called degranulation - the process of cells releasing granules of inflammatory chemicals from their cell membranes. In MCAS, mast cells are quick to release their granules, they are quick to push the body to some state of immunological alert.

The symptoms of mast cell disorders can range from the life-threatening (anaphylactic shock, asthma-like constriction to the lungs) to merely bothersome (moderate hives, rashes, sinus congestion, diarrhea). Some people are surprised to learn that stomach issues are one of the most common complaints among people with MCAS; but that isn’t so surprising when we consider that our gut is the front line against food-born infections and parasites. There are a lot of mast cells that are in and around the stomach and intestines, and if those cells are too quick on the trigger, they will disturb normal gut function.

MCAS can be a chronic condition where the inflammation is always turned on, or it can be intermittent, where some periods are normal or nearly normal, while at other times, there is a flare-up of mast cell activity and greater symptoms.

How is MCAS diagnosed?

In general, three criteria are used:

1) Documenting symptoms consistent with the release of excess mast cell compounds. These include various types of skin inflammation, respiratory symptoms, gastrointestinal symptoms, and neurological complaints. Patients do not have to have all of these, but they have to display an inflammatory pattern that matches what is generally seen in MCAS. Symptoms might include wheezing in the lungs, tightness in the chest, lightheadedness, fatigue, brain fog, nasal congestion and allergies, skin rashes, hives, and gastrointestinal issues like pain or diarrhea not explained by other causes.

2) Blood and/or urine analysis showing elevated levels of histamine, tryptase, chymase, prostaglandins, leukotrienes, and other compounds released by mast cells.

3) Improvement when taking medicines known to block the release or the action of histamine, prostaglandins, leukotrienes, and other mast cell chemicals.

In the study mentioned at the top of this article, the Long Covid group checked the boxes for criteria 1 and 2. And other preliminary studies have shown that the medicines used to treat MCAS seem to be somewhat effective in treating people with Long Covid. A conservative doctor or medical scientist would say that there is not enough evidence to conclusively state that Long Covid patients should be treated as if they have MCAS - but using that standard of proof, there is not really evidence to recommend almost anything at this point.

If one wants absolute scientific certainty, one may have to wait years - or decades. Post-covid patients are left with very real issues, and they can only use what evidence we have now to try to manage their lives. In the absence of scientific certainty, more general evidence is all we have, along with consideration of the safety and cost of potential therapies. Either people use this limited data points, or they wait for certainty … and do nothing.

Is there uncertainty or controversy regarding MCAS?

Yes, some. The idea of MCAS was only proposed in 1991 and formally recognized in 2007. It is a fairly new condition (in terms of how we think, even if it has been around as long as humans have existed). Some ideas about MCAS are likely to change in the next decades. As with many ‘new’ conditions, some doctors are slow to recognize it as real or important. Before the diagnosis of MCAS was recognized, some people with MCAS were informally classified as being allergy-prone. In other cases, the nature of the disruption was not recognized at all, and a person was simply diagnosed with individual diseases like asthma, or hives, or unspecified gut issues (maybe IBS, maybe GERD, maybe “nerves”) … there was no recognition of the fact that the immune system was glitched up and that this glitch was affecting the person in multiple ways. Complaints of fatigue or brain fog were written off as general symptoms of being out of shape, and patients were given advice to exercise more, lose a few pounds, and get plenty of rest. That advice is generally good for people, but doesn’t address the specific immune disturbance that makes it difficult for MCAS patients to function.

The diagnosis of MCAS is based on objective immune markers in the blood that we know are associated with a particular pattern of immune functioning. It is not imaginary, it is not hysterics, it is not malingering. The exact mechanisms are still not completely understood - but that is true of many diseases, like cancers or depression or arthritis. There is still much to learn about how MCAS works, and how it can be treated to improve health. But if one accepts what we do know, that might open a new perspective that can be useful in understanding Long Covid.

What triggers mast cells to degranulate?

In an ideal world, mast cells would only release inflammatory chemicals when there was a real threat to the body: a bacteria, virus, fungus, parasite, or cancer cell. In people with MCAS, that doesn’t hold true - normal activities result in the activation of mast cells. And those mast cells can cause irritation to tissues, which can lead to damage over time.

Mast cells are coated with antibodies (immunoglobin IgE). These antibodies have a sort of molded pattern on one end that is the complement to the shape of something the immune system considers to be a threat. When that molded pattern matches up with its target, it sends a message to the mast cell: “Attack!” And then then mast cell fires its bombs to take out the threat; it degranulates and releases packets of inflammatory molecules to neutralize the invader.

Mast cells have other receptors on their surfaces, and these act as sensors to the general environment of the body. These sensors can be primed by other molecules, which can make the mast cell more likely to degranulate. Interleukins are immune hormones or signaling molecules, and some of these send a message to mast cells that puts them on high alert. Examples include IL-33 and IL-1. Other molecules in the blood induce a condition of tolerance, where mast cells become easy-going and less likely to fire. One part of mast cell disorders is the balance of the chemicals that stimulate or pacify mast cells.

Infection tips the balance of these signals towards more mast cell activity, and some types of infections seem to disturb the signaling long after the infection clears up. With some viruses, there is also the possibility of a low-grade infection that lasts for months or years. The Epstein-Barr virus that causes mononucleosis is one such virus, it can set up a latent infection that simmers in the body for years, and keep the immune system in a state of activation and inflammation. Recent research has demonstrated that chronic Epstein-Barr virus infection is a significant factor in developing multiple sclerosis.

We don’t yet know if Long Covid involves a chronic infection that quietly simmers in pockets of the body, or if the active virus is completely cleared or eliminated after a month or so. We do know that almost everyone stops shedding Covid virus particles a few weeks after infection, and they are not contagious. But the virus could be still active in miniscule amounts - enough to convince the immune system that it is under attack, enough to make a person feel sick. If there is a chronic viral infection, anti-viral therapy might be beneficial for restoring immune balance. If the research shows that most people with Long Covid do not have any sort of viral activity going on, then the focus will shift to finding ways to communicate that to the immune system - then we would look for ways to tell the immune system to ‘stand down’ or chill.

Some common triggers for degranulation in MCAS can include:

• Heat or Cold

• Eating in General (especially large meals), or Eating Particular Foods

• Exercise

• Stress (both emotional and physical)

• Some Prescription and Over-the-Counter medicines

• Some Recreational Drugs

• Exposure to Sunlight

• Insect Bites

• Chafing or Physical Irritation to the Skin

• Perfumes, Industrial Solvents, Alcohol

Not everyone is triggered by the same things, and some people may be susceptible to a trigger at some times but not others. There are reports in the medical literature of mast cells being more active during some parts of a woman’s menstrual cycle.

How are mast cell activation disorders treated?

Future posts will go into more detail about each treatment option, but here is an overview.

1) Corticosteroids like hydrocortisone and dexamethasone have profound, widespread anti-inflammatory effects. They also have major side-effects that set in rather quickly in most people. Corticosteroids trigger weight gain. The skin thins and becomes fragile. Corticosteroids can raise blood sugar, triglycerides, and cholesterol. They can cause restlessness, insomnia, and mood disturbances. In the long run, they have negative effects on almost every system in the body. And dependency quickly sets in because the body stops producing corticosteroids when blood levels are high. A person has to come off this type of steroid very carefully to avoid life-threatening withdrawal; the dose is often limited to a few days, followed by a tapering off. But in some diseases, a short-term course of steroids can break the inflammatory spiral and stabilize a person. The Holy Grail in this area of pharmacy is a corticosteroid without all of the side effects - and there is progress being made in this area, but they have not been deployed yet. There are also “dissociated glucocorticosteroids” that might have fewer side effects.

2) Mast Cell Stabilizers like Cromolyn makes these immune cells less likely to release their bombs. (I have had this prescribed for my allergies at one time). Cromolyn is now available in an over-the-counter nasal spray form (both patented “NasalCrom” and generic versions). This can be somewhat effective for the sinuses, but the dosage and application method prevent it from having much effect on other parts of the body. There is also a form taken orally for asthma and systemic allergies (”Gastrocrom”). Cromolyn is not fast-acting; it requires days or weeks of regular dosing to stabilize the mast cells and reduce inflammation. But once it is in effect, it can make a difference.

3) Flavonoids: A variety of naturally occurring flavonoids also work to stabilize the mast cells. Quercetin is perhaps the best-studied flavonoid when it comes to stabilizing mast cells. Quercetin is found naturally in foods like apples and onions. For people with an acute condition, the amount from even the healthiest diets may not be enough to reduce symptoms. Quercetin is also available as a dietary supplement in many countries. Other flavonoids that may reduce mast cell activation include rutin, naringenin, vitexin, and luteolin.

4) Anti-histamines block many of the effects of histamine, and they are commonly recommended for people with MCAS. Although histamine is only one of the inflammatory signals that mast cells release, antihistamines can be valuable in preventing an inflammatory spiral or cascade. In the same way that scratching an itch often feels great but soon makes the problem much worse, inflammation often begets more inflammation... the mechanical irritation triggers more mast cell activity. Antihistamines are not typically a 100% solution, but they can often bring things down a notch, or at least keep it from becoming much worse. The most common antihistamines block the type I receptor, and these are used in seasonal allergies and cold medicines. Type II histamine receptor blockers are more specific to the gut.

5) Aspirin has been shown to be beneficial to some with MCAS, but it can also make symptoms worse for some MCAS patients. Aspirin inhibits the COX-1 and COX-2 enzymes that are needed to make certain prostaglandins, so there is a clear basis for improvement in people who have excessive levels of PGD2 and PGF2-alpha. Aspirin also carries an increased risk of bleeding, and it would be wise to discuss your personal risks with a doctor before taking aspirin regularly.

6) Montelukast is a prescription blocker of leukotrienes that is often prescribed for people diagnosed with asthma and allergies, and it has been prescribed for people with MCAS. Most commonly sold under the name “Singulair.”

7) “Biologics” are medicines that block various immune responses. The names of these often end in -tab or -ab … These are prescription-only medicines, and some are being used off-label for MCAS. Because they are relatively new, they are not usually available in generic form, and they can be expensive. Some types need to be injected (often only once per month). They can be very effective in bringing down certain types of hyperimmune responses (a friend has had good results in treating his psoriasis with one of the biologics). The ability to powerfully turn down the immune system can come with unwanted consequences; the use of some biologics is associated with an increased risk of infectious diseases or lowered ability to fight certain types of cancer.

8) Photobiomodulation (PBM) is a term used to describe the therapeutic use of light. In the broadest sense, PBM includes ultraviolet light (often used in psoriasis, or in diseases that benefit from increased levels of vitamin D) as well as visible and near-infrared light. Many studies have shown that red and near-infrared light suppresses inflammation in general, and some studies show that red/NIR can reduce mast cell degranulation in particular. Red/NIR light is relatively safe and there are a variety of LED devices available that cost between $50 and $150… some of these are sold as infrared ‘heating packs’ while others are positioned more as ‘light therapy devices’ - regardless, they provide a low-risk, low-cost option that may help some.

MCAS, POTS, and Long Covid

POTS stands for Postural Orthostatic Tachycardia Syndrome - the words literally mean “rapid heartbeat when standing up” but there is more to this condition than the name indicates. A high percentage of people with POTS display elevated mast cells chemicals in their blood. And an unusually high percentage of Long-Covid patients display symptoms of POTS. POTS involves a rapid heartbeat when a person is in an upright standing position - the pulse rate may increase 20 beats per minute or more when standing, and it stays elevated. Hallmarks of POTS include issues with maintaining blood pressure, fatigue, low exercise tolerance, brain fog, and a variety of other general symptoms that make a person feel lousy and run-down.

Different people have POTS for different reasons. It is believed that MCAS is a real cause, but not the only one. Other possible causes of POTS include autoimmunity (some forms of autoimmunity are also common problems in Long Covid) and elevated levels of adrenaline and noradrenaline (less likely, but possible in some with Long Covid). An almost universal symptom of POTS is a smaller left ventricle. With a smaller left ventricle, each beat of the heart moves less blood, so the heart beats faster to move enough blood to keep the body oxygenated. This change to the ventricle is generally reversible with exercise - but other factors like MCAS, high adrenaline levels, or autoimmune processes typically make it harder for people with POTS to exercise.

Some people with POTS and MCAS experience post-prandial hypotension … their blood pressure goes down 10 or 20 points after a meal. This has been explained as ‘the blood pooling around the stomach’ which takes it out of general circulation and lowers the pressure in the arteries. It is possible (but has not been clearly proven) that mast cell activation in the gut after a meal is releasing histamine and other compounds which are part of this ‘blood pooling’- histamine is known to open circulation and lower blood pressure. And as mentioned above, a high percent of mast cells are located in the gut, where they are on stand-by to deal with food-born infections and parasites.

Chronic Fatigue, Mast Cell Activation, and Long Covid

Chronic fatigue syndrome and myalgic encephalomyletis (CFS/ME) are another group of conditions common among people with Long Covid, and chronic fatigue syndrome has been shown to involves a pattern of mast cell activation. This is a big topic that deserves its own post(s), and that is planned. In terms of the symptoms, there is clear overlap between the 3 conditions. In terms of the biology, there is some overlap, but also some differences. Chronic fatigue seems to be characterized by specific mast cells that secrete too much chymase.

Summary Thoughts

Long Covid is more than MCAS. But it appears that MCAS may be a very common part of Long Covid. We don’t know how much benefit will come from treating Long Covid patients as if they have MCAS, but there is a reasonable theoretical basis for doing so. There are preliminary reports that patients treated with medicines used in MCAS do improve to some degree. Some with Long Covid will have other persistent injuries from the disease, but reducing the inflammation generated by mast cells might create a space to heal quicker while improving people’s daily functioning and quality of life. It is not realistic to expect that this approach will provide a ‘cure’ but it may be a decent treatment for some people.

Different patients might have different patterns of increased mast cell chemicals, which means that they will respond best to different types of medicine. Having blood work to identify which mast cell chemicals are elevated would likely be a useful, it might eliminate some of the trial and error of the process and let a person work to treat the disorder with greater specificity.

Future Posts

This post presented 8 possible categories of therapy for the MCAS-like symptoms that are common in people with Long Covid. Each of those provides a topic for a new post (and some categories provide enough material for 2 or more posts). I’ll also be monitoring the overlap between MCAS research and Long Covid, and expect that new studies will be coming out relatively soon - I’ll report on those as they are published. My readers can expect one well-researched, full-length post per week on this topic each week for the next few months, along with posts on other aspects of Long Covid.

Sources

• “Mast cell activation symptoms are prevalent in Long-COVID.” International Journal of Infectious Diseases, November 2021. PMID 34563706.

• “Stabilizing mast cells by commonly used drugs: a novel therapeutic target to relieve post-COVID syndrome?” Drug Discoveries and Therapeutics, Nov 4, 2020. PMID 33116043.

• “COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?” Journal of Biological Regulators and Homeostatic Agents, Sep-Oct, 2020. PMID 33023287

• “Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome.” International Journal of Infectious Diseases, Nov 2020. PMID 32920235.

• “Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments.” Infectious Diseases (London, England), Oct 2021. PMID 34024217.

• “Persistent Antiphospholipid Antibodies, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome and Post-COVID Syndrome: 1 Year On.” European Journal of Case Reports in Internal Medicine, 22 March 2021. PMID 33869099.

• “Post-Acute COVID-19 Syndrome and the cardiovascular system: What is known?” American Heart Journal Plus, May 2021. PMID 34192289.

• “Mast Cell Activation Syndrome.” Wikipedia, https://en.wikipedia.org/wiki/Mast_cell_activation_syndrome.

• “Basophils and Mast Cells in COVID-19 Pathogenesis.” Cells, Oct 14, 2021. PMID 34685733.

• “Mast Cell Activation Disorder and Postural Orthostatic Tachycardia Syndrome: A Clinical Association” Journal of the American Heart Association, 7 Sep 2021. PMID 34398691.

• “Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients.” Asian Pacific Journal of Allergy and Immunology, Jun 2017. PMID 27362406.

• “Recent advances in our understanding of mast cell activation - or should it be mast cell mediator disorders?” Expert Review of Clinical Immunology, Jun 2019. PMID 30884251.

Simple diagram of a mast cell. Red indicates IgE antibodies, which attach to receptors on the surface of the mast cell (brown). When the antibody senses the enemy it is programmed to recognize, the cell releases granules (green) which contained histamine, leukotrienes, free radical oxygen, and other inflammatory markers. Image originally from Wikimedia commons. …