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The Unchecked Immune System: Mast Cell Activation, Mold Allergies, and Long COVID

The Unchecked Immune System: Mast Cell Activation, Mold Allergies, and Long COVID

We have seen a noticeable increase in cases of Mast Cell Activation Syndrome (MCAS) in those who have had an assault on the immune system. Mast cells are an intricate and complex part of the immune system, and exposure to environmental toxins such as mold, heavy metals, and chemicals, or viruses such as COVID-19, can all drive inappropriate mast cell activation. Luckily for these sufferers of the many, varied symptoms, the integrative approach to these assaults on the immune system can help get the immune system back to “homeostasis” – the calmer, balanced state the body naturally seeks.

Various factors can trigger the mechanisms behind MCAS because it is an immune system response to some invader, foreign substance, or health event. It is interesting that the mast cells, the center of some of the action, can have a different response depending on what they encounter!

This is a marvelous, intricate mechanism designed to defend the human body. However, if that mechanism goes awry, one of the outcomes is a continuously stimulated immune system that perpetually produces symptoms. These lingering symptoms often revolve around different aspects of the immune system. What MCAS, Long COVID (seen when symptoms do not resolve until long after the illness’s acute phase has passed (1)), and mold reactions have in common is a disturbance in the immune system, often producing an over-reaction or over-stimulation of the immune system that triggers a cascade of inflammation and unpleasant symptoms. Positively identifying the root cause of these various expressions of illness can be challenging, especially in cases with multiple assaults on the immune system. Integrative doctors can use general principles and treatments to help relieve lingering and immune-related symptoms, even if the exact diagnosis remains undetermined.

Mast Cells

It’s best to start the story with mast cells and their role in immunity. Mast cells are a type of white blood cell that forms part of the immune system, which defends the body’s interior from harm. Mast cells perform defensive functions for the immune system, such as allergic responses. Allergic responses can occur when mast cells encounter molecules, compounds, or cells representing a danger, such as viruses, fungi, bacteria, toxicants, and pollen.

Mast cells have many different reactions to what they encounter in the body. Some reactions involve releasing chemicals called “mediators,” depending on the type of dangerous entity they encounter. Mast cells tend to live in parts of the body where the inside meets the outside (lungs, nose, mouth, skin, and digestive tract) to defend the interior from danger.

Briefly, the typical sequence of events for mast cell activation in a common scenario is as follows. A specific kind of grass pollen lands in the nasal cavity. The immune system recognizes the pollen as a foreign entity and a potential danger, creating an antibody of the type “IgE” (immunoglobulin E). The resulting IgE antibodies are made as a result of this encounter with this particular pollen and then attach to the surface of mast cells. The next time the person encounters that same type of grass pollen, all the mast cells with the equivalent pollen antibodies attached to the outside will release chemical mediators such as cytokines or histamines, which cause inflammation through different pathways.

Cytokines and histamines are the substances that cause symptoms such as headaches, migraines, runny noses, and watery eyes. In other words, mast cell mediators are inflammatory chemicals triggered by an immune response. One of those mediators, histamine, increases the ability of fluids to come out of capillaries and leak into tissues, which causes the nose to run with mucus and the eyes to water with tears. We would say the runny nose and watery eyes result from “mast cell activation.”

Mast Cell Activation Disorders

In a typical system, mast cells are activated when the immune system encounters the danger a second time. Then, it de-activates or gets calmed down after it has launched its defense. If the trigger for activation goes away, so should the mast cell activation. Anti-inflammatory cytokines can also be released to counter the inflammation and “reset” the mast cell. However, this system can get out of balance, and here is where the problem lies. Mast cell activation can get stuck in a state that keeps the immune response, inflammation, and symptoms going!

There are three main terms used in providing a diagnosis:

Mast Cell Disease (MCD) – Mast cell specialists are using this term for all diseases associated with mast cells (2). While not specific, MCD is a diagnosis with a diagnostic code. Several subtypes have been added recently for greater specificity.

Mast Cell Activation Disorder (MCAD) – This general term encompasses any abnormal behavior of mast cells. Some would use MCD instead of this term. Note that MCAD is not a diagnosis and does not have a diagnostic code associated with it.

Mast Cell Activation Syndrome (MCAS) – MCAS indicates an average number of mast cells that mistakenly release a large volume of chemical mediators. Unfortunately, this situation can occur even if the mast cells are unprovoked by foreign matter. The result can be anaphylactic shock or profound, severe allergic responses in the skin or cardiovascular, respiratory, or gastrointestinal systems. MCAS is thought to be quite rare (3). However, anecdotal evidence shows that this and other mast cell activation disorders are rising dramatically. What seems to back up this observation is the steady rise in other immune system abnormalities over the last two decades (4).

Symptoms of MCAS

Mast cells can be triggered by many entities or, conversely, by nothing currently measurable. Their release of chemical mediators affects a wide range of human health – cardiac, endocrine, respiratory, neurologic, gastrointestinal, and dermatologic. This is one reason why MCAS is so challenging to diagnose. The potential symptoms of MCAS are exhaustive, but some common symptoms include:

  • Fatigue

  • Food and chemical sensitivity

  • Joint, bone, and muscle pain

  • Skin issues, including itching, flushing, rashes, hives

  • Chills

  • Palpitations, racing heart

  • Burning mouth

  • Headaches, including migraines

  • Eye irritation

  • Heartburn

  • Bowel function irregularities

  • Pre-Syncope (Dizziness/Lightheadedness)

  • Several gastrointestinal symptoms, including nausea, vomiting, abdominal pain, diarrhea, constipation, and bloating

  • Cognitive issues including brain fog, memory problems, depression, and anxiety

  • Shortness of breath

  • Sinus congestion

  • Endometriosis

  • Osteoporosis

  • Chronic bladder pain (Interstitial cystitis)

  • Syncope (Loss of Consciousness)

  • Neurologic symptoms, including vertigo, numbness, tingling, burning pains, and tinnitus.

One of the most dangerous (but rare) symptoms of MCAS is anaphylactic shock. Anaphylactic shock is a potentially life-threatening, severe allergic reaction that can close off the airway for breathing and drastically reduce blood pressure. Not all anaphylaxis ends in death, but many times anaphylaxis causes painful swelling of the face. However, it happens so quickly and dramatically that most will rush to a hospital for intervention before the airways are compromised.

What’s my Risk?

The current knowledge indicates that any disturbance of the immune system can increase the risk of MCAS. Many times, basic tools to maintain health are neglected, which can leave one vulnerable to imbalances. Mastering the basic pillars of health is important in healing or preventing MCAS. Other factors that appear to increase the risk of having MCAS or frequently exist simultaneously are:

  • Any strong hit to the immune system ( ex: COVID-19)

  • Genetic factors (affecting the ability to detoxify heavy metals and molds, for example, or gene mutations that affect mast cell receptors, enzymes, mediators, or surface molecules)

  • Hidden chronic infections (ex: Lyme disease, Bartonella, Epstein-Barr Virus)

  • Toxic burden: heavy metal toxicity, chemical exposures, mold exposures

  • Gastrointestinal infections (parasites, bacterial or fungal overgrowths)

  • Autoimmune disorders (when the immune system mistakenly attacks healthy cells)

The MCAS Connection: Immune System Overdrive & Toxic Burden

When looking at the risks and co-morbidities of MCAS, two potential underlying root causes stand out – a dysregulated immune system and toxicity. Several of the conditions listed above involve an immune system that seems to get stuck in the “on” state, having a low threshold for being triggered and continuing to elicit symptoms. Some irritants, identified or not, could keep the immune system engaged. Perhaps the problem is the immune system’s inability to “turn off” the protective inflammatory mechanisms when they are no longer needed. Or, it could be that there is something about the nature of the immune stimulation that results in the inability of the immune system to disengage (as in with chronic ongoing infections or ongoing toxic exposures).

The possibility exists that these are two sides of a coin, easily existing simultaneously and even exacerbating each other. The diagnoses for MCAS and other mast cell disorders reflect this complexity. Not only must a range of conditions be ruled out, but particular tests must be performed to identify Mast Cell Activation Syndrome positively (6).

Focus on Risk Factors: Long COVID & Mold Exposures

There are two groups of patients showing signs of MCAS in more significant numbers – those with Long COVID and those with mold-related health issues. A high toxic burden appears to increase this risk.

Those with Long COVID also present with MCAS symptoms. The CDC is still piecing together a definition for Long COVID (1). What stands out is that similar to MCAS, Long COVID displays these symptoms (among others):

  • Fatigue

  • Pre-syncope

  • Muscle/joint pain

  • Headache

  • Gastrointestinal disturbances

  • Cognitive issues like brain fog and mood disorders

  • Rashes

These symptoms indicate a strong immune response and potentially different types of inflammation existing concurrently. It would not be surprising if an individual with Long COVID would fit the diagnosis of MCAS and vice-versa.

Patients with mold-related health issues also frequently exhibit signs and symptoms of MCAS. Different types of mold and mycotoxins can trigger IgE immune reactions, where the immune system rapidly makes antibodies to the particular species of mold or the toxins it produces. Allergy tests can detect these IgE reactions and even identify the species of mold that is causing symptoms.

Symptoms of over-exposure to mold irritants, like Long COVID, overlap with MCAS symptoms. Mold exposure can also trigger respiratory symptoms such as asthma and have neurological effects such as “brain fog.” Once the mold is identified, it may be easier to find and eliminate it from the environment. Some people have a genetic issue that affects how efficiently they detoxify mold toxins from their bodies. Repeated mold exposure can cause serious health issues for these people if there is no intervention.

Putting it All Together: Toxic Burden, Immune System Disturbance, and MCAS Symptoms

Having a heavy toxic burden on the body can lower the threshold for catching infectious diseases. This same toxic burden can make it easier for the immune system to become unbalanced. The toxic load could be due to cumulative heavy metals in the body, a poor diet, genetic predispositions that make it difficult to rid the body of toxins, mold in the air, or hidden infections.

Luckily, integrative medicine approaches can help balance the immune system, reduce the toxic burden on the body, and support the immune system without overstimulating it. The holistic approaches below are great because they work with the whole body and are appropriate for even undiagnosed (but obviously immune-related) health issues.

1. Reduce the Toxic Burden

  • Allergy testing and removal of offending irritant(s)

  • Heavy metal testing and removal of the offending metal

  • A low histamine diet

  • Supplements to assist detoxification (activated folate, activated B12, glutathione, antioxidants)

  • Supplements to break down biofilms, reduce fungal and bacterial loads

  • Ozone + ultraviolet blood irradiation therapy to inactivate viruses and bacteria; reduce inflammation, and help regulate the immune system.

  • IV nutritional therapies to help fight disease through increased antioxidants

  • Colonics to reduce the toxic burden in the intestines

  • Avoiding smoking or excessive consumption of alcohol or caffeine

2. Balance the Immune System

  • Take adaptogens – Adaptogens are nutritional supplements that inhibit or encourage the immune system, whichever is needed by the body. They tend to normalize or bring into balance hormones, but some adaptogens also have this normalizing effect on the immune system. Some immune system adaptogens are ashwagandha, rhodiola, ginseng, holy basil, and turmeric.

  • Increase anti-inflammatory foods and supplements – Try adding anti-inflammatory substances such as turmeric (or its active ingredient, curcumin), Omega 3 fatty acids, ginger, garlic, vitamin C, boswellia, or probiotics.

  • Consider acupuncture – Acupuncture can calm an over-stimulated immune system and reduce inflammation.

  • Improve your gut health – The human gut is intimately involved in immunity. A compromised gut can equate to a compromised immune system.

3. Support the Immune System

  • Master the basics – Review and put into practice the 5 pillars of health, which include getting good sleep and reducing stress.

  • Manage chronic health conditions – Minimizing the effects of a chronic illness can save “wear and tear” on your immune system over time.

  • Identify and address nutritional and hormonal deficiencies – Balancing one aspect of the body often helps balance other aspects of the body. Giving the body the necessary building blocks through good nutrition and normalizing hormones can indirectly help the immune system balance itself.

Immune system irregularities resulting from unchecked mast cell activation can lead to painful inflammation and confusing symptoms. You don’t have to face this type of mystery illness alone. If your symptoms match those listed in this article, please schedule an evaluation with one of the functional medicine doctors at TCIM. Integrative medicine practices will not only drive us to identify root causes but provide many safe and natural approaches to calming your immune system and helping you achieve better health.


Jonathan Vellinga, M.D.

Jonathan Vellinga, MD is an Internal Medicine practitioner with a broad interest in medicine. He graduated Summa cum laude from Weber State University in Clinical Laboratory Sciences and completed his medical degree from the Medical College of Wisconsin.​

Upon graduation from medical school, he completed his Internal Medicine residency at the University of Michigan. Dr. Vellinga is board-certified with the American Board of Internal Medicine and a member of the Institute for Functional Medicine.




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3. Mast cell activation syndrome - about the disease [Internet]. Genetic and Rare Diseases Information Center. U.S. Department of Health and Human Services; [cited 2022Dec29]. Available from:

4. Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. Increasing Prevalence of Antinuclear Antibodies in the United States. Arthritis Rheumatol. 2020 Jun;72(6):1026-1035. doi: 10.1002/art.41214. Epub 2020 Apr 30. PMID: 32266792; PMCID: PMC7255943.

5. Weinstock LB, Brook JB, Molderings GJ. Efficacy and toxicity of hydroxyurea in mast cell activation syndrome patients refractory to standard medical therapy: retrospective case series. Naunyn Schmiedebergs Arch Pharmacol. 2022 Nov;395(11):1441-1447. doi: 10.1007/s00210-022-02282-8. Epub 2022 Aug 19. PMID: 35982335; PMCID: PMC9388361.

6. BlogAdmin. [Internet]. The Dysautonomia Dispatch. 2015 [cited 2022Dec29]. Available from:


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