Is It Long COVID Or Mast Cell Activation Syndrome? Breaking Down the Connection

Long COVID and mast cell activation syndrome (MCAS) are deeply connected. I almost always see a significant mast cell activation component to cases of long COVID, and ongoing research is solidifying this relationship. 

So what’s really going on? Is long COVID actually just a form of MCAS? Why and how is the COVID virus triggering this inflammatory storm for so many people? And what can we do about it? 

This is what I’ll be exploring in this article, including underlying root causes and what we do in the telehealth functional medicine clinic to stabilize mast cells, calm immune system reactivity, and restore wellbeing. 

Mast Cells, MCAS, Long COVID: An Overview of the Terminology 

Before I get into breaking down the connections, I want to provide a clear overview of what the terms I’ll be using actually mean. 

What Are Mast Cells?  

Mast cells are a type of white blood cell found in connective tissue throughout the body, including under the skin, in the respiratory and gastrointestinal tracts, around blood vessels and lymph vessels, and in nerve endings. 

These cells are critical for immune system function. When triggered by the presence of an allergen, infection, pathogen, or other kind of stressor, mast cells activate, releasing inflammatory mediators and chemicals including histamine. This release of inflammatory mediators is called degranulation. 

Likely the most easily understood example of this occurs when someone has a classic allergic reaction. Mast cells encounter the allergen, release natural chemicals including histamine, and histamine creates inflammation and symptoms like hives, flushing, sneezing, or swelling. These symptoms are created by the body in order to help alert us to, and ultimately get rid of, what’s perceived as a threat. 

What Is Mast Cell Activation Syndrome (MCAS)? 

Mast Cell Activation Syndrome occurs when mast cells chronically activate and degranulate excessively. It’s a manifestation of an overactive, hypervigilant immune system, and can result in a wide range of symptoms marked by inflammation. 

This condition is distinct from mastocytosis, a rare disorder that involves an excess number of mast cells. In MCAS, the problem is instead that our normal populations of mast cells are being triggered too often and too easily. 

Symptoms sometimes seem like allergic reactions to nothing, but because mast cells are found throughout the entire body, symptoms can also look very different. Some of the most common symptoms include: 

• Fatigue
• Brain fog
• Digestive problems
• Headaches
• Joint or muscle pain
• Dizziness or vertigo
• Anxiety
• Heart palpitations 
• Sensitivities to heat, cold, exercise, and/or stress 

Those with MCAS often react or experience symptoms in response to triggers including heat, cold, exercise, stress, toxins, or certain medications, supplements, or foods. Other times, symptoms seem to come on randomly. 

What Is Long COVID? 

Long COVID (also referred to by other names including long haul COVID or post-COVID syndrome) occurs when symptoms reoccur or persist for months or even years after an infection with the SARS-CoV-2 virus (which causes COVID-19). Symptoms are sometimes new (not the same symptoms the individual experienced during the active infection). 

Symptoms may include: 

• Fatigue
• Brain fog
• Headaches
• Digestive problems
• Heart palpitations or rapid heartbeat
• Joint pain or muscle pain 
• Shortness of breath 
• Dizziness or dysautonomic symptoms; POTS 

The Long COVID and MCAS Connection

The more research is done on long COVID, and the more clinical experience we gain, the clearer it is that this condition is intertwined with mast cell activation syndrome. (1)

You may have noticed above that the symptoms of both conditions are very similar. Symptoms vary from person to person, but there is significant overlap between the most common presentations of both. As a clear demonstration of this, a 2021 study found that people with long COVID experienced mast-cell-activation-like symptoms that were indistinguishable from those of MCAS patients who had never had COVID. (2) 

It’s not a coincidence, and research suggests that two things may be happening, depending on the individual. First, COVID may be able to unmask or amplify underlying, undiagnosed mast cell activation syndrome. In other cases, COVID may be activating previously normal mast cells, setting off an ongoing inflammatory storm due to lingering viral particles. For example, spike protein has been shown to directly trigger mast cell degranulation. (3) 

Multiple studies have now shown that mast cells become more activated during COVID. (4) Elevated levels of mast cell-derived mediators such as tryptase and chymase have also been identified in COVID cases, with greater elevations in more severe cases. (5) 

After an infection, this heightened mast cell activity may persist, contributing to multisystemic dysfunction and the ongoing inflammatory symptoms we associate with long COVID. 

Studies are looking in more detail at these effects; for example, a 2024 mouse study demonstrated how SARS-CoV-2-triggered mast cell activation may drive neuroinflammation, damaging blood-brain barrier integrity and activating microglia. (6) This offers a clear mechanistic explanation for long COVID’s neurological symptoms. 

Researchers have also found that mast cell activity is not just a side effect but can be used as a predictive biomarker of more severe COVID outcomes. (5) 

Therapies directed at mast cell stabilization are also showing promise for long COVID symptoms, further validating that this mechanism is at play. (7) 

Root Causes of Dysregulation 

One thing that may surprise you about the connection between long COVID and MCAS is that it’s not entirely unique. Over the years, I’ve seen many other chronic or reactivating viral infections like Epstein Barr Virus (EBV) trigger immune system dysfunction, chronic inflammation, and MCAS—in the same way that persistent bacterial or parasitic infections, or toxin buildup from mold, can set off the inflammatory cascade. 

In all of these cases, there’s a significant trigger, but there’s also more to the story. 

We always need to look more closely and figure out why someone’s immune system was primed to overreact to a virus like COVID (or another kind of infection). 

Underlying factors and root causes may include: 

• Genetic factors (often variants in HLA or MTHFR genes) 
• Chronic stress or unresolved trauma 
• Mold or other biotoxin buildup 
• Gut health imbalances or issues including SIBO (small intestinal bacterial overgrowth), gut dysbiosis, leaky gut 
• Other chronic infections 
• Underlying immune system dysregulation 

Usually with MCAS, a combination of factors have come together to create a perfect storm. There may be a genetic component, but it’s the environmental factors that push a genetic susceptibility into a state of disease. Often in the clinic, we’ll see genetic risk factors combined with a chronic stress or trauma component, leaky gut, and then some kind of trigger (such as the COVID virus) that tips everything into an active disease state. 

Testing For Underlying Issues  

Testing for MCAS itself can be complicated; there’s no single test to diagnose the condition, and the available options (which look at levels of mast cell mediators, especially tryptase, and their metabolites) are most effective during an active flare.

Diagnosis is often done through a combination of labs and symptom-based criteria, after ruling out other conditions. 

From a functional medicine perspective, we want to run additional labs to look at the underlying issues and root causes that may be behind long COVID and MCAS. 

Depending on an individual’s health history, specific symptoms, and environmental factors, we may test for mold toxicity, gut microbiome imbalances, leaky gut, cortisol and other hormones, SIBO, and other potential lingering infections. 

This kind of specialized, root cause focused testing helps us get specific when it comes to treatment and resolving what’s really going on beneath the symptoms. 

How to Heal 

There are a few different components to effective, holistic treatment of MCAS triggered by COVID. 

Stabilize Mast Cells  

The first things we need to do is stabilize mast cells and calm down immune system reactivity and inflammation. If the body is in a state of hyperreactivity and active mast cell flares, it’s much harder to move into the next stage of deeper healing. 

These are a few of the key mast cell stabilizers, natural antihistamines, and anti-inflammatory compounds I recommend: 

• Quercetin 
• Vitamin C 
• Luteolin 
• Curcumin 
• Baikal skullcap 
• Boswelia 
• Vitamins D3 and K2 
• Peptides including BPC-157 

Supplementary DAO, the enzyme that helps break down histamine, can also help by reducing overall histamine load. 

An important part of the mast cell stabilization process is also identifying and reducing triggers where possible. I know that before things are a bit more stable it can sometimes feel like everything is a trigger, but focusing on a few things you can somewhat control can make a big difference. Overexercising and excess heat or cold are a few common triggers that can often be cut back on. 

Find a Personalized Eating Plan 

Food is foundational, and specifically eating to avoid inflammation. For some people, this looks like a short term low histamine diet (avoiding dietary histamine helps to reduce overall histamine load when mast cells are also releasing excess amounts). 

But this isn’t the right eating plan for everyone with MCAS, and most important is avoiding foods that trigger inflammation or immune system reactivity for you. Sometimes this is a modified low histamine diet that factors in individual sensitivities and preferences. 

Regardless of the specifics, avoiding objectively inflammatory foods like sugar, refined carbohydrates, and processed or fried foods is key. Alcohol is also known to trigger mast cell activation and inflammation, and is best to avoid. 

Heal the Gut 

Gut microbiome imbalances and leaky gut (impaired intestinal permeability) often underlie MCAS, which is unsurprising given that the majority of the immune system is found in the gut. (8, 9) 

Bringing the gut microbiome back into balance and supporting intestinal lining integrity is an important pillar of treatment. 

Probiotics and prebiotics are foundational, and testing can help to guide individualized gut support from there. 

Support the Nervous System 

There is often a chronic stress or trauma component to MCAS, and these need to be addressed in order to calm both psychological and physiological hypervigilance and restore balance. (10) 

Vagus nerve stimulation through humming, singing, or deep breathing can be very helpful. Stress management practices including meditation, journaling, or yoga should be part of your routine as well. And to address deeper rooted emotional stress, therapeutic options including EMDR and frequency specific microcurrent, combined with talk therapy, can make a big difference.  

Support Detoxification 

Lingering spike protein from the COVID virus or vaccine may for some people contribute to long COVID and MCAS. Supporting natural detoxification through hydration and eating liver-supportive foods (dark leafy greens, dandelion, cruciferous vegetables), and supplementing with glutathione, can help to clear out these proteins and other toxins. 

An enzyme protocol involving nattokinase and bromelain, combined with anti-inflammatory supports like curcumin, may also work to break down and clear spike protein. 

For a more in-depth look at how to clear spike protein specifically, check out my article here. 

Address Unique Underlying Causes

Depending on your unique health profile, there may be other underlying causes to address beyond gut imbalances, stress or trauma, and toxin buildup. Working with a functional medicine practitioner can help you identify these factors and address them in a strategic, supportive way. 

An Upstream Approach

The more we know about what’s going on beneath the surface of symptoms, the more we can do about it, from an upstream, functional medicine standpoint. 

For personalized guidance decoding your own long COVID and MCAS puzzle, you can book a consultation with our telehealth functional medicine clinic. We’d love to help you put the pieces together. 

As one of the first functional medicine telehealth clinics in the world, we provide webcam health consultations for people around the globe.

Image source: Unsplash.com

Sources

• Sumantri, S., & Rengganis, I. (2023). Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pacific Allergy, 13(1), 50-53.
• Weinstock, L. B., Brook, J. B., Walters, A. S., Goris, A., Afrin, L. B., & Molderings, G. J. (2021). Mast cell activation symptoms are prevalent in Long-COVID. International Journal of Infectious Diseases, 112, 217-226.
• Zhang, S., Xu, C. L., Wang, J., Xiong, X., & Wang, J. H. (2025). Spike proteins of coronaviruses activate mast cells for degranulation via stimulating Src/PI3K/AKT/Ca2+ intracellular signaling cascade. Journal of Virology, 99(5), e00078-25.
• Tan, J. Y., Anderson, D. E., Rathore, A. P., O’Neill, A., Mantri, C. K., Saron, W. A., … & John, A. L. S. (2023). Mast cell activation in lungs during SARS-CoV-2 infection associated with lung pathology and severe COVID-19. The Journal of Clinical Investigation, 133(19).
• Meneses-Preza, Y. G., Soria-Castro, R., Alfaro-Doblado, Á. R., Hernández-Solis, A., Álvarez-Maldonado, P., Gómez-Martín, D., … & Chacón-Salinas, R. (2025). Mast cell activation signature as a potential biomarker in COVID-19. Immunology Letters, 275, 107026.
• Wu, M. L., Xie, C., Li, X., Sun, J., Zhao, J., & Wang, J. H. (2024). Mast cell activation triggered by SARS-CoV-2 causes inflammation in brain microvascular endothelial cells and microglia. Frontiers in Cellular and Infection Microbiology, 14, 1358873.
• Salvucci, F., Codella, R., Coppola, A., Zacchei, I., Grassi, G., Anti, M. L., … & Gazzaruso, C. (2023). Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Frontiers in Cardiovascular Medicine, 10, 1202696.
• Papa, V., Pomi, F. L., Di Gioacchino, M., Mangifesta, R., Borgia, F., & Gangemi, S. (2025). Mast cells and microbiome in health and disease. Frontiers in Bioscience-Landmark, 30(3), 26283.
• Albert-Bayo, M., Paracuellos, I., González-Castro, A. M., Rodríguez-Urrutia, A., Rodríguez-Lagunas, M. J.,
• Alonso-Cotoner, C., … & Vicario, M. (2019). Intestinal mucosal mast cells: key modulators of barrier function and homeostasis. Cells, 8(2), 135.
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