Could Your Long COVID Actually Be Mast Cell Activation Syndrome?

By Angelica Clark, PA-C, IFMCP  •  Clark Wellness  •  December 2025  •  9 min read

If you've been struggling with lingering symptoms months after recovering from COVID-19, you're not alone. Millions of Americans are experiencing what's commonly called "long haul or long COVID"—a frustrating constellation of symptoms that conventional medicine often struggles to address.

But here's something many healthcare providers are missing: what's being diagnosed as long COVID may actually be mast cell activation syndrome (MCAS), or the two conditions may be deeply intertwined.

As a functional medicine practitioner, I've seen this pattern repeatedly in my practice. Patients come in exhausted, foggy-headed, and desperate for answers after being told their labs are "normal." When we dig deeper and look at the root causes, we frequently find mast cell dysfunction at the center of their suffering.

In this article, I'll break down the connection between these two conditions, explain why this matters for your healing journey, and share the functional medicine approach we use to help patients finally find relief.

Understanding Mast Cells and Their Role in Your Immune System

Before we explore the connection, let's understand what mast cells actually do. These specialized immune cells are found throughout your body—in your skin, respiratory tract, digestive system, around blood vessels, and even in your nervous system.

Think of them as your body's first responders, constantly on patrol for potential threats.

When mast cells detect something they perceive as dangerous—whether it's an allergen, infection, toxin, or other stressor—they release a cocktail of inflammatory chemicals, including histamine. This process, called degranulation, triggers the symptoms we associate with allergic reactions: hives, flushing, swelling, sneezing, and more.

Under normal circumstances, this is a protective mechanism. The problem arises when mast cells become overly sensitive and start reacting to things that shouldn't trigger them—or when they simply won't calm down.

What Is Mast Cell Activation Syndrome (MCAS)?

Mast Cell Activation Syndrome occurs when your mast cells become chronically overactive, releasing inflammatory mediators too frequently and too easily. Unlike mastocytosis (a rare condition involving an abnormal number of mast cells), people with MCAS have normal mast cell populations—but those cells are essentially stuck in "high alert" mode.

Because mast cells exist throughout the entire body,

MCAS can produce an incredibly diverse range of symptoms:

• Persistent fatigue that doesn't improve with rest

• Brain fog and difficulty concentrating

• Digestive issues (bloating, cramping, diarrhea, or constipation)

• Headaches and migraines

• Joint and muscle pain

• Heart palpitations and rapid heartbeat

• Skin reactions (flushing, hives, itching)

• Dizziness and vertigo

• Anxiety and mood changes

• Sensitivity to heat, cold, stress, or exercise

What makes MCAS particularly challenging is that triggers can vary widely from person to person. Some people react to certain foods, while others flare from temperature changes, stress, or seemingly nothing at all.

Long COVID: When Acute Infection Becomes Chronic Illness

Long COVID (also called post-acute sequelae of SARS-CoV-2, or PASC) describes a condition where symptoms persist or emerge weeks to months after the initial COVID-19 infection has resolved. For some people, symptoms linger for years.

Common long COVID symptoms include:

• Debilitating fatigue

• Cognitive dysfunction ("COVID brain fog")

• Shortness of breath

• Chest pain and heart palpitations

• Headaches

• Digestive problems

• Joint and muscle pain

• Dizziness and POTS-like symptoms

Notice anything? These symptoms look remarkably similar to MCAS. That's not a coincidence.

The Long COVID and MCAS Connection: What Research Reveals

Emerging research is confirming what many functional medicine practitioners have observed clinically: long COVID and mast cell activation are intimately connected. Studies have found that people with long COVID experience mast-cell-activation-like symptoms that are virtually indistinguishable from those of MCAS patients who never had COVID.

So what's happening? Research suggests several mechanisms at play:

-COVID Can Unmask Hidden MCAS

Some individuals have underlying, subclinical mast cell dysfunction that they're unaware of. The stress of COVID infection can push these already-sensitive mast cells over the edge into full-blown MCAS. The viral infection essentially tips a delicate system into dysfunction.

-Direct Mast Cell Activation by Spike Protein

Research has demonstrated that the SARS-CoV-2 spike protein can directly trigger mast cell degranulation. Even after the acute infection resolves, lingering viral particles or spike protein fragments may continue stimulating mast cells, perpetuating the inflammatory cycle.

-Elevated Mast Cell Mediators

Studies have identified elevated levels of mast-cell-derived mediators like tryptase and chymase in COVID patients, with higher levels correlating with more severe disease. This heightened mast cell activity may persist long after the infection clears.

-Neuroinflammation and Blood-Brain Barrier Damage

Recent research has shown that SARS-CoV-2-triggered mast cell activation can drive neuroinflammation, potentially damaging the blood-brain barrier and activating brain immune cells called microglia. This offers a compelling explanation for the neurological symptoms—brain fog, cognitive issues, headaches—that plague so many long COVID sufferers.

Why Did This Happen? Understanding Root Causes

Here's something that may surprise you: the connection between viral infections and immune dysfunction isn't unique to COVID. In my years of practice, I've seen similar patterns with other chronic or reactivating viruses like Epstein-Barr Virus (EBV), as well as with bacterial infections, parasites, and mold exposure.

The viral infection is often the trigger, but there's usually more to the story. We need to ask: Why was this person's immune system primed to overreact in the first place?

Common underlying factors include:

• Genetic susceptibility: Variants in HLA genes, MTHFR, and other genetic factors can predispose someone to immune dysregulation

• Chronic stress and unresolved trauma: Prolonged stress primes the nervous system and immune cells for hypervigilance

• Mold and biotoxin exposure: Mycotoxins from water-damaged buildings can sensitize mast cells and dysregulate immunity

• Gut health imbalances: SIBO, dysbiosis, and intestinal permeability ("leaky gut") directly impact immune function

• Other chronic infections: Underlying infections like Lyme disease or reactivated viruses can compound immune dysfunction

• Hormonal imbalances: Thyroid dysfunction, adrenal issues, and sex hormone imbalances can influence mast cell behavior

In most cases of MCAS, we find a "perfect storm" of factors. There may be genetic predisposition combined with environmental triggers like mold exposure, gut dysfunction, chronic stress—and then something like COVID comes along and tips everything into an active disease state.

How We Test for MCAS and Underlying Dysfunction

Diagnosing MCAS can be challenging because there's no single definitive test. Available testing looks at levels of mast cell mediators (especially tryptase) and their metabolites, but these are most accurate during an active flare. Diagnosis often relies on a combination of laboratory findings, symptom-based criteria, and ruling out other conditions.

From a functional medicine perspective, we go beyond just confirming MCAS. We want to understand why your mast cells became dysregulated in the first place. Depending on your history and symptoms, we may evaluate:

• Mycotoxin testing to assess mold exposure

• Comprehensive stool analysis for gut microbiome imbalances

• Intestinal permeability markers

• DUTCH hormone testing for cortisol patterns and sex hormones

• Organic acids testing (OAT) for metabolic insights

• Testing for SIBO and other GI infections

• Comprehensive thyroid and metabolic panels

• Evaluation for other chronic infections when indicated

This root-cause-focused testing allows us to create a targeted, personalized treatment plan rather than just managing symptoms.

A Functional Medicine Approach to Healing

Effective treatment of MCAS and long COVID requires a comprehensive, multi-pronged approach. Here's how we address this in our practice:

1. Stabilize Mast Cells and Calm Inflammation

The first priority is calming down the hyperactive immune response. While your body is in a state of constant reactivity, deeper healing becomes nearly impossible. Key mast cell stabilizers and natural antihistamines include:

• Quercetin: A powerful natural mast cell stabilizer found in apples, onions, and supplements

• Vitamin C: Supports histamine breakdown and immune balance

• Luteolin: A flavonoid with strong mast cell stabilizing properties

• Curcumin: The active compound in turmeric with potent anti-inflammatory effects

• Vitamins D3 and K2: Critical for immune regulation

• DAO enzyme supplementation: Helps break down dietary histamine and reduce overall histamine load

Equally important is identifying and reducing triggers. Common culprits include overexercising, extreme temperatures, certain foods, and excessive stress.

2. Optimize Your Diet

Food is foundational medicine. For some patients, a temporary low-histamine diet can provide significant relief by reducing the overall histamine burden while mast cells are overactive. However, this isn't appropriate for everyone, and the key is finding what works for your unique biology.

Universal dietary principles for managing MCAS and long COVID include:

• Eliminating processed foods, refined sugars, and inflammatory seed oils

• Avoiding alcohol, which triggers mast cell activation

• Focusing on whole, nutrient-dense foods

• Identifying and eliminating individual food sensitivities

• Supporting blood sugar stability with adequate protein and healthy fats

3. Heal the Gut

Given that approximately 70-80% of your immune system resides in your gut, it's no surprise that gut dysfunction frequently underlies MCAS. We commonly find SIBO, dysbiosis, or intestinal permeability in patients struggling with mast cell issues.

Treatment may include targeted probiotics, prebiotics, gut-healing nutrients like L-glutamine and zinc carnosine, and addressing any underlying infections or imbalances identified through testing.

4. Support the Nervous System

Chronic stress and trauma can keep your nervous system—and by extension, your immune system—locked in a state of hypervigilance. This is why addressing the stress component is essential for lasting healing.

Vagus nerve stimulation through practices like deep breathing, humming, or singing can help activate your parasympathetic ("rest and digest") nervous system. Meditation, yoga, and journaling are also valuable tools. For deeper-rooted emotional stress, therapeutic approaches like EMDR can be transformative.

5. Support Detoxification

For some individuals, lingering spike protein may contribute to ongoing symptoms. Supporting your body's natural detoxification pathways can help clear these proteins and other toxins that may be fueling inflammation.

This includes staying well-hydrated, consuming liver-supportive foods (dark leafy greens, cruciferous vegetables, beets), and potentially supplementing with glutathione, NAC, or targeted enzymes like nattokinase and bromelain.

6. Address Your Unique Root Causes

Beyond these foundational steps, your treatment plan should address whatever specific underlying factors are driving your condition. This might mean treating mold toxicity, balancing hormones, addressing thyroid dysfunction, or supporting mitochondrial health. This is where working with a functional medicine practitioner becomes invaluable.

Finding Your Path Forward

If you've been struggling with long haul or long COVID and conventional medicine hasn't provided answers, I want you to know there is hope. Understanding the mast cell connection opens up new avenues for healing that go far beyond "wait and see" or symptom suppression.

The functional medicine approach looks upstream to identify and address the root causes driving your symptoms. By stabilizing mast cells, healing the gut, supporting your nervous system, optimizing nutrition, and addressing your unique underlying factors, true healing becomes possible.

At Clark Wellness, we specialize in helping patients navigate complex chronic conditions like long haul COVID and MCAS. As an IFM-certified practitioner in the Waco area, I bring over 17 years of clinical experience and a deep commitment to finding answers when others have given up.

If you're ready to stop managing symptoms and start addressing root causes, I'd love to help you put the pieces together and reclaim your health.

Ready to take the next step? Schedule a consultation at Clark Wellness to begin your personalized healing journey. We offer appointments at our Waco and Hamilton locations, as well as telehealth consultations for patients throughout Texas.

Disclaimer: This article is for informational purposes only and is not intended to diagnose, treat, cure, or prevent any disease. Always consult with a qualified healthcare provider before starting any new treatment protocol.