MCAS as an Immune Derangement Syndrome: Why Multiple Triggers Matter in Integrative Medicine & Functional Medicine

By Yoon Hang Kim, MD, MPH | www.directintegrativecare.com

After two decades of practicing integrative medicine, I’ve noticed a pattern that doesn’t fit neatly into conventional diagnostic frameworks. Patient after patient walks into my clinic with a diagnosis of Mast Cell Activation Syndrome—or suspicion of one—and almost invariably, they bring a complex medical history with them. Autoimmune disease. Mold exposure. Lyme disease. Long COVID. Sometimes all of the above.

I don’t think that’s coincidence. And increasingly, the research supports what I’m seeing in clinical practice.

I’ve come to view MCAS not as a standalone diagnosis, but as an immune derangement syndrome—a final common pathway where multiple immunological insults accumulate until the system reaches a tipping point. The immune system, designed to protect us, loses its ability to self-regulate and return to homeostasis. It forgets how to calm down.

What Is Mast Cell Activation Syndrome (MCAS), Really?

Mast Cell Activation Syndrome is characterized by mast cells—immune cells found throughout connective tissue—becoming hyperreactive. They release excessive amounts of chemical mediators like histamine, tryptase, prostaglandins, and cytokines in response to stimuli that wouldn’t normally be problematic. This process is called degranulation, and it can be triggered by foods, infections, stress, or environmental exposures. The result is chronic, multisystem inflammation affecting everything from the cardiovascular and gastrointestinal systems to the skin, brain, and respiratory tract.

The symptoms are notoriously varied: flushing, hives, abdominal pain, brain fog, fatigue, palpitations, shortness of breath—and dozens more. Some patients experience full anaphylactic reactions with low blood pressure and difficulty breathing. Symptoms typically wax and wane, varying in severity and duration, which makes diagnosis even trickier. To meet diagnostic criteria, patients need systemic symptoms involving two or more organ systems.

This heterogeneity makes MCAS both underdiagnosed and overdiagnosed—patients suffer for years without answers, while others receive the label without meeting strict criteria.

A 2024 study from the Karolinska Institute evaluated 703 patients with suspected mast cell disorders and found that only 4.4% met strict criteria for idiopathic MCAS. This tells us two things: we need better diagnostic tools, and we need to look deeper at what’s actually driving mast cell dysfunction in these patients.

Diagnosis and Testing for MCAS

Let me be straight with you: diagnosing MCAS is genuinely difficult. Many of my patients have seen five, ten, even fifteen specialists before landing in my office. That’s not because previous doctors were incompetent—it’s because MCAS symptoms overlap with so many other conditions, and the testing isn’t straightforward.

The diagnosis starts where good medicine always starts: a thorough history and physical exam. I’m listening for patterns—episodic flushing, GI symptoms that don’t follow typical patterns, unexplained allergic-type reactions, chronic pain that doesn’t fit neatly into other diagnoses. I’m also looking at the whole person: physical symptoms, yes, but also stress levels, sleep, emotional health. These factors matter more than many practitioners realize.

Laboratory testing focuses on measuring mast cell mediators—tryptase, histamine, and prostaglandin metabolites—released during degranulation episodes. Serum tryptase and urinary mediator testing are the standard tools. In some cases, bone marrow biopsy may be needed to rule out systemic mastocytosis, which is a different (and more serious) condition.

Here’s what I tell patients: we also need to rule out what MCAS isn’t. That means allergy testing to distinguish true IgE-mediated allergies from mast cell dysfunction. It means considering other conditions—including serious ones like cancer—that can mimic MCAS symptoms. Good diagnosis is as much about ruling things out as ruling things in.

Sometimes the diagnosis becomes clearer through treatment response. When patients improve significantly on H1/H2 antihistamines and mast cell stabilizers, that tells us something important. It’s not a perfect test, but clinical response matters.

What I’ve found essential is building a real partnership with patients. MCAS management requires ongoing adjustments based on individual responses. It’s not a “one prescription and done” situation. Beyond medications, I often integrate approaches like medical acupuncture and mind-body techniques to support overall healing—not as replacements for evidence-based treatment, but as complements to it.

The Multiple Hits Model in Diagnosing MCAS

Here’s what I’ve observed clinically: MCAS rarely emerges from a single trigger. Instead, patients typically present with a history of overlapping immune challenges—what I call “hits” to the system. Stack enough of these hits, and the immune system tips into chronic dysfunction.

This isn’t hardware failure. It’s software. The regulatory system gets stuck in overdrive.

Let me walk through the major contributing factors I see in practice.

Autoimmune Conditions

Chronic autoimmune inflammation creates a persistent state of immune activation that can sensitize mast cells over time. Patients with conditions like hypermobile Ehlers-Danlos syndrome show increased prevalence of inflammatory diseases and autoantibodies. MCAS has been reported alongside connective tissue disorders and dysautonomia, suggesting shared pathophysiology rooted in immune dysregulation.

Mold Exposure and Mycotoxins

Water-damaged buildings harbor toxigenic molds like Stachybotrys, Aspergillus, and Penicillium. The mycotoxins they produce—ochratoxin A, aflatoxins, trichothecenes—are potent immune disruptors. They directly activate mast cells, disrupt mitochondrial function, and promote systemic inflammation. I’ve seen patients whose MCAS symptoms dramatically improved once they addressed their mold exposure—and others who couldn’t make progress until they did.

Lyme Disease and Co-infections

Research has confirmed that Borrelia burgdorferi spirochetes—the bacteria causing Lyme disease—directly trigger mast cell degranulation. A 1999 study in Infection and Immunity showed that mast cells exposed to B. burgdorferi release proinflammatory cytokines like TNF-alpha. More recent work demonstrated that OspC, a surface protein involved in early Borrelia transmission, induces mast cell degranulation.

In my practice, about half of patients with tickborne infections also experience MCAS symptoms. The overlap is striking—and treating the mast cell component often clarifies which symptoms are truly from the underlying infection.

Long COVID

Perhaps the most compelling evidence for the “immune derangement” model comes from Long COVID research. A landmark 2021 study by Weinstock and colleagues compared Long COVID patients with established MCAS patients and healthy controls. The finding was remarkable: before COVID infection, Long COVID patients had virtually identical symptom profiles to healthy controls. After infection, their profiles were virtually identical to MCAS patients.

The researchers concluded that increased mast cell activation induced by SARS-CoV-2 may underlie part of Long COVID’s pathophysiology. This validates what integrative practitioners have been observing clinically—and suggests therapeutic approaches that actually help.

Long COVID involves multiple immune disruptions: T-cell depletion, innate immune hyperactivity, loss of naive T and B cells, and elevated pro-inflammatory cytokines. This pattern of immune chaos—rather than a targeted response—is exactly what I mean by “derangement.”

Why This Matters for Treatment

Understanding MCAS as an immune derangement syndrome with multiple contributing factors fundamentally changes how we approach treatment.

Mast cell stabilizers help. Antihistamines provide symptomatic relief and can reduce flushing and anaphylactic episodes, especially combined with other medications like corticosteroids or prostaglandin inhibitors. But they’re not enough if we ignore what pushed the system over the edge in the first place.

Real treatment means asking: what got you here?

That means comprehensive evaluation for mold exposure, Lyme and co-infections, autoimmune conditions, and viral reactivation. It means accepting that patients may need multimodal strategies rather than single-target interventions. And it means using immunomodulators like low-dose naltrexone as part of a broader approach to restore immune regulation—not just suppress symptoms.

One important note: acute MCAS episodes should be treated like anaphylaxis. If a patient is having a severe reaction, epinephrine comes first. We can address root causes once they’re stable.

In my LDN Primer, I discuss how MCAS fits into a larger framework of complex chronic conditions where LDN serves as one critical component but cannot achieve remission alone. For these patients, LDN calms the immune system enough to make deeper treatment more successful and better tolerated—but we still have to address root causes.

The Path Forward MCAS Integrative Medicine Functional Medicine

I want to be honest about what we don’t know. The underlying mechanisms that lead to mast cell activation in MCAS patients aren’t fully understood. We need better biomarkers, better diagnostic criteria, and more research into why some patients tip into chronic dysfunction while others recover.

But we know enough to help patients now. We know MCAS rarely exists in isolation. We know chronic infections, toxic exposures, and autoimmunity can all sensitize mast cells. And we know that addressing these root causes—rather than just stabilizing mast cells—offers the best hope for meaningful, lasting improvement.

MCAS isn’t a diagnosis. It’s a destination. And the clinical question that matters most is: what got you here?

References

1. Zaghmout T, Maclachlan L, Bedi N, Gülen T. Low prevalence of idiopathic mast cell activation syndrome among 703 patients with suspected mast cell disorders. J Allergy Clin Immunol Pract. 2024;12(3):753-761.

2. Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Mast cell activation symptoms are prevalent in Long-COVID. Int J Infect Dis. 2021;112:217-226.

3. Talkington J, Nickell SP. Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. Infect Immun. 1999;67(3):1107-1115.

4. Bernard Q, Gadería-Fuentes M, Rath E, et al. Interaction of primary mast cells with Borrelia burgdorferi (sensu stricto): role in transmission and dissemination. Parasit Vectors. 2017;10(1):313.

5. Sumantri S, Rengganis I. Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pac Allergy. 2023;13(1):50-53.

6. Castells M, Giannetti MP, Hamilton MJ, et al. Mast cell activation syndrome: Current understanding and research needs. J Allergy Clin Immunol. 2024;154(2):255-263.

7. Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis. 2020;100:327-332.

About the Author

Yoon Hang Kim, MD, MPH is a board-certified preventive medicine physician and graduate of the University of Arizona Integrative Medicine Fellowship. He has been prescribing low-dose naltrexone for over two decades and has presented at multiple LDN Research Trust conferences. Dr. Kim practices telemedicine through Direct Integrative Care, serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas.

www.directintegrativecare.com