A patient who breaks out into hives after every business deal, one who’s prone to flushing and swelling, and another who has been hospitalized with anaphylaxis are among those Theoharis Theoharides, MD, PhD, sees in his practice treating patients with mast cell activation syndrome (MCAS).

MCAS has been associated with wide-ranging symptoms, including flushing, hives, swelling, abdominal pain, diarrhea, breathing problems, rapid heart rate, and drops in blood pressure. Symptoms range from mild to life-threatening anaphylaxis. The condition can significantly interfere with daily life. 

Triggers include exercise, temperature changes, exposure to chemicals such as those found in cleaning or skincare products, medications such as nonsteroidal anti-inflammatory drugs, stress, hormonal changes, infections, physical stimulation such as massage, and high-histamine foods.

Concern about MCAS is increasingly bringing people to doctors’ offices. Specialist referrals have risen substantially over the past 15 years, a trend some experts attribute to greater awareness of the disease and growing access to information and misinformation online. Theoharides pointed to COVID as a potential contributor to the condition.

Theoharides, executive director of the Center of Excellence for Neuroinflammation Research Center for Collaborative Research at Nova Southeastern University in Fort Lauderdale, Florida, is among the physicians at the forefront of a growing debate over how the condition should be diagnosed and how to approach patients who do not meet established diagnostic criteria. The dispute centers on a complicated question: Are some clinicians appropriately avoiding an unsupported diagnosis, or are current criteria failing to identify some patients who actually have the syndrome?

“Most of my patients have gone about 10 years looking for answers,” Theoharides said. “They usually reach me after they’ve given up hope.”

Guidance from the American Academy of Allergy, Asthma, & Immunology endorses a diagnostic approach, termed consensus 1, that requires recurrent symptoms in multiple organ systems, objective evidence of increased mast cell mediators, and improvement with mast cell-targeted treatment such as antihistamines.

A broader framework, known as consensus 2, recognizes more symptoms and lab findings and does not require an abnormal mast cell mediator test in every patient. 

The difference has major implications for estimates of how many people may have MCAS. Lawrence Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine in New York City, and a leading proponent of consensus 2, said MCAS may affect up to 17% of the population, an estimate disputed by proponents of the narrower framework.

Controversy Over Diagnosis

Lab testing is central to the disagreement over who should receive an MCAS diagnosis. 

“We require documentation that mast cell activation is occurring in order to call something a mast cell activation syndrome,” said Cem Akin, MD, PhD, professor of medicine in the Division of Allergy and Clinical Immunology at the University of Michigan in Ann Arbor, and one of the developers of consensus 1. 

Akin called serum tryptase the “gold standard” because it is the best-validated biomarker, with an acute increase of 20% above a patient’s baseline plus 2 ng/mL considered to be evidence of systemic mast cell activation. Certain other mediator measurements can also provide evidence of activation. 

Testing can be difficult in practice. Tryptase measurement should be obtained within several hours of symptom onset and compared with a baseline measurement. Theoharides said patients may not always be able to reach a laboratory while an episode is occurring. 

In accordance with the consensus 2 framework, Theoharides also questions how heavily clinicians should rely on tryptase, arguing that many patients with MCAS do not experience significant elevations, nor the anaphylactic episodes that consensus 1 emphasizes as most characteristic of MCAS.

Afrin argues that testing available now may not capture the full complexity of mast cell activity. Mast cells can release hundreds of different mediators. Testing can also be challenging because many mediators are unstable and require careful specimen handling, and specialized testing may not be available in every clinical setting, he said. 

Not meeting MCAS criteria does not necessarily mean mast cells play no role in symptoms, according to Akin. He and his colleagues identify another category for patients who don’t meet full MCAS criteria called “mast cell activation, unspecified,” when mast cell involvement is possible but remains unconfirmed.

Theoharides said he tells patients not to get too caught up in the label.

Technically, some patients with unspecified mast cell activation don’t have MCAS, he said, “but nevertheless, they may have nearly identical symptoms.”

Akin and colleagues caution, however, that unspecified mast cell activation should remain a provisional diagnosis rather than a final explanation for multisystem symptoms. They urge clinicians to continue investigating other possible causes.

According to Afrin, some patients whose testing doesn’t support an MCAS diagnosis under consensus 1 criteria are simply told, “Sorry, you don’t have mast cell disease. There’s nothing else I can do to help you.”

Barriers to Care

Navigating these distinctions can be difficult without specialized knowledge of mast cell disorders. 

A 2025 American College of Allergy, Asthma & Immunology educational program identified limited familiarity with the spectrum of mast cell disorders and diagnostic criteria as practice gaps. A 2026 European Academy of Allergy & Clinical Immunology position paper similarly called for further education.

Access can compound the problem. Theoharides said complex multisystem presentations may require lengthy evaluations that insurers do not adequately reimburse. Specialists may also be thousands of miles away and prohibitively expensive. 

Once diagnosed, treatment involves reducing symptoms and blocking the effects of mast cell mediators. Patients may receive oral H1 and H2 antihistamines, mast cell stabilizers such as cromolyn sodium, or leukotriene-modifying drugs. Some patients with persistent symptoms receive the injectable biologic omalizumab (Xolair). Epinephrine is used for anaphylaxis. Some patients turn to plant flavonoids such as luteolin for their mast cell-stabilizing effects.

Patients Caught in the Middle 

Many patients who don’t receive an MCAS diagnosis may struggle to find another explanation for their symptoms. Some describe not being taken seriously or spending years having physical symptoms attributed to psychological causes. 

“They’ve been told, ‘It’s all in your head,’ or ‘you’re imagining it,’ or ‘it’s psychosomatic,’” Afrin said.

Leonard Bielory, MD, a professor of medicine, allergy, immunology, and ophthalmology at Hackensack Meridian School of Medicine in Clifton, New Jersey, said most patients referred to him for suspected MCAS do not ultimately have the syndrome and expressed concern that it is becoming a “wastebasket” diagnosis for people searching for an explanation for vague or unexplained symptoms. 

“People want to be classified,” Bielory said. “They read about it online, say ‘I have that,’ and come in preformatted. I say, ‘We have to reformat. I need the data. I need the observation.’ Because one thing is to say you have it; it’s another to say it’s been observed.” 

Theoharides sees another danger — patients receiving inaccurate or dangerous guidance from unverified online sources. A 2026 study of popular MCAS-related TikTok videos found that most contained information researchers classified as inaccurate. 

Finding the Line Between Underdiagnosis and Overdiagnosis

For Akin, questioning an MCAS diagnosis does not mean questioning whether a patient’s symptoms are genuine.

“If the patient is telling me that they have a symptom, of course they are having the symptom,” he said. “This is very real.”

But an incorrect diagnosis could also be a disservice if it obscures the search for another cause, Akin said. 

He acknowledged that established criteria may sometimes miss patients. 

“If the patient is presenting with typical anaphylactic-type symptoms like flushing, low blood pressure, abdominal pain, breathing problems, hives, occurring all at the same time, then the diagnosis could be possible or even highly likely even when there’s no chance to measure the mediator,” Akin said. 

Bielory described mast cell activation as a spectrum, noting that some degree of activation occurs normally — such as an occasional outbreak of hives — and does not necessarily constitute MCAS. He compared the distinction with an occasional sleep disturbance vs chronic insomnia.

Theoharides said clinicians ultimately need to navigate between two risks: attributing too many symptoms to mast cell activation and overlooking it when it may be contributing to a patient’s illness. 

Theoharides, Bielory, Afrin, and Akin reported having no conflicts of interest.

Brittany Vargas is a journalist covering medicine, mental health, and wellness.