Mast cell activation disease diagnosis can reveal PI

Allergies are a common reaction to potential triggers like dander, pollen, dust mites, foods, medications, and stinging insects. Most people recover by taking an allergy medicine or avoiding the trigger. But for some, the cells in the body that respond to allergens, mast cells, over-activate due to internal signals and cause a condition known as mast cell activation disease (MCAD).

Mast cells are immune cells that live throughout your body in bone marrow and in tissues that serve as the barrier between your body and the outside world, such as your airway, gastrointestinal tract, and skin. When activated, mast cells release chemicals that assist in healing. They protect from foreign substances and infection and are part of the inflammation process. For example, when your body produces swelling from an insect bite or your nose gets stuffy because of seasonal allergies, those symptoms result from mast cell activation.

MCAD refers to at least two distinct conditions: mastocytosis and mast cell activation syndrome (MCAS). When a person has MCAD, they either produce too many mast cells, known as mastocytosis, and/or their mast cells release inappropriate amounts of mast cell chemicals, known as MCAS. Persons with MCAD experience chronic and severe symptoms such as joint pain, cough, brain fog, fatigue, nasal inflammation, rashes, headaches, and stomach upset.

In an Immune Deficiency Foundation (IDF) presentation on mast cell activation, Dr. Anne Maitland, an allergy and immunology specialist with the MetroDora Institute, described how, in the process of diagnosing some of her patients with MCAD, she also discovered that they had primary immunodeficiency (PI).

Maitland said she’s identified MCAD patients that have primary immunodeficiencies, including CD4 lymphocytopenia, complement deficiencies, and antibody deficiencies.

“Mast cells are acting like the engine light on your car saying something's wrong underneath, whether you're hiving, coughing, having brain fog, or joint issues. Trying to understand why the mast cells are misbehaving is what led me to understand that, for individuals with immunodeficiency, it is a hypersensitive disorder that pointed the way to them having an unidentified primary immunodeficiency,” said Maitland.

Mast cells in persons with PI aren’t properly regulated and don’t get turned off because the other immune system components aren’t functioning.

“In many ways, if you have an immunodeficiency, like you're lacking an antibody that can’t recognize bacteria or viruses or a component in your lymphocyte compartment or complement, mast cells will not stand down. Their job as a first responder is to back up whatever danger and try to contain it to the best of their ability. And once that danger is under control, the mast cells will stand down,” said Maitland.

“If you're having a chronic condition, it's really important to understand whether or not your mast cells are doing their job or they're doing it inappropriately. The idea is to understand your mast cells are releasing these chemicals, causing you to have chronic issues, whether it's in your nose, your lungs, your skin, your gut, your bladder, or your brain. And then if you can identify why the mast cells are misbehaving, you can then have better-tailored therapeutics to help you feel better.”

Evaluations for mysomastocytosis include blood or urine tests, bone marrow, biopsies of the skin and affected organ, imaging tests, and genetic testing.

The diagnostic protocol to determine MCAS is a multi-step process. The first step is to determine if a patient is impacted by symptoms in at least two organ systems, including:

• Constitutional/systemic—fatigue, weight loss, and inability to lose weight.
• Neurologic disorders—headache, brain fog, memory impairment, sleep disorders, unable to concentrate or focus.
• Rhinitis—nasal congestion, runny nose, post-nasal drip, throat swelling.
• Cardiovascular—fast heart rates, low blood pressure, chest pain, lightheadedness.
• Respiratory lower airway—coughing, difficulty breathing, chest tightness, wheezing.
• Digestive disorders—bloating, nausea, diarrhea, constipation, heartburn/reflux, abdominal cramps.
• Skin—hives, itch, flushing, swelling of the skin.
• Urinary tract disorders—burning with urination, pain syndrome.
• Musculoskeletal—arthritis, muscle aches, joint pain, joint swelling, bone pain, bone loss.

When symptoms are recurrent, accompanied by increased mast cell-derived chemical mediators in blood or urine, and responsive to treatment with anti-mast cell or mast cell mediator medications, the diagnosis of MCAS is appropriate.

A skin biopsy and checking for mast cells in the gastrointestinal tract through a colonoscopy or an endoscopy are also crucial for diagnosing and differentiating between a genetic cause like mastocytosis versus MCAS.

“The gold standard for diagnosing misbehaving mast cells is the tissue. There are some mast cell progenitor cells in the blood, but the majority of mast cells are found in the tissue,” said Maitland. “Once I find out that their mast cells are misbehaving, it's important to identify why those mast cells are misbehaving. Do you have some rogue broken mast cells such as systemic mastocytosis or hypertryptasemia? Or do you have another process that's driving the mast cells in this behavior? Like, do you have POTS? Do you have an immunodeficiency? Do you have an autoimmune disorder?”

In addition to PI, other immunologic triggers of MCAD include:

• IgE-mediated reactions to foods, drugs, and other allergens, and some autoimmune conditions.
• Chronic infections.
• Serum sickness.

Non-immunologic triggers include connective tissue disorders such as Ehlers-Danlos syndrome, thyroid disease, and tumors.

Proper diagnosis allows greater specificity in treatment, said Maitland.

“Once you've identified someone that has MCAS or MCAD and you've identified why, such that they have, for instance, positive allergy tests or they're dealing with recurrent infections, or they have an immunodeficiency, depending on what is tickling the mast cells to release those chemicals inappropriately, you then can tailor the therapies based on the positive testing,” she said.

For people with allergies to pollen, food, medications, or stinging insects, treatments include allergen desensitization and avoidance measures; medications that block receptors on other cells from reacting to the chemicals mast cells release; medications that stabilize the mast cells themselves; and biologics such as omalizumab that block IgE.

Infections require appropriate antimicrobials, possible corticosteroids to modify the overactive immune response, and anti-inflammatory agents, including immunoglobulin. Anti-inflammatories are also used for treatment when MCAD is triggered by autoimmune disorders.

For individuals with PI, Maitland uses prophylactic antibodies to treat MCAS and has had success using the antimicrobial azithromycin three times a week to help prevent hives in patients with selective IgA deficiency.

Maitland said providers should know that other health conditions, such as cardiac conditions, endocrine disorders, digestive ailments, immunologic conditions, neurologic/psychiatric conditions, skin conditions, and connective tissue disorders, may look like MCAD.

“We need more data and validated tests to identify whether or not somebody's mast cells are misbehaving. But just because we're still trying to elucidate why the mast cells are misbehaving or may be contributing to a patient's illnesses, it's important to maintain every effort to continue pursuing the possibility of underlying and undiagnosed immunodeficiency, for instance, and then also tailor the therapies based on what might be causing your mast cells to misbehave,” she said.