Meet the Humble Mast Cell

COVID-19 vaccine allergic reactions have put mast cells in the clinical research spotlight like never before. That’s not only because they play a key role in the human immune response, but also because mast cells are at the root of allergic reactions, including anaphylaxis – making them a prime target of inquiry as we try to understand why, in rare cases, COVID-19 vaccines trigger an allergic response.

Mast cells are found in connective tissue throughout our bodies. In mast cell disorders, these cells are overly active and may proliferate, resulting in a variety of harmful – and potentially life-threatening – effects. The inappropriate activation of mast cells is considered a clinical disorder falling into one of two broad categories: mastocytosis or mast cell activation syndrome (MCAS) (1).

Mastocytosis is defined as an abnormal accumulation of mast cells in one or more organ systems. In addition to putting a patient at greater risk of anaphylaxis, this systemic disorder can also have adverse effects on other organ systems, including the skin, cardiovascular system, gastrointestinal tract, and bone marrow. The diagnostic criteria for mastocytosis are well-established and the condition is usually identified through tissue biopsy in combination with genetic and/or blood tests. Serum tryptase is a common test that can be ordered as part of the initial workup, but the diagnostic criteria for mastocytosis are described below in more detail. 

The World Health Organization (WHO) has a consensus on definitions of various forms of mastocytosis and on diagnostic criteria (2). The major criteria include histological or immunohistochemical alterations, such as mast cell aggregates containing more than 15 mast cells in bone marrow sections. The minor criteria include cytological alterations (for example, greater than 25 percent of mast cells morphologically abnormal), detection of c-KIT mutations on codon 816, and immunophenotypic alterations. These last may include expression of CD25 (with or without CD2) in mast cells from bone marrow, peripheral blood, or other organs, and total serum tryptase levels persistently >20 ng/mL (not applicable if there is a comorbid blood disorder or evidence of acute mast cell release). The diagnosis of systemic mastocytosis requires at least one major criterion plus one minor criterion or at least three minor criteria.

When patients do not meet the clinical criteria for mastocytosis, but still experience chronic allergic reactions to triggers such as food, prescription drugs, or insect stings, they may be diagnosed with MCAS. Although the allergic responses can vary in severity, the symptoms of MCAS typically include hives, swelling, low blood pressure, difficulty breathing, and diarrhea.

Because there have been cases of allergic reactions – including anaphylaxis – following COVID-19 vaccinations, many are now wondering whether mast cell hyperactivity or mast cell disorders are playing a role. If so, what are the risk factors for allergic reactions to COVID-19 vaccination? Are patients diagnosed with mastocytosis or MCAS at higher risk? And should they take precautions before or after immunization?

First, it is important to keep in mind that allergic reactions to the COVID-19 vaccine are quite rare. As more and more people are vaccinated, the statistics continue to evolve – but, as of this writing, allergic reactions occur at 11.1 cases per million Pfizer-BioNTech vaccine doses (3), 2.5 cases per 1 million Moderna vaccine doses (4), and fewer than 0.5 cases per 1 million Janssen vaccine doses (5). According to the UK’s Medicines & Healthcare products Regulatory Agency, out of 19.5 million administered doses of the Oxford-AstraZeneca vaccine, also known as Vaxzevria, only 455 (0.002%) were associated with an anaphylaxis-related adverse reaction (6). There has also been conflicting data regarding risk factors for allergic reactions to COVID-19 vaccines. Some patients who have reactions appear to have a history of eczema, asthma, and allergies, whereas others do not (7).

Because allergic reactions to COVID-19 vaccines are so rare and the data surrounding them so uncertain, the risk factors and mechanisms of these reactions require further investigation. According to the Centers for Disease Control and Prevention, health care providers who suspect a patient is having an allergic reaction may consider obtaining a serum tryptase test. Because tryptase is released during anaphylaxis, clinicians should aim to collect tryptase between 30 and 90 minutes after the start of the reaction, but patients can be tested for elevated tryptase up to six hours after the start of a reaction (8).

Tryptase is an enzyme released by activated mast cells during normal and abnormal immune responses – meaning that serum tryptase concentrations can indicate mast cell activity (9). If mast cells are activated appropriately, there is a brief rise in serum tryptase concentration; however, patients with mast cell disorders show a high level of serum tryptase over a prolonged period and a higher count of mast cells in the body. These higher levels of tryptase trigger an inflammatory response, including symptoms such as flushing, rapid decreases in blood pressure, and even anaphylactic shock. An anaphylactic reaction like this must be treated immediately with epinephrine (adrenaline); without immediate treatment, anaphylaxis can be fatal.

The suspected allergen in the COVID-19 vaccine is polyethylene glycol (PEG) or polysorbate, but additional studies are needed to confirm the culprit allergen(s) and the mechanisms involved in the allergic response. To that end, the National Institutes of Health is currently conducting a multi-site national clinical trial, the Systemic Allergic Reactions to SARS-CoV-2 Vaccination study, to further evaluate COVID-19 vaccine allergic reactions and risk factors (10). The study team will enroll 3,400 participants, of whom 60 percent will have either a history of severe allergic reactions or a diagnosis of a mast cell disorder and 40 percent will not. The findings of this phase II trial will provide more clarity around the risks and benefits of receiving the COVID-19 vaccines, particularly for people who have allergies or have been diagnosed with a mast cell disorder. However, based on current recommendations, the COVID-19 vaccine is not contraindicated in individuals with mastocytosis or severe allergies unless they have a known allergy to a vaccine ingredient (11).