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Mast Cell Activation Syndrome: Immune Response Gone Wrong

by Grace Gibson

Graphic design by Jeah Kim

The COVID-19 pandemic has brought with it several health challenges, one of which is an increase in autonomic disease post-COVID-19 infection.1,2 One such disorder is mast cell activation syndrome (MCAS), a condition characterized by the improper activation of immune cells.3 The rise MCAS symptoms after COVID-19 infection suggests that medical professionals should increase awareness of MCAS, promote education on the disease, and familiarize themselves with treatments.3 

As actors in the body’s immune system, mast cells react to the introduction of foreign materials by releasing molecules that cause the inflammatory response we associate with an infection.4 In a healthy immune system, mast cells have  several critical functions, not only acting in the body’s defenses against pathogens but also promoting blood vessel growth and tissue repairs.  Widespread distribution of these cells ensures that they can react rapidly to an infection.6 Their immune response maximizes its reach by secreting molecules with varied effects on different tissues they encounter. For example, one type of molecule released by mast cells is a cytokine, a small protein involved in immunity. Cytokines can both increase mucous in the respiratory tract and promote movement in the gastrointestinal tract, mobilizing multiple body systems in immunity.4 

 MCAS distorts these necessary functions of mast cells by causing improper activation or hyperactivation.4 Improper mast cell activation plays a role in “traditional” allergies, causing an allergic response when the body is exposed to certain triggers, or allergens.5 MCAS patients, however, may experience similar responses, possibly even anaphylaxis, without the presence of allergens.5 Therefore, MCAS patients may undergo life-threatening anaphylaxis events without clear external cause, in addition to experiencing other symptoms associated with improper mast cell activation.5,7  

Because of the distribution of mast cells throughout the body, disorders like MCAS impact multiple body systems, not only worsening patient experiences but also making diagnosis and treatment more difficult.5,7 Symptoms of MCAS can include hives on the skin, neurological symptoms like memory loss, musculoskeletal pain, and more.5 Additionally, MCAS symptoms frequently overlap with those of other conditions, and MCAS is frequently seen in patients with multiple chronic illnesses, most notably Long COVID. These factors contribute to misdiagnoses with other disorders.3,7 The complexity of MCAS requires multiple diagnostic tools and considerations: evaluations of all symptoms in conjunction with each other, blood tests for levels of molecules released by mast cells, and trials with drugs targeting mast cell actions.  A patient with ongoing symptoms affecting multiple bodily systems, especially if anaphylaxis is present, may receive an MCAS diagnosis on that basis. However, a positive diagnosis usually requires these symptoms to be found alongside other positive criteria (blood test results and drug test responses).5,7  

Because mast cell disorders are not limited to MCAS, an MCAS diagnosis is still rare, and the condition is considered uncommon.5,7 However, ongoing research on the relationship between mast cell activation and COVID-19 suggests that COVID infections may increase MCAS symptoms. Studies of Long COVID (LC) patients, who experience severe symptoms months to years after an initial COVID-19 infection, have shown that mast cell hyperactivation may be responsible for LC symptoms.8 Unfortunately, LC is not a rare condition: surveys of people infected with COVID-19 found that 23.2% of people developed at least one LC symptom after their infection; that number jumped to around 50 percent of those who had been hospitalized with a severe COVID-19 case.8,9,10 These results show that millions of people are at risk of developing LC and accompanying MCAS symptoms as the pandemic continues.  

In light of this evidence, medical professionals should familiarize themselves with this condition. MCAS can be difficult to manage, with the triggers for mast cell activation hard to predict and the symptoms varied and potentially severe. For MCAS patients, understanding medical professionals and comprehensive care plans are crucial. While no cure exists, treatments like antihistamines, mast cell stabilizers, and epinephrine can manage symptoms. A new drug option, omalizumab (Xolair), also appears to effectively decrease anaphylaxis in MCAS patients, offering another new treatment options for severe cases, and ongoing drug trials are examining further options.11 Receiving an accurate diagnosis and effective treatment will help to relieve debilitating symptoms of potentially thousands of people who develop the disease.5 MCAS may seem like a scary diagnosis, but promoting new treatments and increasing awareness can make it much more manageable for patients. 

References 

  1. Blitshteyn S, Whitelaw S. Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients. Immunol Res. 2021;69,205–211. 
  2. Jammoul M, Naddour J, Madi A, et al. Investigating the possible mechanisms of autonomic dysfunction post-COVID-19. Autonomic Neuroscience. 2023;245,103071. 
  3. 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. 
  4. Fong M, Crane JS. Histology, Mast Cells [Internet]. Treasure Island (FL): StatPearls Publishing. Available from https://www.ncbi.nlm.nih.gov/books/NBK499904/ 
  5. Cleveland Clinic. Mast Cell Activation Syndrome [Internet]. [Cited 1 February 2025]. Available from https://my.clevelandclinic.org/health/diseases/mast-cell-activation-syndrome  
  6. Church M, Levi-Schaffer F. The human mast cell. JACI. 1997;99(2):155–160. 
  7. Valent P. Mast cell activation syndromes: definition and classification. Allergy. 15 Feb 2013; 68(4),417–424. 
  8. Weinstock LB, Brook JB, Walters AS, et al. Mast cell activation symptoms are prevalent in Long-COVID. Int J Infect Dis. 2021 Nov;112:217-226. 
  9. Munblit D, Bobkova P, Spiridonova E, et al. Incidence and risk factors for persistent symptoms in adults previously hospitalized for COVID‐19. Clin Exp Allergy. 2021;51(9),1107–1120.  
  10. FAIR Health White Paper. A detailed study of patients with long-haul COVID. 15 June 2021. 
  11. Frieri M. Mast Cell Activation Syndrome. Clinic Rev Allerg Immunol. 2018;54,353–365.