(The main portion of this article was posted in 2021, but further research citations at the end support what the original article asserted. Mast Cells play a significant role in acute and long COVID symptoms. While the final cited study goes against the grain, most studies indicate mast cells have a significant role in long COVID. For that reason, this “Oldie but Goodie” rerun is a great reminder of what the past 5 years of COVID have taught us about mast cells’ important role in immune health.)
Several voices express suspicions that mast cell activation plays a role in both the acute and chronic phases of COVID 19 disease. While these immune cells get more attention for their ability to release histamine, causing allergic symptoms, they play a more common role than most would suspect. With the predicted frequency of mast cell dysfunction in society mirroring the observed frequency of both severe COVID disease and post-COVID disease, some are asking whether mast cell hyper-activation plays a role in COVID 19 manifestations. The similarity in symptoms makes us even more suspicious.
As other articles on my website describe in more detail, mast cells are early, general responders to microbial invaders like bacteria and viruses. This places them in the innate system which simply says “good guy” or “bad guy” based on certain surface protein markers on the microbes. The innate system does not depend on antibodies which target specific microbes and ignores others. That is the job of the adaptive system, primarily B-cells that make the antibodies. The mast cells, after encountering something they consider “bad guy’ release chemical messengers which activate other processes and cells. They are best known for releasing histamine but also release or trigger the release of dozens of others. If overstimulated they can contribute to anaphylaxis or in COVID 19, possibly contribute to cytokine storm. (For a deeper understanding of the immune system, purchase my Immune Prepper course at SFMEmpower.com.)
Those clinicians who have been working with mast cell activation disorder for decades, like Dr. Afrin in the primary cited paper, contend that we have several lines of evidence to connect mast cells and SARS- CoV2 pathology. Besides the frequency overlap mentioned earlier, the symptoms experienced by mast cell activation disorder patients parallels that of acute and chronic COVID 19: episodic and sometimes severe fatigue, randomly triggered chemical sensitivities, palpitations, brain fog, migraines, postural orthostatic tachycardia syndrome, dizziness, and more.
Mechanistically, mast cells possess ACE-2 receptors on their surfaces which are the prime target for Sars CoV2 entry into cells. Further potential mechanistic links include enzymes like TMPRSS2 and chymase as well as immune messengers like transforming growth factor beta. First, a protein called Transmembrane serine protease 2 (TMPRSS2) which primes the viral spike protein is produced by mast cells (Theoharides, Conti 2020). Mast cells produce an enzyme called chymase which activates transforming growth factor beta and matrix metalloproteinase 9 which are involved in lung fibrosis (Chen 2017). Other articles I addressed in my recent long hauler videos (on Facebook page) indicate that several lines of research hint that transforming growth factor beta is involved in the heart and kidney disease of COVID 19.
In looking at the crime scene, large numbers of mast cells have been found in the lung tissue after severe lung disease (Junior 2020). The primary article by Afrin et al notes that therapies effective for mast cell disease also show benefit in COVID 19 disease.
With all these lines of evidence, we at least deserve some further research into the links between mast cells and COVID 19 – and into the therapies that might help both acute and post COVID disease. Until then, we are using mast cell stabilizers like quercetin, NAC, vitamin C, and more to treat both our acute and long hauler patients with success. Caring for patients in 2021 and beyond requires an understanding of the underlying science as well as willingness to apply what we know to our current patients to save and to restore healthier lives.
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Primary Article:
Afrin, Lawrence B et al. “Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome.” International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases vol. 100 (2020): 327-332. doi:10.1016/j.ijid.2020.09.016
Other References:
Chen H., Xu Y., Yang G., Zhang Q., Huang X., Yu L., Dong X. Mast cell chymase promotes hypertrophic scar fibroblast proliferation and collagen synthesis by activating TGF-β1/Smads signaling pathway. Exp. Med. 2017;14:4438–4442. doi: 10.3892/etm.2017.5082.
Conti, P et al. “Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19.” Journal of biological regulators and homeostatic agents vol. 34,5 (2020): 1629-1632. doi:10.23812/20-2EDIT
Hafezi, Bahareh et al. “Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells.” Cells vol. 10,7 1761. 12 Jul. 2021, doi:10.3390/cells10071761
Junior J.M., Miggiolaro A.S., Nagashima S., De Paula C.B.V., Baena C.P., Scharfstein J., DE NORONHA L. Mast cell degranulation in alveolar septa and SARS-COV-2: A pathogenic pathway linking interstitial edema to immunothrombosis. Front. Immunol. 2020;11:2369.
Theoharides, Theoharis C. “Potential association of mast cells with coronavirus disease 2019.” Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology vol. 126,3 (2021): 217-218. doi:10.1016/j.anai.2020.11.003
Theoharides T.C., Conti P. COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome? J. Biol. Regul. Homeost. Agents. 2020;34:1633–1636. doi: 10.23812/20-EDIT3.
2025 Updated References
Weinstock, L. B., Brook, J. B., Walters, A. S., Goris, A., Afrin, L. B., & Molderings, G. J. (2021). Mast cell activation symptoms are prevalent in Long-COVID. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 112, 217–226. https://doi.org/10.1016/j.ijid.2021.09.043
Arun, S., Storan, A., & Myers, B. (2022). Mast cell activation syndrome and the link with long COVID. British journal of hospital medicine (London, England : 2005), 83(7), 1–10. https://doi.org/10.12968/hmed.2022.0123
Sumantri, S., & Rengganis, I. (2023). Immunological dysfunction and mast cell activation syndrome in long COVID. Asia Pacific allergy, 13(1), 50–53. https://doi.org/10.5415/apallergy.0000000000000022
Salvucci, F., Codella, R., Coppola, A., Zacchei, I., Grassi, G., Anti, M. L., Nitisoara, N., Luzi, L., & Gazzaruso, C. (2023). Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation. Frontiers in cardiovascular medicine, 10, 1202696. https://doi.org/10.3389/fcvm.2023.1202696
A Contrary Opinion to be Fair
Lenning, O. B., Jonsson, G., Grimstad, T., Janssen, E. A. M., Braut, G. S., Berven, F., & Omdal, R. (2024). No signs of mast cell involvement in long-COVID: A case-control study. Scandinavian journal of immunology, 100(5), e13407. https://doi.org/10.1111/sji.13407
Sanctuary Functional Medicine, under the direction of Dr Eric Potter, IFMCP MD, provides functional medicine services to Nashville, Middle Tennessee and beyond. We frequently treat patients from Kentucky, Alabama, Mississippi, Georgia, Ohio, Indiana, and more... offering the hope of healthier more abundant lives to those with chronic illness.
Dr. Eric Potter graduated from Vanderbilt Medical School and then went on to specialize in internal medicine (adult) and pediatric care, spending significant time and effort in growing his medical understanding while caring for patients from all walks of life.
