If It Looks Like A Duck

A Biased Look at Mast Cells and COVID Long Haul Syndrome

Patricia Weltin

As COVID-19 rages on, an often overlooked group of people suffering with symptoms long after they have tested negative for COVID-19 wonders why and how they got here. A voracious reader of all things COVID-19, I started to notice an emerging trend; adults and children were developing Postural Orthostatic Tachycardia Syndrome(POTS) and gastroparesis. As a mother of two children suffering with Ehlers-Danlos Syndrome(EDS) and it’s common comorbids, including POTS, I immediately began questioning the link between COVID-19 Long Haul Syndrome and EDS. It quickly became apparent to me, to mast cell expert Dr. Afrin (https://www.sciencedirect.com/science/article/pii/S1201971220307323), and to our family of EDSers that mast cells seems like the likely culprit. In this article, I’m going to explore the mast cell links to COVID Long Haul and recent effective treatments, most mast cell stabilizers. I know I am biased. I know I see mast cells everywhere. I know I’m not taking into consideration any other possibilities that could account for COVID Long Haul symptoms, but I also know there is an overwhelming connection to mast cells.

What are Mast Cells

Mast cells are immune system cells meant to help the body fight infection. Mast cells have small sacs containing many different mediators, like histamine and tryptase. In Mast Cell Activation Syndrome(MCAS), mast cells seem to degranulate and release mediators, even in situations that seem harmless. Mast cells are found everywhere in the body, so the symptoms can be many and debilitating. What do mast cells have to do with COVID Long Haul? 

Hypothesis

Growing up, my oldest daughter suffered from chronic sinusitis and ear infections. She had seven sets of eustachian tubes and two endoscopic sinus surgeries. After yet another ear infection and headed toward another surgery, I suggested that my daughter may have allergies. She had severe eczema as a baby, but really had no signs of allergies. The allergy test showed that she was highly allergic to many things. She was put on allergy medication and never needed tubes or sinus surgery again. If you had asked me at the time if my child had a chronic illness, I would have said no. People don’t think of allergies as a chronic illness, just an annoyance. So, I wonder do people suffering with COVID Long Haul have an undiagnosed mast cell disorder or did the virus create a mast cell disorder?

Symptoms

In a study conducted by Dr. Natalie Lambert and Survivor Corps,(https://precisionhealth.iu.edu/news-multimedia/_news/lambert-covid-symptom-study-doc.pdf) members of the Survivor Corps Facebook group, created to support COVID-19 survivors, were surveyed to determine the most common COVID Long Haul symptoms. The survey resulted in a list of 50 of the most common symptoms, all of which can be connected to mast cells. Half of the symptom list (fatigue, muscle or body aches, shortness of breath, difficulty concentrating or focusing, inability to exercise or be active, headache, memory problems, persistent chest pain or pressure, cough, joint pain, heart palpitations, diarrhea, sore throat, tachycardia, congestion or runny nose, neuropathy in feet and hands, reflux or heartburn, phlegm in back of throat, abdominal pain, nausea or vomiting, sleeping more than normal, rash, nerve sensations, sharp or sudden chest pain, confusion) and their connection to mast cells can be found in a single article by Theo Theoharides, an expert in mast cells( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003574/). 

The following symptoms: difficulty sleeping(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689741/), anxiety, sadness, irritability(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682652/), hair loss(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514792/), and clogged ears(https://pubmed.ncbi.nlm.nih.gov/16080642/) all have links to mast cells.

As for the other few symptoms I could not scientifically link to mast cells, I can most certainly link them to my two children, who both have MCAS, and the many thousands and thousands of posts I have read from sufferers of MCAS or their caregivers.

Treatments

Having immunocompromised children has led me to research each an every possible treatment or preventative for COVID19, including both pharmaceuticals and supplements.

Fluvoxamine, an antidepressant, was shown to lower the likelihood of clinical deterioration over 15 days(https://edhub.ama-assn.org/jn-learning/module/2773108. Fluvoxamine also inhibits mast cell degranulation(https://www.jimmunol.org/content/202/1_Supplement/54.11).

Quercetin, a flavonoid, has shown to interfere with SARS-CoV-2 replication(https://onlinelibrary.wiley.com/doi/10.1002/ptr.6887). My children have been taking Quercetin for years as part of their MCAS treatment. I recognize the competing interests here, but still have faith in the results of this study(https://pubmed.ncbi.nlm.nih.gov/22470478/).

And now to my favorite, Clemastine! A few years ago, I came across a study of clemastine(https://pubmed.ncbi.nlm.nih.gov/29029896/) as a treatment for repairing the myelin sheath in MS patients with chronic optic neuropathy. Clemastine is a decades old antihistamine that I had never seen recommended to anyone with MCAS. I suspect it fell out of favor because the binder uses corn, to which many MCAS patients are allergic. For my children, who have no allergies to corn, clemastine was a game changer. As I began to make connections to COVID-19 and mast cells, I wondered if clemastine might be a viable treatment for COVID-19. Recently, I came across a study published in October by researchers in China(https://www.nature.com/articles/s41401-020-00556-6). The researchers went through 1,800 drugs as possible COVID-19 treatments, but clemastine came out on top! In fact, the top three candidates from this study were all antihistamines. Histamine is a mast cell mediator. Clemastine works by preventing the SARS-CoV-2 protein spike from binding to cells.

Conclusion

It’s a duck.

References

Lawrence B. Afrin, Leonard B. Weinstock, Gerhard J. Molderings, Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome, International Journal of Infectious Diseases, Volume 100, 2020: 327-332.

Lambert, N. J. & Survivor Corps. COVID-19 “Long Hauler” Symptoms Survey Report. Indiana University School of Medicine; 2020.

Theoharides TC, Tsilioni I, Ren H. Recent advances in our understanding of mast cell activation - or should it be mast cell mediator disorders?. Expert Rev Clin Immunol. 2019;15(6):639-656. doi:10.1080/1744666X.2019.1596800.

Besedovsky L, Lange T, Haack M. The Sleep-Immune Crosstalk in Health and Disease. Physiol Rev. 2019;99(3):1325-1380. doi:10.1152/physrev.00010.2018.

Traina G. Mast Cells in Gut and Brain and Their Potential Role as an Emerging Therapeutic Target for Neural Diseases. Front Cell Neurosci. 2019;13:345. Published 2019 Jul 30. doi:10.3389/fncel.2019.00345.

Grace SA, Sutton AM, Abraham N, Armbrecht ES, Vidal CI. Presence of Mast Cells and Mast Cell Degranulation in Scalp Biopsies of Telogen Effluvium. Int J Trichology. 2017;9(1):25-29. doi:10.4103/ijt.ijt_43_16.

Sankovic S, Dergenc R, Bojic P. Mast cells in chronic inflammation of the middle ear mucosa. Rev Laryngol Otol Rhinol (Bord). 2005;126(1):15-8. PMID: 16080642.

Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. Published online November 12, 2020. doi:10.1001/jama.2020.22760.

Tamara Haque, John Ryan. Selective Serotonin Reuptake Inhibitors Suppress Mast Cell Function. J Immunol May 1, 2019, 202 (1 Supplement) 54.11.

Derosa, G, Maffioli, P, D'Angelo, A, Di Pierro, F. A role for quercetin in coronavirus disease 2019 (COVID‐19). Phytotherapy Research. 2020; 1– 7. https://doi.org/10.1002/ptr.6887.

Weng Z, Zhang B, Asadi S, Sismanopoulos N, Butcher A, Fu X, Katsarou-Katsari A, Antoniou C, Theoharides TC. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PLoS One. 2012;7(3):e33805. doi: 10.1371/journal.pone.0033805. Epub 2012 Mar 28. PMID: 22470478;PMCID: PMC3314669.

Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Büdingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis(ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10. PMID:29029896.

Yang, L., Pei, Rj., Li, H. et al. Identification of SARS-CoV-2 entry inhibitors among already approved drugs. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-00556-6.