What role does mast cell disorder play in Long COVID?

Current reporting on COVID-19 tends to focus heavily on two areas: serious cases, where patients require intensive care treatment, and the number of deaths. Now, we are gradually seeing an increasing number of people still suffering from the associated health problems of COVID-19, however mildly, many months after becoming infected. These long-term consequences of the coronavirus are often referred to as "Long COVID" or Post-COVID Syndrome. Here we summarize the current findings surrounding Long COVID and explore the involvement of mast cells in the case of infection as well as the implications for those with a histamine intolerance.


What is Post-COVID Syndrome?

A person may potentially be suffering from Long COVID if they have not made a complete recovery and exhibit recurring or chronic symptoms of fatigue for several weeks or even months after contracting COVID-19. Due to the novelty of the virus and its varying effects on different subjects, there is still no set definition of Long COVID. At present, very little is known about its causes, and the information required for a reliable diagnosis is still insufficient.

It is known that other viral diseases including SARS, MERS or polio can trigger states of exhaustion [1]. Inflammatory reactions appear to play an important role in the diseases aforementioned. With COVID-19, the virus is unknown to the body and triggers abnormal inflammatory reactions. Characterizing these inflammatory processes to gain a better understanding of the disease is the current endeavor of doctors and scientists from across the medical industry.

A study of comparatively few participants showed that women in the health sector, who had suffered only mild symptoms of the disease, exhibited biomarkers that indicated persistent inflammatory reactions and stress responses, even 40 days after recovery [2].

What symptoms do those affected report?

The vast majority of Long COVID sufferers initially report mild or moderate sickness, along with the typical symptoms of a slight fever, coughing, difficulty breathing, tiredness, or loss of taste and/or smell.

Unfortunately, for some the symptoms simply do not go away, especially the extreme tiredness or fatigue which can sometimes last for months and weigh heavily on those affected. Fatigue is by far the most common long-term after-effect of the coronavirus, and roughly one in seven people that develop Long COVID after suffering mild COVID-19 symptoms is afflicted. In severe cases, as many as 53–71% of patients complain of persistent chronic fatigue [3]; this higher rate undoubtedly reflects the greater severity of the disease’s development. Those affected suffer major disruptions to their daily routine. At its worst, the fatigue renders even simple household activities a burden, and we may only speculate as to its long-term effects on working life.

Many sufferers do not regain their sense of taste or smell for several months, and there are now even websites with recipes catering for such people.

And it does not stop there. The extensive list of Long COVID symptoms ranges from nausea, weight loss, and trembling hands to cognitive impairment ("brain fog") and pericarditis. Some people feel anxious or become depressed, and in rare instances, existing allergies may worsen and new allergies can develop. There are also many examples of people who overcame a coronavirus infection and then experience poor toleration of foods containing histamines [4].

How many people are affected by Long COVID?

Initial research tended to focus on individual cases, but the passing of time has seen more and more systematic studies being conducted, slowly producing a clearer picture.

In one prospective study involving over 4,000 participants, 13.3% of those infected complained of persistent symptoms after four weeks [5]. Another study conducted by the University of Washington showed that of those patients who had mild symptoms but had to receive outpatient treatment, roughly 30% complained of persistent symptoms months after first contracting the infection [3]. Among hospitalized sufferers. i.e. in the more severe cases, this rate is significantly higher at 40% [6].

Overall, there appears to be a correlation between the number of symptoms during the first week of infection and the long-term after-effects of coronavirus. If you suffer from more than five symptoms, you have a greater likelihood of developing Long COVID [5].

Women appear to be significantly more likely to be affected by these long-term effects than men [5], which could be due to the differences in the immune system of men and women.

Is vaccination a protection against Long COVID?

Unfortunately, too little information is known on the subject of vaccination efficacy against Long COVID. The data currently focuses heavily on severe cases and the avoidance of deaths. In the case of Long COVID, it would be hugely beneficial to know to what extent infections and mild disease courses can be prevented by vaccination. However, without months of regular follow-up testing, no statistically reliable conclusion can be drawn on this subject.

For example, in Israel, where a high proportion of the population has already been vaccinated, the preliminary results currently indicate strong evidence that vaccination both alleviates symptoms and also prevents infection (facilitating “sterilizing immunity”) [8]. Were this data to be confirmed by more robust testing, then vaccinating a sufficiently large section of the population could also effectively prevent Long COVID.

Whether the vaccination aids the recovery of those already suffering from Long COVID or not, the data is mixed. It is largely based on individual case reports or initial studies involving small numbers of participants and which in part are yet to be peer-reviewed. Symptoms do appear to recede among some vaccinated patients, and it is probably wise for those suffereing from Long COVID to have the vaccination [9]. However, contradicting reports where vaccination apparently leads to an aggravation of symptoms can also be found [10]. It is hoped that further data will paint a clearer picture of this subject in the near future.

Where do mast cells come in?

One possible explanation for the development of Long COVID is the abnormal overactivity of mast cells. Mast cells are known to many in the context of allergic reactions. Found almost all over the body, these defense cells store particular chemical messengers, such as histamine, which they can suddenly release in the event that the body detects a potential poison, allergen, or virus. The release sets in motion inflammatory reactions that are important for protecting against harmful substances.

However, for some people these mast cells do not function properly and are over-sensitive to certain triggers, releasing more inflammation mediators than they should, even with weak stimuli. This reaction is what is known as Mast Cell Activation Syndrome (MCAS).

This disorder is rarely recognised because it can have so many forms, since it depends on the part of the body it affects. This could be the skin, digestive tract or other organs. Very few of those affected may even know that they have a mast cell activation disorder, and the disease is likely much more widespread than we think. Some estimates assert that up to 17% of the western population is affected. The most common cause for this is likely to be a genetic mutation [7].

In the event of a SARS-CoV-2 infection, the mast cells are activated with activity usually returning to normal levels after the COVID infection has receded. However, that does not appear to be the case with Long COVID; the abnormal activation of the mast cells continues along with the side effects mentioned above. It is therefore possible that a COVID infection can lead to an escalation in an existing but undetected mast cell disorder [7].

Can you protect yourself from Long COVID?

Mast cells as an effective defence against Long COVID remains a theory at present, but it does seem plausible. Nevertheless, further investigation is needed to confirm that COVID-19 indeed causes mast cell activity to spiral out of control.

In a study by Dr. Afrin et al., no severe cases of Long COVID were observed in their MCAS patients, so long as they were well medicated. However, they recommend that as soon as you notice the onset of an illness, you should immediately take antihistamines – specifically H1 and H2 receptor antagonists – as a preventative measure to slow down the over-reaction of the mast cells. These treatments are cheap, have been tried and tested against allergic diseases for decades, and have very few side effects [7].

Other substances that stabilize the activity of mast cells, such as cromoglicic acid or aspirin (if tolerated), can likely keep the illness in check and prevent or alleviate long-term consequences, too [7].

What does this mean for people with mast cell activation syndrome (MCAS) and histamine intolerance?

As noted above, there is a lack of reliable data. However, if you have a known mast cell activation disorder or a histamine intolerance, with a strong reaction to histamine liberators, this should serve as an additional reason for extreme caution when it comes to COVID-19. Unfortunately, it can be assumed that with increasing vaccinations of older, risk groups, the public’s discipline in adhering to the still-recommended coronavirus restrictions will waver. There will in all likelihood be a sharp increase in the number of infections in the next few months, leading to many Long COVID cases, too.

It goes without saying that preventing an infection should always be the top priority. Be sure to get vaccinated as soon as possible. If you are infected despite taking all the necessary precautions, contact your doctor immediately. Even if you have mild symptoms, administering the medication outlined above in a timely fashion will stabilize your mast cells during the infection.

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[1] https://edition.cnn.com/­2021/03/12/health/­ron-davis-covid-long-hauler-scn-wellness/index.html (03/2021)
[2] I. Doykov et al., The long tail of Covid-19 – The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients, F1000Research 9:1349 (2021), 1–10
[3] J. Logue et al., Sequelae in Adults at 6 Months After COVID-19 Infection, JAMA Network Open. 2021;4(2):e210830. doi: 10.1001/jamanetworkopen.2021.0830
[4] H. Davies et al., Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact, medRxiv preprint doi: https://doi.org/­10.1101/2020.12.24.20248802
[5] C. Sudre et al., Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms 1collected by the Covid Symptoms Study App, doi: https://doi.org/­10.1101/2020.10.19.20214494
[6] Research NIfH. Living with Covid19 2020 [updated 15.10.2020. Available from: https://evidence.nihr.ac.uk/­themedreview/­living-with-covid19/.
[7] L. Afrin et al., Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome, International Journal of Infectious Diseases 100 (2020), 327–332
[8] https://www.theguardian.com/­commentisfree/­2021/mar/12/­vaccines-long-covid-health-answers (03/2021)
[9] D. Arnold et al., Are vaccines safe in patients with Long COVID? A prospective observational study, medRxiv preprint doi: https://doi.org/­10.1101/2021.03.11.21253225
[10] https://www.nytimes.com/­2021/03/17/­health/coronavirus-patients-and-vaccine-effects (03/2021)