What could be the value of allergy experts for long COVID management when the symptoms are not sneezing or hives? The secret lies in the complex functions of the allergy-master-cell…
As we all know, the COVID-19 pandemic has taken the world by storm. It took a while to make sense of it, and we still need to elucidate some aspects.
Firstly, a confusing and worrying characteristic was the fact that the illness seemed unpredictable. It would hit hard both those with obvious risk factors such as other illnesses, but also apparently healthy people. Then again, other individuals from the same population categories would recover amazingly well.
The virus was the same, so there must have been host-associated factors that influenced the outcomes. Quite obvious, but difficult to pinpoint initially.
COVID-19 and the immune system
We have known for a long time that the expression of disease, especially of an infectious disease, is crucially influenced by the immune system’s response. Indeed, this held true for COVID-19, and the most severe cases had an exaggerated immune activation leading to poor outcomes (1). Moreover, some experienced allergy and immunology experts also noticed signs of a certain type of innate immunity activation in long COVID.
Certainly, we have pharmacological means of dampening the immune reaction. However, some of them, such as corticosteroids, may not be ideal in the context of a viral infection. Therefore, we need to strike a good balance to achieve benefit with the least amount of harm.
Long COVID has become more and more prevalent, and research has started to uncover the most relevant mechanisms of this oftentimes debilitating illness. Guess what? It’s the immune system again…
Immune system overview
The immune system is extremely complex, but, in short, our defence mechanisms are the sum of innate and adaptive immunity.
Innate immunity is the early response to a threat. It unfolds in the same way, irrespective of what caused its activation. Thus, it is very rapid and essential in maintaining the body’s integrity. Imagine an aggressive doorman – anybody who attempts to enter without wearing a name tag, is immediately attacked, no questions asked and no delay.
Adaptive immunity consists of more specialised defence mechanisms. It is based on recognition of certain foreign structures and on mounting a specific immune response against those invaders. It is what we train with vaccines and that may be the subject of discussion on another occasion. In the above analogy, adaptive immunity would be the doorman that has a list of unwanted persons and checks IDs before taking action against anybody.
Enter the allergists’ favourite cell: the mast cell
Part of the innate immune system, mast cells act as sentinels ready to detect danger and react accordingly. They are permanently present around blood vessels and wherever we come into contact with the external environment (i.e., in our skin, digestive tract and respiratory system).
Mast cells contain granules with chemical mediators (e.g., histamine) that can be immediately released when the cell is stimulated, like in an acute allergic reaction. Furthermore, they have the ability to produce and release other pro-inflammatory molecules (e.g., prostaglandins, leukotrienes and cytokines).
Research has confirmed that mast cells can be activated not only by allergens, but also by bacteria, viruses, parasites and toxins. This happens via different pathways, thus leading to different inflammatory responses (2). For example, mast cells may not release the histamine-rich granules leading to the immediate allergic-like symptoms, but may contribute to inflammation via other mediators.
In conclusion, mast cells are well-known for being involved in allergy symptoms, but they are an essential part of our immune defence.
How can we manipulate mast cells’ function?
Mast cells are the main source of symptom-causing histamine release in allergic reactions. So, many of the strategies employed by allergists target this degranulation mechanism. For example, that may mean blocking the histamine or other mediators’ receptors, or stabilising the mast cell membrane to prevent degranulation.
Receptors are structures present on cells throughout the body. They recognise and bind specific chemical mediators. Thus, receptors allow these mediators to influence cell function and cause symptoms.
We currently have drugs that can block different types of histamine receptors. Similarly, we have medication available to block receptors for other mast cell mediators, leukotrienes, and drugs that inhibit the production of yet another type of chemicals produced by mast cells – prostaglandins.
There are also Functional Medicine complex and personalised strategies to optimise immune function.
Mast Cell Activation Syndrome (MCAS)
There are situations when mast cells maintain a state of activation, and are easily triggered by different stimuli. Some of the conditions which lead to this are known (such as genetic mutations or allergies), and others have not yet been identified (the latter situation being referred to as idiopathic MCAS).
The recurrent MCAS symptomatic episodes affecting different parts of the body, associated with measurable increase in mast cell mediators, and successful treatment with mast cell stabilisers or inhibitors of mast cell mediators, can confirm the diagnosis of idiopathic MCAS (3,4), whilst another set of diagnostic criteria also includes findings on bone marrow aspirate and biopsies of skin and other tissues (5).
So, what exactly are MCAS symptoms? In short, given mast cells’ distribution throughout the body, symptoms of MCAS can be varied and sometimes difficult make sense of. That is, if the clinician is not aware of this potential diagnosis.
Among the many possible manifestations of MCAS are: low blood pressure, rapid pulse, itching, hives, diarrhoea, abdominal cramping, respiratory symptoms, headache, fatigue, and even life-threatening anaphylaxis (6). As you will discover next, allergy experts will have found long COVID symptoms quite familiar.
Generally, what we describe as long COVID are various symptoms lasting for weeks and months (typically over 3 months) after the initial infection with the SARS-CoV-2 virus. Interestingly, cases occur in all age groups and irrespective of the severity of the acute illness. On average, long COVID affects about a quarter of all people infected with Sars-CoV-2, ranging from about half of those hospitalised with COVID-19, to an astonishing 19% of asymptomatic cases (7).
Damage caused by the acute infection (for instance, pulmonary scarring), virus persistence in certain parts of the body, and immune dysregulation (including autoimmunity and persistent inflammation), are possible mechanisms of long COVID symptoms (8).
Symptoms of long COVID can vary quite a lot between patients, but most often they include fatigue, cognitive dysfunction (‘brain fog’), respiratory and cardiovascular symptoms, headache, dizziness, joint or muscle pain, gastrointestinal issues, changes in the sense of smell or taste, anxiety, depression, new allergies, fever (9).
The value of allergy experts for long COVID management
Recently, the hypothesis of mast cell activation driving the pathogenesis of some COVID-19 cases, has been explored (10) and laboratory findings have confirmed the activation of mast cells in real human cases of COVID-19 (11). In addition, long COVID symptoms are highly suggestive of mast cell activation (12). Furthermore, studies have shown benefit for COVID-19 from drugs that act on the mast cell activation mechanism (13) and allergy experts have proposed complex protocols designed to stabilise mast cells in long COVID syndrome (14).
Find your allergist – or, better yet, find your functional allergist
Arguably, the infectious diseases specialists’ job in treating COVID-19 should be quite easy and straightforward – unless the immune system overreacts and starts causing unexpected harm. In these cases, the input of an immune system specialist should be welcome. Luckily, we have started to build an evidence base documenting putative mechanisms of severe and long COVID – many having to do with the immune system function, and clinical trials are conducted to identify the most effective therapeutic strategies.
In the case of the MCAS hypothesis, these strategies build upon allergists’ long-term experience in managing such conditions. Allergists that are part of intensive care teams may be a rare find, but you can certainly seek an allergy expert for long COVID, if months have passed and you still experience symptoms. And no, if all tests run by your GP are normal, it doesn’t mean you have an imaginary disease.
Get the help you need
To sum up, proper expertise in recognising the immune dysfunction and in managing adequate medication, might be just what you need to overcome a condition that alters your quality of life. Arguably, in light of the above, allergy experts may be best suited to oversee long COVID cases.
Even better, the Functional Medicine approach, employed at The Allergy-Immunology Doctor, will add science-based lifestyle and diet interventions tailored to each patient, to achieve optimal immune modulation and support, alongside pharmacological management.
Last but not least, you may want to book a free discovery call to find out how suitable is our approach for your current goals.
- Gustine JN, Jones D. Immunopathology of Hyperinflammation in COVID-19. Am J Pathol. 2021;191(1):4–17.
- Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology: Introduction and overview. Adv Exp Med Biol. 2011;716:2–12.
- Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol [Internet]. 2010 Dec 1;126(6):1099-1104.e4.
- Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: A consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215–25.
- Afrin LB, Butterfield JJ, Raithel M, Molderings GG. Often seen, rarely recognized: Mast cell activation disease – A guide to diagnosis and therapeutic options. Ann Med. 2016;48(3):190–201.
- Valent P. Mast cell activation syndromes: Definition and classification. Allergy Eur J Allergy Clin Immunol. 2013;68(4):417–24.
- Long-haul COVID WHITE PAPER – A Detailed Study of Patients with An Analysis of Private Healthcare Claims. 2021
- Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Auckl). 2021;53(10):737–54.
- Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. eClinicalMedicine. 2021;38.
- 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 [Internet]. 2020;100:327–32.
- Gebremeskel S, Schanin J, Coyle KM, Butuci M, Luu T, Brock EC, et al. Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody. Front Immunol. 2021;12(March):1–12.
- Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Mast cell activation symptoms are prevalent in Long-COVID. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2021 Nov;112:217–26.
- Malone RW, Tisdall P, Fremont-Smith P, Liu Y, Huang XP, White KM, et al. COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms. Front Pharmacol. 2021;12(March):1–21.
- Kazama I. Stabilizing mast cells by commonly used drugs: a novel therapeutic target to relieve post-COVID syndrome? Drug Discov Ther. 2020;14(5):259–61.