Dr Joneja's Guides to Histamine Intolerance

Dr Janice Joneja, a world expert on histamine intolerance, has published two books on histamine intolerance:

A Beginner's Guide to Histamine Intolerance – read more about it here.

Buy the paperback from Amazon here; buy the e-book from Amazon here.

Histamine Intolerance: The Comprehensive Guide for Healthcare Professionals – read more about it here.

Buy the ebook from Amazon here.

You can buy all of Dr Joneja's books here in the UK or here in the US.



Histamine intolerance and viral infections


Question:

What can be done for a person with a histamine intolerance who has responded well to diet change, but still suffers episodes when exposed to a virus like the common cold? I don't know if this histamine over-reaction would be gut related. Episodes consist of severe nausea and vomiting for 3-4 days, copiously runny nose, flushing, rash, rapid heart rate, and anxiety. An oral anti-histamine helps with a food reaction, but nothing seems to work for a viral exposure. This is not a normal cold, but a severe reaction. Now that all of the food reactions have been eliminated, a virus is the only thing that will trigger. This histamine intolerance has been going on for twelve years with the only relief coming two years ago with anti-histamines and diet change.

There is much information about foods that are triggers, but I cannot find information about viruses.

Have you ever heard of a connection between histamine intolerance and the medication Singulair?

Answer:

Your question actually raises a very interesting and important topic that is currently being researched and debated by immunologists.  I am going to take this opportunity to discuss this in some detail as it is likely to be of interest to both patients and clinicians as they search for answers beyond the currently available approaches to conditions that may involve both histamine and infection.

As you will have learned from my numerous publications, histamine is produced and stored within white blood cells called mast cells (MC) that are located in tissues throughout the body.  These cells and their content of inflammatory mediators, which are stored within granules inside the cells, have been studied extensively in allergy.  Allergens trigger the production of IgE antibodies.  When the allergens and antibodies couple together on the surface of the mast cell, the cells release the mediators in a process of degranulation.  The mediators then act on surrounding tissues, resulting in symptoms of an allergic reaction.  The first and one of the most powerful of the mediators released is histamine.  Many of the symptoms of the allergic response are due to the activity of histamine [Please refer to my publications for details of this process]. 

Mast cells

Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses were not really studied to any extent until fairly recently.  Now, current research is indicating that they also play important roles in a variety of physiological and pathological processes beyond allergic reactions .

It has been known for a long time that MCs possess surface receptors that are activated by IgE in the allergic response.  However, it is now being recognised that other agents can also activate mast cells.  MCs have been shown to be activated by various inflammatory mediators, IgG, light chains of antibodies, complement fragments, proteases, hormones, neuropeptides, and microbial products.i Following activation, they produce a battery of pro-inflammatory mediators and participate in inflammatory reactions in many organs.    As a result of recent studies it is becoming apparent that MCs play an important role in the recognition of disease-causing microorganisms (pathogens) and modulation of appropriate immune responses. Because of their ability to instantly release several pro-inflammatory mediators from intracellular stores and their location at vulnerable sites within the body, mast cells appear to be crucial for optimal immune responses during infection. Mast cells seem to exert these effects by altering the inflammatory environment after detection of a pathogen and by mobilizing various immune cells to the site of infection. Furthermore, these responses can vary depending on the type of pathogen, where the pathogen is encountered, and the state of the responding mast cells.

Mast cells and viral infections

The importance of mast cells during bacterial and parasitic infections has been extensively studied , , but the role of these cells during viral infections is comparatively poorly understood. Recently, it has been shown that mast cells can be directly activated in response to influenza a virus (IAV), releasing mediators such as histamine, proteases, leukotrienes, inflammatory cytokines, and antiviral chemokines, which participate in the excessive inflammatory and pathological response observed during IAV infections.

However, the role of mast cells in viral infections appears to be far from straightforward.  In certain viral infections mast cells can be protective .  However, in some highly pathogenic viral infections, such as IAV, research is indicating that mast cells can be more detrimental than beneficial . Studies in mice have shown that activation and release of mediators from mast cells in response to these viruses correlates with the severity of the disease.  Furthermore, using a mast-cell stabilizer such as ketotifen, to prevent degranulation of the MC and thus inhibit release of the mediators, protected the experimental mice from the life-threatening effects of the virus.

Managing viral infections

So you can see that your question is highly relevant to the current research findings in that you experience quite severe symptoms when you have a respiratory viral infection.  Although it is not possible to provide you with specific answers to your dilemma at the present time, given the limited amount of knowledge that we have about the processes involved, it would be logical to assume that excess histamine is impacting negatively on your body’s ability to fight the infection.  This negative effect is probably only relevant to viral infections; bacterial and parasitic infections should not be similarly affected.  The question that cannot be answered is whether your long-standing histamine intolerance, which is likely to be due to an inherent histamine-degrading enzyme (probably DAO) deficiency, is resulting in even higher histamine levels.  This of course would increase the severity of your infection-associated symptoms as well as triggering histamine related effects in other organ systems [please refer to my Guides for details about symptoms of histamine sensitivity], exactly as you report.  Until clinicians and scientists recognise the importance of histamine sensitivity or intolerance resulting from histamine catabolizing enzyme deficiencies, the crucial research in mast cell-related effects such as yours will not be rigorously pursued as it should.

In the meantime I would suggest that the most effective approach when you have a viral infection would be to carefully follow a histamine-restricted diet, take supplemental DAO before each meal and at bedtime to break down any residual histamine before it can enter the body, and take antihistamines to reduce the severity of your symptoms.  I strongly encourage you to discuss this approach with your doctor or health care provider to ensure the best possible outcome.

Singulair / Montelukast

Now to address your question about Singulair, which also is relevant to mast cells and their mediators.  Singulair is a brand name for Montelukast, an anti-leukotriene drug.   It acts by blocking the receptors for leukotrienes in cells in the lungs in much the same way that antihistamines block the coupling of histamine to histamine receptors on a variety of body cells [For more information on histamine receptors please refer to my Guides to Histamine Intolerance].

Leukotrienes

Leukotrienes are among the mediators released from mast cells in the inflammatory process.  Unlike histamine, leukotrienes are not stored within the mast cell, but are produced rapidly after the cell is activated.  An enzyme called phospholipase A2 is released from the intracellular granules, which acts on the cell membrane, releasing arachidonic acid, an omega-6 20-carbon chain fatty acid.  This in turn provides the substrate for the production of very powerful mediators: the leukotrienes via the lipoxygenase pathway, and the prostaglandins via the cyclo-oxygenase pathway.  The leukotrienes released from the mast cell in allergy and asthma bind to receptors in the airway cells, such as macrophages and smooth muscle cells.  This results in swelling of the airway, contraction of the smooth muscle, and impairment of the normal activity of respiratory tract cells, leading to the typical symptoms of bronchospasm and respiratory distress.  When Montelukast blocks the receptors, leukotrienes are unable to attach to the cell, and so their adverse effects are prevented. 

You ask whether there is a connection between Singulair and histamine.  The question should really be whether there is a connection between leukotrienes and histamine.  Both histamine and leukotrienes are present in an allergic reaction when mast cells are activated, so often both mediators acting on similar cells produce their effects in the same environment.  For example, histamine is also involved in triggering the symptoms of asthma when leukotrienes are simultaneously exerting their effects as discussed above.  By attaching to the H1R receptor in the lungs, histamine causes bronchospasm and swelling, and via the H2R receptor, secretion of mucus.

Eczema and urticaria

Another situation where we see the effects of both histamine and leukotrienes is in the skin, in conditions such as eczema and urticaria (hives).  Cells in the skin exhibit receptors for both types of mediators.  In allergy, symptoms result from attachment of the mediators to their respective receptors when they are released from mast cells in the skin.  In several cases Montelukast has been successfully employed in treating such conditions .  In a recent research report the combined use of antihistamines and leukotriene inhibitors controlled angioedema which had resisted other methods of treatment.   Angioedema is an allergic condition that involves swelling in the deeper layers of skin, including the dermis and subcutaneous tissues in contrast to urticaria that involves only the upper layer of the dermis.  Antihistamines and leukotriene antagonists separately did not control the condition.  So this paper suggests that histamine and leukotrienes together are involved in causing the type of angioedema discussed in this study.

Singulair and histamine

After all that scientific discussion, we should focus on your specific question: the connection between Singulair and histamine.  You can now appreciate that Singulair prevents the effects of leukotrienes in much the same way that antihistamines block the effects of histamine.  Both histamine and leukotrienes are product of mast cells, but they have different mechanisms of action, may exert their effects on different types of cells, and have completely different receptors, although in some situations the two may be co-offenders.  However, Singulair will not prevent the activity of histamine, nor would antihistamines block the activity of leukotrienes.

From your query, I might conclude that you may be suffering from asthma, or a related respiratory condition and have been prescribed Singulair as a remedy.  However, not knowing anything about your medical history I am unable to help you further.  Nevertheless, since leukotrienes, histamine, and viral infections are all related through mast cells, as I have described above, I might suggest that you discuss with your doctors the possibility of a trial on a mast cell stabilizer, such as ketotifen or cromolyn sodium, to determine whether this might alleviate your most severe symptoms by preventing the release of the inflammatory mediators, especially histamine, before they can do any harm.

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  Trivedi NH, Guentzel MN, Rodriguez AR, Yu JJ, Forsthuber TG, Arulanandam BP. Mast cells: multitalented facilitators of protection against bacterial pathogens. Expert Rev Clin Immunol. 2013 Feb;9(2):129-138

  Voehringer D. Protective and pathological roles of mast cells and basophils. Review. Nat Rev Immunol. 2013 May;13(5):362-375.

Graham AC, Temple RM, Obar JJ.  Mast cells and influenza a virus: association with allergic responses and beyond.  Frontiers In  Immunology 2015 May 18;6(article 238):1-12 

Aoki R, Kawamura T, Goshima F, Ogawa Y, Nakae S, Nakao A, et al. Mast cells play a key role in host defense against herpes simplex virus infection through TNF-alpha and IL-6 production. J Invest Dermatol 2013;133(9):2170–2179.

Hu Y, Jin Y, Han D, Zhang G, Cao S, Xie J, et al. Mast cell-induced lung injury in mice infected with H5N1 influenza virus. J Virol 2012;86(6):3347–3356. 

Badri T, Pellegrini MV. Montelukast. [Updated 2017 Oct 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; June 2017 

  Nettis E, D'Erasmo M, Di Leo E, Calogiuri G, Montinaro V, Ferrannini A, Vacca A. The employment of leukotriene antagonists in cutaneous diseases belonging to allergological field.  Mediators Inflamm 2010;2010 Article 628171:1-6 

Wong BN, Vadas P.  Angioedema suppressed by a combination of anti-histamine and leukotriene modifier.  Allergy Asthma Clin Immunol. 2017 Jun 13;13:28-31

You can buy DAO supplements here in the UK or here in the US. You can buy all of Dr Joneja's books here in the UK or here in the US.


If you found this article interesting, you will find many more articles on anaphylaxis here, and reports of research into anaphylaxis here.
You can also find articles on peanut and tree-nut allergy here, cow's milk allergies here, egg allergy here, histamine intolerance hereand articles on a wide range of other allergic and intolerance reactions to a wide range of other foods here.

 

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