• Dr. Nicole Vumbaco, DVM

Bartonella and Mast Cell Activation Syndrome (MCAS):

Updated: Feb 21

Many patients with Bartonellosis and other Vector-Borne Disease suffer from a multitude of syndromes and disorders. Mast Cell Activation Syndrome or MCAS is one of the most complicated. It is sometimes the limiting factor in one's ability to treat for infection.


In short, MCAS is a type of mast cell activation disorder during which a specific immune cell (the mast cells) inappropriately and excessively, release pro-inflammatory chemical mediators, like histamine. Outwardly, this appears similar to an allergic reaction or allergy. Internally, the chronic inflammation leads to disorders of our connective tissue, small vessels, nervous tissue and immune system. Irritable Bowel Syndrome, Chronic Fatigue Syndrome and Fibromyalgia are just a few of the diseases involving mast cell dysfunction.


MCAS is a newer diagnosis, attaining it's name a little over a decade ago. The first case reports were published in 2007. An important distinction between other Mast Cell Disorders and Mast Cell Activation Syndrome is that patients typically have a normal number of mast cells circulating in their body. The problem isn't too many mast cells, the problem is they are too active. The severity of MCAS can incrementally escalate, which occur secondary to one or many triggers. Researchers are working hard to further define the syndrome but there has been vast implications. It is best to start with explaining what a mast cell is and what it does before we dive in to understanding this syndrome.


What are Mast Cells?

Mast cells were discovered in the late 1800's. They are a type of white blood cell and an integral part of the immune response. Mast cells have powerful granules within them that can release certain defensive chemical mediators in response to a potential threat. Mast Cells play an important role in protecting neurons from pathogens (this is called the neuroimmune system) and is our 1st line of defense to any invading infectious disease process.

Mast cells play a key role in the body's inflammatory response. When activated, they selectively release mediators through the process of degranulation (a process where the granules within a Mast Cell release it's defensive contents). These cells carry an arsenal of mediators (>200 are presently known). This includes pro-inflammatory cytokines, chemokines, growth factors, vasodilatory chemicals, heparin, superoxide dismutase, histamine, serotonin, tryptase, chymase, and proteoglycans. All of which are awaiting activation and have a specific indication for immune defense. [Image Credit]

Microscopically, these are beautiful, robust cells. They are considered a 'jack of all trades' and are found surveilling and circulating in every tissue of the body.


Histamine is the most commonly known mediator amongst the general public. When a mast cell's receptor becomes activated by a trigger, it prompts the cell to undergo selective degranulation, causing a release of histamine or other necessary mediators. Histamine specifically activates the endothelium which increases blood vessel permeability and dilates the vessel. Anyone who has been bitten by a mosquito has experienced this (the area became red, was warm, itchy, sometimes painful and swollen). While mast cells are best known for their role in allergic conditions and anaphylaxis, they are key in other bodily functions. This includes wound healing, vascular permeability (ability for a vessel to allow molecules to pass through), angiogenesis (formation of new blood vessels when needed), and immune tolerance, to name a few.


Mast cells communicate intimately with the central and peripheral nervous system and are primarily found in connective tissue. Connective tissue is present throughout our entire body. Examples include, 1) Loose Connective Tissue (holding our organs in place) 2) Dense Connective Tissue (bring bones together at a joint, muscle attachments) 3) Specialized Connective Tissue (cartilage, adipose or fatty tissue, bone, blood and lymph). There are many more classifications as well. This connection correlates to rheumatic and neurologic manifestations of disease which is further discussed in the Mast Cell Implication and symptom section.


These mast cells are integral to our immune response. Not a cell you really want misbehaving, but unfortunately with Mast Cell Activation Disorders and Syndromes, it does.


A Closer Look at Mast Cell Activation Syndrome:

The American Journal of Medical Sciences defines MCAS as a "non-cancerous disease driving chronic multisystem inflammation and allergy", appearing prevalent and of great relevance. In this situation, patients have a normal number of mast cells circulating but they are acting or functionally abnormal. They ignite a disproportionate and aggressive response to a trigger. As Dr. Afrin puts it in his webinar, the mast cell sends out the wrong mediator at the wrong place...at the wrong time...in the wrong amount.


Like Bartonellosis, the symptom profile of MCAS presents differently in each person. MCAS can have impacts locally, systemically, in distant tissues, remote locations...it can be acute, chronic or acute on chronic. The symptoms are often irritating and uncomfortable. It involves anything that contains connective tissue like the skin, GI, urogenital system, cardiovascular, respiratory, musculoskeletal and neurologic system. Symptoms can develop anywhere mast cells are found, meaning any organ system, especially those at the environmental interface (GI, skin, airway, etc). The condition is difficult to identify and difficult to diagnose because the symptomology overlaps with many other conditions. The basic theme here is inflammation.


What are some common MCAS symptoms?

Symptoms can range from mild to severe. They can manifest on the skin in the form of a rash, hives, swelling, irritation, itching, prickling, bruising, a burning sensation, sensitivity to types of fabric and red erythematous area which can be patchy or linear...most likely following an episode of emotional or physical stress.


Additional images of skin manifestations are available at Link 1 and Link 2.


Other common symptoms are more internal and can include joint or muscle pain, acid reflux, increased heart rate, fatigue, headaches, migraines, constipation, dizziness and anxiety. As escalation occurs, symptoms become incrementally more severe and your list of possible triggers or “allergies” grows. This can become distressing, disabling and affect quality of life and lifestyle.


The chart below is from a 2016 journal publication and outlines an exhaustive list of possible symptoms seen with MCAS. These symptoms also overlap with other syndromes (Fibromyalgia, Chronic Fatigue Syndromes) and symptoms of Vector-Borne Diseases (like Lyme and Bartonella). Additionally, other causes can include a medication allergy, a true IgE mediated allergic reaction (that is your mosquito bite), and a Jarisch-Herxheimer Reaction (a systemic reaction to an overabundance of endotoxins produced by dying bacteria). It demonstrates the extent of possible symptoms which does not have to involve every system listed.

It is quite the list, isn't it? As you start to trend patterns and isolate variables, it can become easier to determine. My case profile demonstrates symptoms from each category, even with that we have continued to rule-out other possible sequalae and underlying causes.


Diagnosing MCAS

The vast, non-specific symptomology makes pattern recognition and diagnosis difficult. There is also a large gap between emerging research and the way it is integrated into medical practice, especially with complex, chronic illness. In many studies, patients suffered for years before the diagnosis was made. It is a tough one.


As you learn more about this syndrome, you will find criteria to try to aid in a diagnosis. Of the most prevalent were these 3 criteria:

  1. Establish suspicion (symptoms correspond with mast cell derangements)

  2. A positive response to treatment agents (decrease in symptomology)

  3. Documenting elevation of mast cell mediators in certain fluids like blood tryptase or urine histamine, leukotrienes and prostaglandins

Serum and Urine Mast Cell Mediators increase during an episode or flare. You can measure the level of mediators present during those episodes and compare to a baseline while not in a flare. Keep in mind that there are over 200 mast cell mediators and our testing ability focuses on only a few. Generally the improvement in symptoms and severity/frequency of episodes with the use of appropriate medication can be enough evidence for a diagnosis.


What are some possible triggers?

There is a myriad of potential triggers:

MCAS Implications:

More common than an acute development is the likelihood that MCAS symptoms have been present, in some degree, for a long duration but infrequent and benign in severity. Then the patient experiences one or more triggers that lead to an escalation in the misbehavior of functional mast cells, worsening the symptom profile and seeming like a downward spiral. There are mechanisms that stress (physical or emotional) can directly and indirectly lead to MCAS escalation.


Because it is a chronic inflammatory condition involving multiple systems (with multiple symptoms), MCAS is a associated with a number of conditions and diseases. Increased evidence of mast cell involvement is seen with Irritable Bowel Syndrome, Chronic Fatigue Syndrome, Fibromyalgia, Asthma, Obesity, Depression, Vector-Borne Disease and Diabetes Mellitus. Additionally, Chronic Headaches, Autoimmune Syndromes, Neuropsychiatric Disorders, Interstitial Cystitis (painful bladder syndrome) and even Osteoporosis are included.


People with Connective Tissue Disorders and EDS (Ehler-Danlos Syndrome)/hypermobility commonly experience symptoms of MCAS. This suggests that mast cells are targeting connective tissue. A number of mast cell mediators are fibrogenic, meaning they are capable of causing tissue scarring and fibrosis. This implies that MCAS causes alteration in collagen formation. Whether or not it leads to weakness in collagen is still being researched.


There is also suspicion that it plays a role in dysautonomia. When mast cells degranulate, they also cause vasodilation which play a role in conditions like Postural Orthostatic Tachycardia Syndrome (POTS).


Secondary to the release of heparin, some patients experience bleeding and bruising. Heparin is a blood thinner and activates fibrinolytic activity, which breaks up blood clots.


Mast cell dysfunction can also increase the risk of certain blood malignancies, autoimmune disease, infection and cause delayed healing.


What about Vector-Borne Disease?

Many patients suffering from Vector-Borne Disease (like Lyme or Bartonella) display symptoms consistent with this disorder. It can be painful, unpleasant and intolerable. The correlation exists in the pathogenesis of Bartonellosis. A study published in 1996 described mast cells as the principal cell in the modulation of inflammation. It further reported that mast cells arise from "CD34+ pluripotential stem cells". Why is this important? Well, CD34+ cells are generated in the bone marrow. They have the capacity to differentiate into at least 8 distinct blood cell lines "including erythrocytes, granulocytes, monocytes, megacaryocytes, and lymphocytes." They are self-renewing pluripotent stem cells...meaning they are awaiting direction from the body to turn into whatever cell the body is needing at that time.


Here is where it gets interesting...Of the many cells that Bartonella species target and infect, CD34+ cells are one of them! A 2005 study provided evidence that infection of these cells with bartonella results in the presence of bacteria in differentiated cells like erythrocytes (red blood cells). Bartonella also influences the release of cytokine IL-8 (Interleukin-8) which is responsible for recruiting cells to a site of damage or infection. This, in turn, stimulates the release of CD34+ cells from the bone marrow to which Bartonella uses for it's own gain. If mast cells are a cell line that is derived from CD34+ cells, and these CD34+ cells are targeted and infected by Bartonella...then how might this pathogenic strategy influence, trigger or mimic MCAS? I tried to find some objective distinction but could not find anything further addressing proposed mechanisms in regard to Bartonella. There were multiple on Lyme Disease, however. A study in 1999 published in the Journal of the American Society for Microbiology, discussed how "B. burgdorferi spirochetes induce mast cell and cytokine release". An even earlier 1990 study from the Journal of Infection also observed this...supporting that the origin of mast cell dysfunction is instigated or triggered by the Borrelia spirochete.


While finding definitive mechanisms of actions were scarce, the bottom-line is that Vector-Borne Disease (VBD) can influence, trigger, or mimic the symptoms of MCAS. Let's call it a villainous gift.


Treatment of MCAS

The primary goal of treatment is patient relief and improvement of quality of life. A positive response to treatment can also help with diagnosis.


Dr. Lawrence Afrin provides a great outline for treatment focuses including:

  1. Identify and avoid triggers

  2. Inhibit mediator release from mast cells

  3. Inhibit mediator production

  4. Block actions of mediators that are released

  5. Treat secondary co-morbidities

Patients experiencing an anaphylactic reaction require emergency treatment with an epi pen or trip to the ER. Otherwise there is a multi-modal approach to help quell MCAS.


Types of treatment involve a combination of natural options (low histamine diet, Quercetin, Curcumin, St Johns Wart, Vitamin C), lifestyle changes (like decreasing stress, avoiding triggers) and a plethora of pharmaceutical options.


Pharmaceutical intervention focuses on drugs that do one of the following:

  1. Inhibit mediator production (Vitamin C, NSAIDS, Steroids)

  2. Block the release of mediators (reduce histamine release ie-H1 and H2 antihistamines, inhibit leukotrienes (like Montelukast) and target IgE receptors (like Omalziumab)

  3. Stabilize mast cells (cromolyn, quercetin, benzodiazepines)

  4. Block mediators that have been released (antihistamines are a classic example). A patient may require one or many. A combination approach tends to provide the best results.


Antihistamines:

This is generally the 1st line of treatment. Antihistamines are best known for helping to decrease an allergic response, itching, and flushing. The two most common antihistamines are H1 and H2 receptor blockers. H1 blockers, like Benadryl and hydroxyzine, can be extremely effective but do have a side effect of drowsiness. H2 blockers like Zyrtec, Famotidine, Ranitidine add a complimentary effect but are extremely helpful in targeting stomach pain or nausea by decreasing stomach acid.


When histamine is released, it can lead to an over-production of stomach acid. This can cause heart burn, regurgitation, vomiting, abdominal pain and nausea. For example, when I see a canine patient for a severe allergic reaction they too can develop vomiting and decreased appetite because of this acid production. In addition to treating their allergic reaction, my canine patients are often treated with GI protectants (like an anti-nausea injection and antacid like famotidine).


A combination of H1 and H2 will provide the best results. Each patient is different and may find one drug more useful than the other (ie- the combination that works best for me is Hydroxyzine (H1), Benadryl (H1) and Zyrtec (H2), all taken at night). The dose range is quite flexible. With doctor advisement, you can increase the amount you are taking during flares. Side effects for heavy handed antihistamine use are drowsiness, headache, low blood pressure, dry mouth or eyes, constipation and thickening of airway secretions. Figuring out the maximum and minimum dose and frequency of each will be beneficial while you are working through finding a responsive combination.


A side note on corticosteroids:

The amount necessary to help quell a reaction can cause immune suppression, depending on dose and length of script. If you are suffering from Lyme, Bartonella, or any other VBD, this can and will make your symptomology worse. Steroids seem to be a controversial subject in the treatment of MCAS, especially with concurrent infectious processes


Low Histamine Diet

People with MCAS/MCAD generally follow a low-histamine diet. Because we already have enough problems with mast cells releasing histamine, it is best to avoid ingestion of histamine-rich food sources. MastCellActivationSyndrome.org has an extended list of foods to avoid if you are in need of a low histamine diet

Associated Literature and Educational Material:

Resources/Learning Material

  1. Foundation for the Study of Inflammatory Disease

  2. Innate Non-specific Host Defenses: Educational Material explaining more about our immune system

  3. Dr. Lawrence Afrin presents “Mast Cell Activation Syndrome”. Video Presentation

  4. The Mast Cell Disease Society: Discussion of primary, secondary and idiopathic MCAS

Associated Literature:

  1. Mast Cell Activation Syndrome. Clinical Reviews in Allergy & Immunology, June 2018

  2. Mast Cell Activation Syndrome: a review. Current Allergy & Asthma Reports, Feb 2013

  3. Characterization of Mast Cell Activation Syndrome. American Journal of the Medical Sciences, March 2017

  4. Association of Postural Tachycardia Syndrome and Ehlers-Danlos Syndrome with Mast Cell Activation Disorders. Immunology and Allergy Clinics of North America, August 2018

  5. Mast Cell Activation Syndrome. Skin Medicine, December 2017

  6. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Archives of Pharmacology, July 2016

  7. Interaction of primary mast cells with Borrelia burgdorferi (sensu stricto): role in transmission and dissemination in C57BL/6 mice. Journal of Parasites & Vectors, June 2017

  8. Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. Journal of Infection and Immunology, March 1999

  9. A Review of the Dermatologic Symptoms of Idiopathic Mast Cell Activation Syndrome. Journal of Drugs and Dermatology, February 2019

**Image credits**:

Mast Cell Activation Syndromes, Urticaria and Atopic Dermatitis

Mast cell activation disease vs histamine intolerance (differences).

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