The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 50

62. Is it possible to become tolerant of a trigger again?

Yes, sometimes.

Desensitization is the term for when your body becomes tolerant of something that it previously reacted to. While it usually means becoming tolerant of a medication, it is a general term so many mast cell patients use “desensitization” to mean becoming tolerant of anything they used to react to, including food or environmental triggers.

Traditionally, desensitizing is done by exposing the body to a small amount of a trigger, then a little more at a later time, and so on until the body accepts a reasonable amount. In the regular allergies, in the US, “allergy shots” are used for this. A patient is injected with a tiny amount of an allergen repeatedly until their immune system stays calm when exposed to the trigger.

There are some newer approaches for desensitization that use certain newer medications. In particular, anti-IgE therapy has been very well described for helping to force a patient to tolerate a trigger. Antihistamines and/or corticosteroids can be used to control the level of allergic response.

In some instances, a rapid desensitization procedure can be used to force tolerance. These procedures are performed in a medical setting and may provide tolerance in a matter of days. They are usually used in situations where the benefit of a drug to which the patient reacts outweighs the risk of anaphylaxis, such as patients who need to use a specific chemotherapy drug to treat an aggressive disease.

Importantly, if a patient becomes desensitized to a substance, they must be regularly exposed to that substance in order to continue tolerating it. Sometimes, a patient must be exposed daily in order to not react to the trigger. This is very patient and substance specific.

Mast cell patients are different from typical allergy patients in a lot of ways, many of which we don’t understand. Patients ask from time to time if “allergy shots” or something similar will help them. Mast cell patients who have an IgE allergy to a substance may get some benefit from allergy shots. Specifically, allergy shots are recommended for mastocytosis patients who have allergies to certain insect stings.

But what if they don’t have an IgE allergy? Will gradually increasing the amount of trigger in a series of exposures allow the body to accept it?  I know plenty of mast cell patients who have used allergy shots or oral immunotherapy to improve trigger tolerance. I can’t think of any reason why this wouldn’t help if you could safely increase the exposures.

For mast cell patients, the issue is that reactions can be so serious that desensitization is difficult to achieve. Patients can sometimes overcome this by using IV Benadryl, IV steroids, or a continuous IV epinephrine infusion. Mast cell patients should never attempt to force tolerance to any trigger without receiving advice from a health care provider that understands their specific health situation.

Food allergies are widely recognized as being different from other kinds of allergies. We are learning about food allergies in real time right now. Food allergies are on the rise and now affect huge numbers of people around the world. This means that there’s tons of research on it, which is great. But it means that we still don’t understand them that well. For this reason, desensitization to food is trickier.

There are a few methods commonly used in mast cell patients to manage food reactions. Sometimes a gradually increasing amount of trigger is eaten while the patient is monitored and given medications to manage any reactions, essentially a rapid desensitization for food. I find this approach is taken more commonly with children, largely because it is the recommended procedure for reintroducing triggers to children with FPIES. Sometimes people find that when they are exposed to a trigger for the first time in a while, they tolerate it until a second exposure. In these scenarios, rotation diets can be helpful. Allergy shots or oral immunotherapy for substances found in food are sometimes given. Results vary.

I have talked a lot before about the fact that mast cell reactions are often the cumulative result of things that activate your mast cells. This means that if you do something that activates your mast cells before eating a trigger, your reaction may be worse. In some instances, you may only react if you do something irritating to your mast cells shortly before eating it. This doesn’t just happen to mast cell patients. There are many mentions in literature of allergy patients who only experience anaphylaxis to trigger foods if they have exercised shortly before eating.

This means that if you are able to control the experience of eating triggers, you may have better success. You may do better if you refrain from doing anything irritating to mast cells like exercising, getting too hot, or being in a stressful situation. Food temperature can play a role. Many patients react to foods that are too hot or too cold. How you time medications can help. If you eat in the window of time when your medications are most active, you might find that a trigger is less activating. Solids are harder to digest and cause more histamine release than liquids (even thick liquids) so what form your food takes can matter, too.

Additionally, if you are able to control your disease and inflammation, you may find yourself more tolerant of triggers overall. Patients who find that their symptoms are better controlled should discuss trials with their health care providers to see if they can try exposures to previous triggers.

I can tell you that I have personally had a lot of success with using an anti-IgE medication to help me regain foods I lost. I have one IgE food allergy (chicken egg whites) and have no plans to ever try to consume them without thorough cooking (I’m tolerant of well cooked egg whites.) However, I do have a spectacular amount of food triggers that cause reactions ranging in severity from flushing to anaphylactic shock. My severe food reactions largely resolved when I started anti-IgE injections a few months ago. I eat all kinds of things I used to react badly to. I can eat cookies. I can eat cherry pie. I can eat bread. I try not to push my luck with things that have are loaded in histamine. I will never try alcohol or anything fermented again.

Prior to taking the anti-IgE medication, I had some success with rotation diets in which I ate gradually increasing amounts of a trigger every four days. It didn’t really make the reactions stop but it did make them less severe, enough that I could reintroduce small amounts of some previous triggers into my diet. This happened after I had GI surgery that decreased my overall level of inflammation and mast cell reactivity.

For more detailed reading, please visit these posts:

Food allergy series: FPIES (Part 1)

Food allergy series: FPIES (Part 2)

Food allergy series: Mast cell food reactions and the low histamine diet

Reintroduction of food to a child with SM

The Devil’s Arithmetic

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 46

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, part 49

60. Is anaphylaxis the same as anaphylactic shock?

No. Anaphylaxis can result in anaphylactic shock but it often doesn’t. When talking about anaphylactic shock, people are referring to circulatory shock that was caused by anaphylaxis. Circulatory shock occurs when there is not enough blood to carry oxygen to all the tissues that need it. When the tissues don’t get enough oxygen, your organs stop working correctly.

Circulatory shock is usually caused by low blood pressure. Anaphylaxis commonly causes low blood pressure and that can cause shock. However, anaphylaxis does not always cause low blood pressure, and it does not always cause shock.

61. If a tryptase level over 10.9 ng/mL is high, why is one of the criteria for systemic mastocytosis a tryptase level of 20.0 ng/mL or higher?

Tryptase level is used in two ways in assessing mast cell patients: as a marker for activation, and as a marker for how many mast cells are in the body.

There are two primary methods of using tryptase to indicate mast cell activation.

The first way is to compare a tryptase level when a patient is reacting to a tryptase level when they are not reacting (baseline). Mast cells release more tryptase when they are activated. For mast cell patients, an increase of 20% + 2 ng/mL is considered evidence of mast cell activation. So if a patient has a baseline tryptase of 5 ng/mL when they are not reacting, anything 8 ng/mL (20% of 5 ng/mL is 1 ng/mL, then add 2 ng/mL = 8 ng/mL) or higher is considered evidence of activation.

The second way is to count anything over 10.9 ng/mL as evidence of activation.

When you are using tryptase as a measure of how many mast cells are in the body, the patient should not be reacting beyond their normal day to day symptoms. This is because you don’t want an increase in tryptase from activation to make the baseline level look higher than it is. Tryptase is used to measure how many mast cells are present because mast cells release some tryptase all the time, even when they aren’t activated.

Anything over 10.9 ng/mL is considered an elevation of tryptase. The reason that 20 ng/mL is the cutoff for the SM criterion is that patients are likely to have a positive bone marrow biopsy when the tryptase level is twice normal (21.8 ng/mL). They round the number down to 20 ng/mL because all tests have a margin of error. By rounding down to 20 ng/mL, they catch patients that might not have made the cutoff before because of an error in the test. This means that a patient who has a tryptase level of 20 ng/mL or higher is likely to have a bone marrow biopsy that will be positive for systemic mastocytosis.

For more detailed reading, please visit these posts:

Anaphylaxis and mast cell reactions

The Provider Primer Series: Mediator Testing

Patient questions: Everything you wanted to know about tryptase

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, part 8

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 46

56. Why do I react every time I eat?

When you swallow food, your nervous system sends signals to tell the cells in the stomach that food is on the way. As a result of this neurologic signal, hormones are released to tell your stomach to get ready to digest. These hormones cause histamine to be released by cells in the stomach. The histamine tells your stomach to make acid to digest your food. Solid food is more activating to the stomach in this way than liquids are.

This is a normal function of the body and happens in everyone, not just people with mast cell disease. However, histamine released in the stomach can activate mast cells and cause typical mast cell symptoms. Like everything else in mast cell disease, how much this affects patients varies a lot. But something to keep in mind is that a lot of mast cell patients who are “allergic to everything they eat” are actually reacting to the normal histamine release that contributes to digestion. They are essentially allergic not just to what they are eating, but to the process of eating.

57. Do I have to go to the hospital every time I use an epipen?

Unless you have received very explicit instructions not to do so from a health care provider that is familiar with the particulars of your life and your health, you need to go to the hospital every time you use an epipen. The reason for this is because an epipen is a temporary measure. The purpose of the epipen is to give you time to get to a hospital for more advanced care. Epinephrine is broken down by your body in a matter of minutes so it only provides a small window of protection. While many patients only need one epipen, there is no way to know if you will have another wave of anaphylaxis after the first one. Additionally, many patients require other medications and IV fluids to treat anaphylaxis. These can be provided at a hospital.

The reason you have to go to the hospital is to give you access to more comprehensive care, not because using an epipen is dangerous.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 39

46. What does it mean to be a “leaker” or “shocker”?

These are terms patients use to describe the way mast cell disease affects them rather than defined medical terms. A leaker is someone who has a lot of symptoms day to day but has fewer severe attacks or anaphylaxis. A shocker is someone who has fewer day to day symptoms but more frequent severe attacks or anaphylaxis.

Leakers and shockers are not considered to have different subtypes of mast cell disease because symptom presentation varies hugely in all forms of mast cell disease. There are no tests to identify if you are a leaker or shocker. You can start a leaker and become a shocker or vice versa. The terms themselves have no medical meaning. They are just shorthand for patients to describe their experience with their disease.

47. What does “sense of impending doom” mean?

Sense of impending doom is the medical term for a feeling of terrible anxiety or fear, literally a feeling that something awful is about to happen. It is a medical symptom for lots of conditions, including anaphylaxis. The biological basis behind this sensation has been the subject of debate for a long time but there’s really no decisive answer as to the cause

48. Why do I taste metal when I’m having a bad reaction or anaphylaxis?

A metallic taste is also a symptom of many things, including anaphylaxis. It is also debated and an exact cause has never been identified. One of the more prevalent explanations is that it is the taste of epinephrine, which your body releases as an initial defense against anaphylaxis or mast cell degranulation. As far as I know, there is no data to support this.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 36

43. What is a rebound reaction?

Rebound is a term that gets used a lot in the mast cell community, often incorrectly. Rebound reactions occur when medication taken to suppress symptoms wears off. This phenomenon is easiest to see with the older H1 antihistamines like diphenhydramine (Benadryl). Benadryl is broken down pretty quickly by the body so it wears off in about 4-6 hours. In some situations, it can break down even faster.

When you take diphenhydramine, as soon as it’s in your body, the diphenhydramine looks for the molecules on the outsides of cells called histamine receptors. In order for histamine to affect your body, they have to find one of these histamine receptors and sit on it. If it can’t do that, the histamine is not able to cause symptoms or perform its normal function. The antihistamine finds those receptors and sits on top of it so that the histamine can’t fit in. This translates into fewer symptoms because the histamine is blocked.

How effective antihistamines are at finding those receptors and sitting on them differs from drug to drug. Some do this really quickly but others take a few hours to find the receptors. Some drugs can get knocked off the histamine receptors they sat on. Drugs like this are less effective antihistamines.

Diphenhydramine finds the histamine receptors very quickly and sticks to them very strongly. This is why it is such an effective antihistamine. Because it is such a strong antihistamine, when your body breaks it down, your symptoms can come back quickly and forcefully. This is called rebound. Your symptoms reappear because there’s no longer enough medication in your body to keep the histamine from working. (Please note that rebound reactions can also happen with other medications for other diseases in ways that do not affect histamine. I’m just being general here for the mast cell disease audience.)

Rebound reactions can be tricky to get out of because the natural response to take medication again to control the symptoms. However, when you do this, you may just be setting yourself up for another rebound reaction when this dose wears off. This is one of the reasons why many doctors prefer that their mast cell patients not take Benadryl frequently. When you are stuck in a rebound loop, it can cause a lot of inflammation and that can trigger your mast cells even more.

There are a few strategies to help decrease the likelihood of rebound reactions. One is to stagger medication dosing. If a couple of your medications can cause rebound, don’t take them at the same time if you can avoid it. Take one an hour or two after the other. Some patients find benefit in layering antihistamines. By taking multiple antihistamines, you can cover lots of histamine receptors. Sometimes, it covers enough that when your diphenhydramine wears off, your body doesn’t notice as much. This could lessen a rebound reaction or even prevent one in some circumstances. You could also take another strong medication to help control your mast cells in another way, like a steroid.

Following a major reaction or anaphylaxis, many providers opt to use a taper for diphenhydramine and steroids. This can help with rebound reactions. A patient doing this might take diphenhydramine every 4 hours for one day, then every 6 hours for two more days, then every 12 hours for two more days. By not stopping cold turkey, you can allow your body to adapt. Steroid tapers do the same thing. You want to give your body a chance to compensate for not having the medication around.

Not all medications cause rebound reactions. The second generation H1 antihistamines like cetirizine or loratadine do not normally cause rebound reactions.

One important point is that many people use the term “rebounding” when they actually mean a different thing called biphasic anaphylaxis. Rebounding specifically means the reappearance of symptoms because the medication controlling them has worn off. Biphasic anaphylaxis is when you have anaphylaxis again after having a first anaphylactic event, regardless of treatment. In this scenario, a person has anaphylaxis and takes medications to treat the anaphylaxis effectively. Sometime later on, the body has a second anaphylaxis event without being exposed again to a trigger. This is not tied to any specific treatment and is different than rebounding.

For more detailed reading, please visit these posts:

How to get out of a reaction cycle

Anaphylaxis and mast cell reactions

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 35

Author’s note: This is not medical advice. Any information found here should be used as a tool for discussions you have with a provider who knows you and your specific health situation.

42. How is anaphylaxis related to mast cell disease? How do I know when to use my epipen?

Anaphylaxis is a complication of mast cell disease. It is not an inherent part of mast cell disease or a symptom of mast cell disease. Many patients never experience it.

One study found that among mastocytosis patients, adult patients with SM are more likely to experience anaphylaxis than adults with CM or children with mastocytosis. But as many as half of adult patients and even more pediatric patients never have anaphylaxis. For MCAS, the number is reported as less frequent with incidence of anaphylaxis in one group around 17%. I personally think this number is very low and sampling error. It is my experience that MCAS patients are at least as likely to anaphylax as mastocytosis patients, if not more likely.

Even though lots of mast cell patients never experience it, it is important to be aware of the risk of anaphylaxis and take precautions. Mast cells are critical in the biology of anaphylaxis so having mast cells that are very reactive, or having more mast cells than usual, can lead to more severe anaphylaxis more often than someone in the general population might experience. All mast cell patients should carry two epipens at all time. They should also carry diphenhydramine (Benadryl, liquid preferred), and many also carry steroids to use in case of anaphylaxis.

One of the most common questions I am asked is when to use your epipen. The answer to this is complicated largely because so many symptoms of mast cell disease are also symptoms of anaphylaxis. It can be hard to figure out what is going on. I have written extensively about the difference between anaphylaxis and mast cell reactions before so I recommend you read those posts also if you have not already.

The answer to when you should use your epipen is pretty much always that you should ask your doctor or provider. This answer is true and is always right. It is important that someone who knows your health situation well weighs in.

But there’s another answer we can give to this question: that you should use you epipen when it will save your life.

There are various charts and scales that people and groups use to categorize the severity of anaphylaxis. These are not useful for mast cell disease. Do not use them. They are meaningless for us.

The purpose of those charts is to allow people to figure out when a bad anaphylaxis episode is on the way. It allows people to estimate by symptoms when they should use their epipen and call 911. The charts are saying, if you have these three symptoms, you could be heading for anaphylaxis, use your epipen. But for mast cell patients, you can have those three symptoms for a variety of reasons that are not anaphylaxis. It could be mast cell reaction or just regular symptoms. So mast cell patients can’t really predict anaphylaxis in the way described in the charts. These charts just do not work for us.

So when should mast cell patients use an epipen? Generally, the answer is that they should use it when they have trouble breathing or a significant drop in blood pressure. If you are looking for independent markers for when to use an epipen and not symptoms, this lines up with a pulse ox of below 91, or systolic blood pressure below 90 (for adults), or a 30% drop in blood pressure from baseline (for children or adults). Speaking abstractly, in mast cell patients, trouble breathing and significant drop in blood pressure are usually considered as signs of anaphylaxis that warrant use of an epipen. Additionally, if the patient has a set of symptoms that they know will lead to trouble breathing or low blood pressure, their provider will direct them to use an epipen as soon as those symptoms start.

Again, when you use an epipen is a discussion that you must have with your provider. Mast cell patients should all carry two epipens on them at all time and whatever else they use for rescue meds, usually liquid diphenhydramine, and sometimes other medications.

For more detailed reading, please visit these posts:

The definition of anaphylaxis

Anaphylaxis and mast cell reactions

Treatment of anaphylaxis

The MastAttack 107: The Layperson’s Guide to Mast Cell Diseases, Part 17

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

25. How do I know what I will react to?
There is no way to definitively know what things will make you react. It is difficult to predict. There are some general guidelines many of us use to figure out what may be a problem but the only way to really know is to try something.
• Please note that because mast cell reactions are not known to be triggered by the same mechanisms as traditional allergies, you cannot exclude an entire class of drugs because you react to one in the way that you do for traditional allergies. This is particularly worth noting for opiates: reaction to morphine, for example, does not exclude fentanyl or hydromorphone.
• Mast cell reactions are not inherently triggered by IgE the way that “true” allergies are. This means that blood tests for IgE allergies will not identify triggers accurately for most mast cell patients. (Although some mast cell patients do have some IgE allergies.)
• Additionally, skin testing is wildly inaccurate in mast cell patients because of how reactive our skin is.
Stopping antihistamines is dangerous for mast cell patients.
Allergy testing is not accurate for mast cell patients.
• There are several ways that various things can cause mast cell reactions. Generally, they do it in one of the following ways: they cause mast cells to empty the chemicals in their pockets into the body (degranulation); they cause mast cells to release chemicals in another way; they already contain significant amounts of histamine; or the interfere with the mechanisms for controlling mast cell activation.
There are a number of medications that can cause mast cell degranulation or histamine release. Please note that not all of these medications are problematic for every patient. Only a provider managing your case can determine if these are safe for you or not. The major medications that may cause degranulation or histamine are listed below. This list is not exhaustive.

-Alcohol: Widely used to sterilize body area, surfaces, or tools; also used when preparing many medications that are not soluble in water
-Amphoterecin: Antifungal
-Aspirin: NSAID, for pain, inflammation, to block prostaglandins, to prevent clot formation
-Atracurium, mivacurium, rocuronium: Muscle relaxant
-Caine anesthetics (esters): Anesthetics, to numb
-Codeine, morphine, meperidine: Opiates, for pain or cough
-Colistin: Antibiotic
-Dextran: Volume expander, used in surgical or emergency situations to improve blood pressure
-Dextromethorphan: Cough suppressant
-Miconazole: Antifungal
-Nefopam: For pain
-NSAIDs (non steroidal anti-inflammatory drugs): For pain, inflammation, blocking production of prostaglandin
-Polymyxin B: Antibiotic
-Radioopaque contrast: To visualize structures in medical scanning procedures
-Reserpine: High blood pressure medication and antipsychotic
-Succinylcholine: Paralytic used for surgical procedures
-Thiopental: Anesthesia induction for surgical procedures
-Vancomycin (especially IV): Antibiotic

• There are a number of medications that are known to interfere with the mechanisms for controlling mast cell activation. Adrenaline is naturally made by the body to help control mast cell activation and other activities. When you interfere with the ability of adrenaline to act, it can potentially trigger mast cell activation. Drug classes that do this include beta blockers and alpha adrenergic blockers. This is particularly an issue if there is a history of anaphylaxis because these medications can interfere with Epipens.
Many foods either contain histamine or can trigger mast cell release of histamine. As with medication, you cannot exclude an entire family of foods because you react to one in the way that you do for traditional allergies.
• There are many lists of foods to avoid. They often conflict with each other. There is not yet a definitive list available. Despite this, there are some general rules of thumb that are agreed upon on what to avoid.
• Products that are fermented, contain alcohol, are overly ripe or leftover from previous days (especially meats), or contain dyes or preservatives are generally excluded.
• Beyond this, recommendations vary a lot more. Many diets recommend excluding yeast, citrus fruits, and nightshade vegetables.
Many activities inherently activate mast cells. Being too hot, standing or sitting in direct sunlight, exercise, sexual activities, menstruation, infection, and any type of physical trauma, even minor, can trigger mast cell activation as part of normal mast cell function.
Premedication is recommended for any medical procedure, even minor, as they can trigger mast cell activation.
• Patients may find that premedication prior to other activating activities is helpful for suppressing reactions.
Ultimately, the only way to know what is activating is through trial and error. Patients should consult their care team about what to trial, when, and how to make it as safe as possible.

For more detailed reading, please visit these posts:

Food allergy series: Mast cell reactions and the low histamine diet

The Provider Primer Series: Introduction to Mast Cells

The Provider Primer Series: Medications that impact degranulation and anaphylaxis

Beta blockers and epinephrine

Beta blockers (often styled β-blockers) are medications used primarily for their impact on blood pressure and heart rhythm. Given their low cost and relative safety, beta blockers are very commonly prescribed for a number of other conditions as well, including anxiety. They work by blocking beta adrenergic receptors found throughout the body and specifically interfere with the action of norepinephrine and epinephrine.

The use of beta blockers in patients with risk of anaphylaxis requires some special consideration. This is because beta blockers directly block many of the places where epinephrine works to mitigate anaphylaxis. This means that using epinephrine to treat the anaphylaxis may be ineffective. This particular topic has been heavily researched and has not always yielded uniform findings.

The largest and most robust study included over 5000 patients with a history of systemic allergic reactions. This study found that patient use of beta blockers increased the risk of severe anaphylaxis. Use of ACE inhibitors, another drug class that impacts blood pressure, also increased the risk of severe anaphylaxis but to a smaller extent.

However, the risk of severe anaphylaxis was most increased in patients who took both beta blockers and ACE inhibitors together. Both beta blockers and ACE inhibitors were found to both decrease the threshold for mast cell activation and to prime mast cells (make them more easily activated).

Ongoing treatment with beta blockers has been found to be a risk factor for fatal anaphylaxis in some studies. It has also been found to be a risk factor for biphasic anaphylaxis, a type of anaphylaxis in which you have a second anaphylactic episode in the hours that follow successfully treated anaphylaxis.

Patients who must take beta blockers may be given a glucagon autoinjector for use prior to using injectable epinephrine. The reason for this is glucagon is the antidote to beta blocker overdose. When epinephrine binds to the beta receptor, it results in the cells making a molecule called cAMP. cAMP is a very important molecule for cells and it sends signals within the cell to regulate bodily processes. When a patient takes beta blockers, epinephrine can’t tell the cell to make cAMP. Glucagon is able to tell the cell to make cAMP even if the beta receptor is blocked. This action effectively counteracts the beta blocker.

Mast cell patients are usually recommended to use other medications to manage blood pressure and arrhythmias, including calcium channel blockers or renin inhibitors.

 

References:

Simons FER, et al. (2015) 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organization Journal, 8(32).

Nassiri M, et al. (2015) Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. J Allergy Clin Immunol, 135: 491-499.

Shephard G. (2006) Treatment of poisoning caused by β-adrenergic and calcium-channel blockers. American Journal of Health-System Pharmacy, 63(19): 1828-1835.

Tole J, Lieberman P. (2007) Biphasic anaphylaxis: review of incidence, clinical predictors, and observation recommendations. Immunol Allergy Clin N Am, 27(2): 309-326.

Kolch UW, et al. (2016) Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research, x: 1-10.

Reitter M, et al. (2014) Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and management analysis. Allergy, 69: 954-959.

The Provider Primers Series: Medications that impact mast cell degranulation and anaphylaxis

A number of medications can induce mast cell degranulation and histamine release. Other medications increase the risk of anaphylaxis and can increase the severity of anaphylaxis.

Medication reaction profile is very individual and not all mast cell patients react to the medications listed below. Additionally, there may be a need for some mast cell patients to take  medications listed below if the benefit outweighs the risk.

Medications that are reported to induce mast cell degranulation and histamine release
Alcohol[i] Amphoterecin B[ii] Aspirin[i] Atracurium[iii]
Caine anesthetics (esters)[iv] Codeine[v] Colistin (polymyxin E)[vi] Dextran[iii]
Dextromethorphan[iii] Gelatine[iii] Iodine based radiographic dye[vii] Meperidine[viii]
Miconazole[ix] Mivacurium[iii] Morphine[iv] Nefopam[iii]
NSAIDs[x] Phentolamine[xi] Polymyxin B[v] Reserpine[xii]
Rocuronium[iv] Succinylcholine[iv][xiii] Thiopental[iv] Tolazoline[v]
Vancomycin[xiv] (especially when given intravenously)

 

Patients on beta blockers are more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. Beta blockers also impede treatment of anaphylaxis by interfering with the action of epinephrine[xvi]. Patients at risk for anaphylaxis who are on beta blockers should get a glucagon pen to use prior to epinephrine[xv].

Beta adrenergic blockers[xvi] (Note: List is not exhaustive)
Acebutolol Atenolol Betaxolol Bisoprolol
Bucindolol Butaxamine Cartelol Carvedilol
Celiprolol Esmolol Metoprolol Nadolol
Nebivolol Oxprenolol Penbutolol Pindolol
Propranolol Sotalol Timolol

 

Alpha blockers impede treatment of anaphylaxis by interfering with the action of epinephrine[xvii].

Alpha-1 adrenergic blockers[xvii] (Note: List is not exhaustive)
Alfuzosin Amitryptiline Amoxapine Atiprosin
Carvedilol Chlorpromazine Clomipramine Clozapine
Dapiprazole Dihydroergotamine Doxazosin Doxepin
Ergotamine Etoperidone Fluphenazine Hydroxyzine
Imipramine Labetalol Loxapine Mianserin
Nefazodone Olanzapine Phentolamine Prazosin
Quetiapine Risperidone Silodosin Tamsulosin
Thimipramine Thioridazine Trazodone

 

Alpha-2 adrenergic blockers[xvii] (Note: List is not exhaustive)
Buspirone Chlorpromazine Clozapine Esmirtazapine
Fluophenazine Idazoxan Loxapine Lurasidone
Mianserin Mirtazapine Olanzapine Phentolamine
Risperidone Thioridazine Yohimbe

Patients on angiotensin-converting enzyme (ACE) inhibitors are also more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. The exact reason for this is unclear but ACE inhibitors impede appropriate bradykinin metabolism which may contribute to anaphylaxis[xvi].

Angiotensin converting enzyme (ACE) inhibitors[xvi] (Note: List is not exhaustive)
Benazopril Captopril Enalapril Fosinopril
Lisinopril Moexipril Perindopril Quinapril
Ramipril Trandolopril

Special notes:

Aspirin use in mast cell patients to suppress prostaglandin production is becoming increasingly common[xviii]. In some situations, other NSAIDs are also used.

Fentanyl, sufentanil, remifentanil and alfentanil are the preferred opioids for mast cell patientsiv. Hydromorphone releases minimal histamine and is also used in mast cell patients.[xix]

References:

[i] Valent P. (2014). Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clinical & Experimental Allergy, 44, 914-920.

[ii] Lange M, et al. (2012). Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci, 8(3), 533-541.

[iii] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[iv] Eggleston ST, Lush LW. (1996). Understanding allergic reactions to local anesthetics. Ann Pharmacother, 30(7-8), 851-857.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Kwa A, et al. (2014). Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Review of Anti-infective Therapy, 5(5), 811-821.

[vii] Kun T, Jakubowski L. (2012). Pol J Radiol, 77(3), 19-24.

[viii] Blunk JA, et al. (2004). Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analq, 98(2), 364-370.

[ix] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[x] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xi] Powell JR, Shamel LB. (1979). Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors. J Cardiovasc Pharmacol, 1(6), 633-640.

[xii] Muroi N, et al. (1991). Effect of reserpine on histamine metabolism in the muse brain. J Pharmacol Exp Ther, 256(3), 967-972.

[xiii] Sadleir PH, et al. (2013). Anaphylaxis to neuromuscular blocking drugs : incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth, 110(6), 981-987.

[xiv] Sanchez-Borges M, et al. (2013). Hypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy. World Allergy Organization Journal, 6(18), doi:10.1186/1939-4551-6-18

[xv] Thomas M, Crawford I. (2005). Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J, 22(4), 272-273.

[xvi] Lieberman P, Simons FER. (2015). Anaphylaxis and cardiovascular disease: therapeutic dilemmas. Clinical & Experimental Allergy, 45, 1288-1295.

[xvii] Higuchi H, et al.(2014). Hemodynamic changes by drug interaction of adrenaline with chlorpromazine. Anesth Prog, 61(4), 150-154.

[xviii] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xix] Guedes AG, et al. (2007). Comparison of plasma histamine levels after intravenous administration of hydromorphone and morphine in dogs. J Vet Pharmacol Ther, 30(6), 516-522.

The Provider Primers Series: Introduction to Mast Cells

Mast cells : Introduction

  • Mast cells are bone marrow derived. They migrate to tissues before maturity and remain tissue bound.[i]
  • Mast cell development in tissues is regulated by a number of molecules, most significantly stem cell factor (SCF) which binds at the CKIT (CD117) receptor. A number of other molecules, including IL-3, IL-4 and IL-10, also participate in this process.[ii]
  • Mast cells are long lived, with some living for years in tissue.[ii]
  • Mast cells are versatile actors. Their functions and granule contents are tailored to the needs of the local microenvironment.[iii]
  • Mast cells perform a number of critical roles, including immune defense against microbes and larger parasites; clotting; wound repair; tissue remodeling; angiogenesis; regulation of reproductive cycle; digestion and GI motility; pain response; participation in stress response via interaction with HPA axis; inflammatory response; and regulation of sleep and some aspects of cognition.[iv]
  • Mast cells produce a multitude of mediators which are stored in granules or produced de novo. Stored mediators of consequence include histamine; tryptase; heparin; bradykinin; serotonin; and substance P. De novo mediators include prostaglandin D2; leukotrienes C4, D4, and E4; platelet activating factor; tumor necrosis factor; interferons; and a number of interleukins, including IL-1a, IL-1b and IL-6, among many others. [iii]

Mast cell involvement in disease

  • Mast cells are involved in the pathology of many conditions, including asthma[iv]; autoimmune diseases[iv]; GI dysmotility, including post-operative ileus[v]; cardiovascular events[iv], such as myocardial infarction, rupture of atherosclerotic plaques or aneurysms, and coronary syndromes, including Kounis syndrome[vi]; cardiovascular disease; malignant and neoplastic [iv]; chronic kidney disease[iv]; cutaneous conditions[iv], including many forms of urticaria; depression and anxiety; and chronic pain[vii].
  • Mast cells are effectors in all mast cell diseases.
  • Most famously, mast cells are involved in allergy and anaphylaxis.[viii]

Mechanisms of mast cell activation

  • Mast cells are primarily activated via IgE crosslinking at the FcεRI receptor. This is the mechanism for the classic allergy model in which specific IgE binds the target allergen and crosslinks at the FcεRI receptor on the surface of mast cells and basophils. In this traditional model, crosslinking causes immediate degranulation of stored mediators and late phase release of mediators produced de novo upon activation[viii].
  • There are several other mechanisms for direct mast cell activation that are independent of IgE.
  • A number of inflammatory molecules can directly activate mast cells by binding surface receptors including corticotropin releasing hormone; substance P; histamine; cysteinyl leukotrienes; adenosine; stem cell factor; IL-3; IL-4; IL-9; and IL-33, among others[ix].
  • Substances associated with immune defense and infection can directly activate mast cells. Products derived from pathogens can activate via toll like receptors (TLR2 and TLR4), Dectin-1 or CD48. Host production of β-defensins and complement C3a and C5a can also provoke mast cell activation[ix].
  • IgG can bind at FcγR receptors on mast cell surfaces. Immunoglobulin free light chains have triggered degranulation in murine models but this has not yet been demonstrated in humans[ix].

Definition of anaphylaxis

  • The definition of anaphylaxis continues to be disputed. The 2006 NIAID/FAAN criteria detailed below have been validated and are widely used.[x]
  • Anaphylaxis is likely when any one of the following three criteria is met:
  • Criterion 1: Acute onset of illness with skin and mucosal issue involvement (hives, itching, flushing, swelling of lips/tongue/uvula) with at least one of the following: compromised airway (difficulty breathing, wheezing, low blood oxygenation); or reduced blood pressure or symptoms thereof (fainting, incontinence.)
  • Criterion 2: Two or more of the following occurring after exposure to a likely allergen: skin or mucosal tissue involvement (hives, itching, flushing, swollen lips/tongue/uvula), compromised airway (difficulty breathing, wheezing, low blood oxygenation); reduced blood pressure or symptoms thereof (fainting, incontinence); or persistent GI symptoms (cramping, abdominal pain, vomiting).
  • Criterion 3: Reduced blood pressure after exposure to known allergen.  For adults, this is <90 mm Hg systolic, or at least 30% decrease from baseline.  For children under 1 year of age, this is <70 mm Hg systolic; ages 11-17, <90 mm Hg systolic.  For children 1-10 years of age, this is <(70 mm Hg + (2x age)).  So for a child who is 8 years old, this would be <(70 + (2 x 8)) = <86 mm Hg.

References:

[i] Dahlin JS, Hallgren J. (2015). Mast cell progenitors: origin, development and migration to tissues. Molecular Immunology 63, 9-17.

[ii] Amin K. (2012). The role of mast cells in allergic inflammation. Respiratory Medicine, 106, 9-14.

[iii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[iv] Rao KN, Brown MA. (2008). Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci, 1143, 83-104.

[v] De Winter, BY. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta, 1822, 66-73.

[vi] Kounis NG. (2016). Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[vii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1), 38-44.

[viii] Galli SJ, Tsai M. (2013). IgE and mast cells in allergic disease. Nat Med, 18(5), 693-704.

[ix] Yu Y, et al. (2016). Non-IgE mediated mast cell activation. European Journal of Pharmacology 778, 33-43.

[x] Sampson HA, et al. (2006). Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 117(2), 391-397.