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 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 40

49. What is the relationship between FPIES and MCAS?

FPIES is food protein induced enterocolitis syndrome, a severe type of food allergy. It causes continuous vomiting and diarrhea upon ingestion of a trigger. FPIES reactions can cause dehydration and dangerous drop in blood pressure. I cannot emphasize enough that FPIES can be extremely serious and that the reactions can be life threatening if they are not managed properly.

FPIES almost exclusively affects children starting in infancy and resolves around the age of 5. The reasons for this are unknown. FPIES is a diagnosis of exclusion. There are no tests to identify FPIES.

An important point is that trigger avoidance is generally sufficient for management in children with FPIES. When the child is not being exposed to a trigger, they should not have lingering symptoms.

If a child with FPIES continues to have symptoms, the conventional thinking is often that there must be a trigger that has not yet been eliminated from their diet. In children with continuing symptoms, they frequently have more traditional allergy type symptoms than the profuse GI issues seen with FPIES exposures. This is where FPIES starts to overlap with MCAS. MCAS can cause the same reactions to foods seen in FPIES. MCAS can also cause daily symptoms even if food triggers are avoided. Increasingly, children who were initially diagnosed with FPIES are later diagnosed with MCAS.

There are a few possible scenarios here. Firstly, it is possible that the child has FPIES and has MCAS secondarily to the FPIES. It is also possible that the child was misdiagnosed with FPIES and had MCAS all along. It may also be that FPIES is some form of MCAS. They have a lot in common.

Because there is no test for FPIES, and it is very difficult to accurately perform mediator testing to look for mast cell disease in infants, it is hard to be definitive at that age anyway. In some cases, investigation of MCAS as a possible diagnosis for these children only occurs when they fail to “grow out of” FPIES around age 5. Having anaphylaxis also provides a clue towards MCAS as a potential diagnosis.

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

The Provider Primers Series: Mast cell activation syndrome (MCAS)

The absence

My port is currently deaccessed. It has been accessed in the same place, 24 hours a day, 7 days a week, for three years. Except when the needle is changed weekly, or it is briefly deaccessed for another reason, like to go swimming, it is accessed all the time. I feel much safer with it accessed as it gives me ready IV access in case of bad reactions or anaphylaxis. As much as I do not like needing a port, I am very happy to have it. It makes me feel much safer and more secure.

Last weekend, I accidentally tore the needle out of the port. I already have a permanent hole in my skin from being constantly accessed and it made the hole bigger. I was able to get it accessed again safely but something will have to be done about my access site. I may need to get a temporary line placed so that I can deaccess my port for a few weeks and give my skin a chance to heal.

For now, I’m deaccessing for three hours three nights a week and slathering my site with MML (magic masto lotion – recipe at the bottom) to soothe the skin and the site. Meanwhile, I just finished doing yoga on my living room floor, and am sitting here, thinking about my port, the absence of the needle, and the other absences my disease has rendered me.

 

I didn’t immediately realize what was happening when I started losing my hearing. I imagine it is that way for many people. It was springtime and I was training to once again walk 60 miles in 3 days for a breast cancer fundraising event. I walked a lot, 8-10 miles at a whack, people watching and getting lost in my head, music loud in my ears. When I noticed that the music wasn’t as loud in my left ear, I assumed my headphones were broken. I bought new ones and shortly realized that I had the same problem. Because I am not overly bright, I bought new headphones AGAIN, only to discover that I was being targeted by a complex conspiracy to deprive my left ear of sound.

It was still a few days before I realized that all of these headphones worked fine and that it was my left ear that wasn’t. I could hear in my left ear but it was dampened. I was also beginning to have balance issues. I will never forget the moment when I understood that I couldn’t hear well on my left side and that there was no obvious explanation for it. I somehow just knew that this would not be something that could be readily fixed. I felt this wave of panic, electric and silent, hidden under the beat of my quickening pulse. Always there, waiting without a sound.

I was pretty terrified while I was losing my hearing. Over several months, I lost all the hearing in my left ear and most of the hearing in my right. I listened to music compulsively, constantly. I noticed the blank moments where there used to be notes. I noticed the empty spaces in words. It grew. This hollowness grew and swallowed all these pieces of the world where there used to be sound.

You learn to live around absence. It is an instinct to adapt to your environment. And even though my environment didn’t change, it changed for me. It was both terrifying and fascinating. The way I interacted with the world was fundamentally changed. I was present in a world full of absence.

As strange as it sounds, when I lost my hearing, I wasn’t terribly “sick”. Like I lost my hearing but my overall, day to day functionality was still very good. It was over the next couple of years that things took a serious turn. And you get sick, like properly sick, you lost things. It’s not always a lot at once but it is steady and unending. You lost friends. Opportunities. Money. Jobs. Dignity. A million little things and a lot of big ones.

One of the big losses for many of us with mast cell disease is food. I didn’t start really losing foods in a significant way until late 2013/early 2014. Things picked up speed and soon I was down to very few foods that I could keep down that wouldn’t trigger mast cell reactions or anaphylaxis. I have regained and lost a lot of foods in the last few years. This past winter was the worst patch in a while. I was mostly limited to liquids, and very few liquids, at that. I was still eating plain potato chips because without any other solids, I would wake up because of the hunger pains. I lost a ton of weight, a lot of muscle, and a whole lot of hope.

I started Xolair injections in late February. My expectations were pretty tempered but it was worth a shot. Within a week, I could keep down some solids. My stomach has become a lot of smaller and I still can’t eat a lot of food at once but I can eat again. I can eat things I haven’t eaten safely in years. I still react to certain foods but I don’t seem to react anymore to the process of eating.

I am very aware that I could lose solids again at any time. For now, I’m just trying to be present.
*Magic masto lotion (MML): a cream applied to the skin for hives, itchiness, eczema, really any type of mast cell skin irritation. It is made by mixing liquid cromolyn with whatever your safe cream or lotion is. Some of us have prescription liquid cromolyn ampules while other people making it using over the counter Nasal Crom. I put about 3 ml of cromolyn liquid in a plastic bag, squirt some cream in there, close the bag, mix it up, and then slather it on wherever I want. Always speak with your health provider before adjusting your treatment plan.

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

Reintroduction of food to a child with SM

I recently put together some recommendations on reintroducing foods to a child with SM who has been exclusively on IV nutrition (TPN) for an extended period of time. I thought you might find some use in it so I have posted it here.

Before people ask, there are no significant publications on children with MCAS because there are not currently unifying diagnostic criteria.

****

Author’s note: I am not a medical doctor. Protocols for reintroducing foods must be developed by the managing care team and tailored to each patient.

There are no large population studies for pediatric systemic mastocytosis. True systemic mastocytosis (in which WHO diagnostic criteria are satisfied) is rare in children. Accordingly, SM in children is generally reported as case reports rather than studies given the population size[i].

Given the lack of in depth literature specifically regarding food challenge in children with SM, I would draw from data in similar situations to identify a safe and appropriate protocol for reintroducing for [name redacted].

There are five scenarios that may contribute insight for food reintroduction in this patient: oral food challenges for FPIES patients; desensitization procedures for delayed hypersensitivity reactions; reintroduction of food after long term parenteral therapy; premedication of patients with mast cell activation disease, including systemic mastocytosis; and mast cell involvement in gastroparesis, ileus and GI dysmotility.

Based upon these scenarios, we can infer the following:

  • Reintroduction of food to this patient should follow a long, repetitive schedule with gradually increasing quantities.
  • Premedication with antihistamines and glucocorticoids to avoid mast cell reaction should be considered.
  • Mast cell activation can directly induce GI dysmotility. Drug management of mast cell activation can suppress impact upon function.
  • Enteral feeds should be gradually increased while parenteral feeds are gradually decreased.
Scenario Application to food reintroduction in a mast cell patient
1 Oral food challenge in setting of FPIES FPIES and food reactions secondary to mast cell disease are both non-IgE mediated and can culminate in shock requiring emergency intervention.
2 Desensitization for delayed drug hypersensitivity reactions Mast cell degranulation and anaphylactic reactions are not type I hypersensitivity reactions. They may also present on a delayed schedule.
3 Reintroduction of food after long term parenteral nutrition Reintroducing food to patients after long term parenteral nutrition may impact GI function. Gradual reintroduction is recommended.
4 Premedication of patients with mast cell activation disease Patients with mast cell activation disease, including systemic mastocytosis, are advised to premedicate prior to all procedures to decrease risk of reaction and anaphylaxis.
5 Mast cell involvement in gastroparesis, ileus, and GI dysmotility Mast cells contribute significantly to GI motility disorders including gastroparesis and ileus.

 

  1. Oral food challenge in patients with food protein induced enterocolitis syndrome (Caubet 2014[ii], Leonard 2011[iii])
  • Food protein induced enterocolitis syndrome (FPIES) is a severe non –IgE mediated GI food hypersensitivity syndrome.  Patients with FPIES are children. The condition is managed by removing the offending food from the diet for extended periods, usually years.
  • Food challenge in FPIES can result in severe, repetitive vomiting; diarrhea; lethargy; pallor; hypothermia; abdominal distension; and low blood pressure. Not all of these features are universally present for all patients.
  • The following procedure is recommended for oral food challenge in FPIES children:
  • All FPIES oral food challenges must be physician supervised with appropriate supportive care available.
  • Over the first hour, 0.06-0.6 g/kg body weight of food protein should be administered in three equal doses. It should not exceed 3g of total protein or 10g of total food or 100ml of liquid for initial feeding.
  • If patient has no reaction, give a full serving of food as determined by their age.
  • Observe patient for several hours afterward.
  • In the event of severe reaction, administer 1mg/kg methylprednisolone intravenously, up to 60-80 mg total; 20 ml/kg boluses of NS; and epinephrine.
  • Food challenge is considered positive for reaction if patient experiences typical symptoms as a direct result of the challenge.

 

  1. Desensitization for delayed hypersensitivity medication reactions (Scherer 2014[iv], Leoung 2001[v])
  • There are no controlled studies available on desensitization for delayed reactions to drugs.
  • Described procedures have timespans ranging from hours to weeks.
  • Patients who initially failed rapid protocols have succeeded using slower procedures.
  • It may take 2-3 days before hypersensitivity symptoms develop in a delayed reaction.
  • Long protocols with repetitive, gradually escalating dosing are recommended.
  • Antihistamine prophylaxis is often recommended. Drug and dosing vary.
  • The following procedure describes an example of a gradually escalating dosing:

Dose escalation for desensitization, adapted from antibiotic desensitization procedure

(Leoung 2001)[v]

Dosing level Drug portion Frequency of daily dosing
1 12.5% QD
2 25% BID
3 37.5% TID
4 50% BID
5 75% TID
6 100% QD

 

  1. Reintroduction of food after long term parenteral nutrition (Hartl 2009[vi], Oley Foundation)
  • Long term TPN may increase intestinal permeability.
  • Long term TPN may result in diminished enzymatic activity in GI mucosa.
  • The Oley Foundation suggests decreasing parenteral nutrition by 25% while increasing enteral feeds by 25% as the patient tolerates.

 

  1. Premedication of patients with mast cell activation disease (Castells 2016[vii])
  • Mast cell patients are recommended to premedicate for all procedures using H1 and H2 antihistamines, glucocorticoids, and leukotriene receptor antagonists.

 

  1. Mast cell involvement in gastroparesis, ileus, and GI dysmotility (Nguyen 2015[viii], de Winter 2012[ix])
  • Mast cells can be activated by a number of pathways which do not involve IgE, including neuropeptides, complement factors, cytokines and hormones.
  • Mast cells in the GI tract are closely associated with afferent nerve endings.
  • Mast cell behavior in the GI tract is largely controlled by the central nervous system.
  • Mast cells are directly involved in GI dysmotility disorders including gastroparesis and ileus.
  • Mast cell activation and population may be upregulated in the setting of GI inflammation.

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

[ii] Caubet JC, et al. (2014) Clinical features and resolution of food protein induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol, 134(2): 382-389.

[iii] Leonard S, et al. (2011) Food protein induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol, 107:95-101.

[iv] Scherer K, et al. (2013) Desensitization in delayed drug hypersensitivity reactions – an EAACI position paper of the Drug Allergy Interest Group. European Journal of Allergy and Clinical Immunology, 68(7): 844-852.

[v] Leoung GS, et al. (2011) Trimethoprim-sulfamethoxazole (TMP-SMZ) Dose Escalation versus direct rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. Journal of Infectious Diseases, 184:992-997.

[vi] Hartl WH, et al. (2009) Complications and monitoring – Guidelines on Parenteral Nutrition, Chapter 11. Gen Med Sci, 7:Doc17.

[vii] http://www.tmsforacure.org/documents/ER_Protocol.pdf

[viii] Nguyen LA, et al. (2015) Clinical presentation and pathophysiology of gastroparesis. Gastroenterol Clin N Am, 44: 21-30.

[ix] de Winter BY, et al. (2012) Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Act, 1822: 66-73.

The Provider Primer Series: Relevance of mast cells in common health scenarios

 

Symptom Cough
Role of mast cells Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough:

•             Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i]

•             Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i]

•             Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i]

•             Tryptase promotes overall increased reactivity of the airway.[i]

Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i]

Mast cells remain activated in inflamed airways.[i]

Impact of condition on mast cells Mast cell activation can occur as a result of the physical stimuli such as coughing[ii].

Pain can trigger mast cell activation[iii].

Notes regarding condition treatment Dextromethorphan can trigger mast cell degranulation[iv].

Codeine and derivatives can trigger mast cell degranulation[v].

Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].

Notes regarding mast cell treatment Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii]

Racemic epinephrine can provide relief of pulmonary symptoms.[viii]

Special considerations for mast cell patients Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix]

Mast cell patients frequently have reactive airways.[ix]

Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x].

Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

 

Symptom Sore throat
Role of mast cells Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix]

Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix]

Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii]

Oral allergy syndrome should be considered.[ix]

 

Symptom Rash
Role of mast cells Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi]

Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]

Impact of condition on mast cells Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii]

Pain can trigger mast cell activation.[iii]

Notes regarding condition treatment Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients Mediator release by activated mast cells can produce systemic symptoms.[x]

In patients with a history of mast cell disease, mastocytosis in the skin should be considered.

o             Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii]

o             Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii]

o             A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii]

o             Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

 

Symptom Fever
Role of mast cells Mast cells can produce prostaglandin E2.[x]

Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]

Impact of condition on mast cells Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

 

Symptom Earache
Role of mast cells Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii]

Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Steroids (local and systemic) can stabilize mast cells.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]

Antihistamines can provide relief for vestibular symptoms.[vi]

Special considerations for mast cell patients Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix]

Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix]

Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix]

Mast cell disease can also cause auditory processing disorder.[ix]

Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

 

Symptom Stomachache
Role of mast cells Mast cells are commonly found in the GI tract.[xvi]

Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi]

Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]

Impact of condition on mast cells GI inflammation can recruit mast cells to inflamed tissues.[xvi]

GI inflammation can trigger mast cell mediator release.[xvi]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment
Notes regarding mast cell treatment Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

 

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

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

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

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

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

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

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1):35-45.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] 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.

[xv] 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.

[xvi] Ramsay DB, et al. (2010). Mast cells in gastrointestinal disease. Gastroenterology & Hepatology, 6(12): 772-777.

 

The Devil’s Arithmetic

When I was in grad school, I took immunology. I still have my textbook and refer to it sometimes, my crowded notes in the margins. The chapter on allergy and anaphylaxis is highlighted in green, somehow aggressively bright after eleven years.

It’s kind of amusing to recall this time in my life, before every mast cell activation pathway had been hammered into my brain. There’s also some black humor in reading about how IgE activation is the allergy pathway. You know, THE allergy pathway. This book doesn’t cover any other pathways. As if you cannot possibly be allergic to something without IgE.

That’s the problem, of course. This is what most healthcare providers or science majors learn in school. They learn about allergy and anaphylaxis, but they learn about the textbook description which invariably refers to IgE mediated food anaphylaxis. They learn about peanut allergy.

I don’t have a peanut allergy. I literally don’t have a single food allergy that displays the hallmark swelling/closing airway that people expect. But I have major food allergies, some bad enough to require epinephrine, IV Benadryl, Pepcid, Solu Medrol, Zofran and IV fluids.

The problem is not just that I’m allergic to some foods. It’s that I’m not always allergic to the same foods as I was the day before. Or the same medications. Or the same environmental exposures. My reactions on a given day are the cumulative product of the amount of irritation my mast cells have experienced in the previous day or two. There is always a running tally in my mind.

There are a lot of analogies and models used to describe mast cell attacks both to patients and to people who don’t have them. I have always thought of it as a bank. You make deposits and you make withdrawals. Like this:

For the sake of simplicity, let’s assume you have $100 in a bank account. Any activity that can cause mast cell activation has to be paid for. The cost is proportionate to the amount of activation. Getting a splinter: $2. Being hot: $10. Being in direct sunlight: $10. Standing up for 20 minutes while being hot in direct sunlight: $35. Cardiovascular exercise: $40. Arguing with your spouse: $60. Moderate pain experienced in your day to day life: $50. A painful medical procedure: $70. Mild cold: $40.

Some things are too costly to ever attempt.  Undercooked egg whites: $9000.  Massive bleach exposure: $7500.

You can make deposits into the bank with medications and physical changes. Getting enough sleep: $30. Wearing loose, comfortable clothes: $15. Doing orthostatic manuevers before standing up: $10. Taking baseline mast cell medications on your normal schedule: $50. Eating food that is warm but not hot: $15. Monitoring your exercise and stopping for breaks: $15. Wearing a cooling vest on a hot day: $20. Oral Benadryl: $25. IV Benadryl: $50. Steroids: $50.

So you have this running tally in your head all day long. When you start getting close to $100, you get stressed. You know you can’t afford to spend more than $100. Things that you could have done four hours ago safely are no longer safe. Things you could eat on a day spent relaxing at home inside with comfortable ambient temperature cannot be eaten if your apartment is too hot or if you are in a lot of pain.

You are constantly trying to avoid running out of dollars before you can get home and go to bed. Part of this is because you don’t want to trigger a physical reaction. Part of it is that this phenomenon – allergies as a function of circulating histamine/mast cell activation rather than IgE – is hard to explain briefly to people who don’t have this disease. So people will see you on a super crappy day only being able to eat one thing at a party and then four months later, when your body is much less inflamed, will see you eat three things at a party. And then it’s a thing, because these people invariably think that you are faking/being overdramatic as if somehow it is worth the effort to “pretend to have allergies.” WHO FUCKING DOES THAT?

Cost for being around someone who gives you shit for not always having the same restrictions: $75.

So everyday, you get $100. Except this is the US and our banks hate us so we have overdraft. This means that you can spend more money than you have but then they charge a steep fee and so the next day, you don’t have $100. You have maybe $30 dollars. After overspending, it can take a few days to get back to baseline.

Sometimes it’s worth it. Sometimes you can sort of game your body into getting more than $100 out of a day. This is the purpose of premedication for procedures and surgery. This is the purpose of good sleep hygiene, eating safe foods, not getting stressed, taking medications appropriately and on a schedule. You can bank a little. Not as much as you can overdraft, but you can get ahead a little bit.

Today, I went to the supermarket to grab some things for lunch at work. They didn’t have organic apples that looked in decent shape. They had non-organic apples and my safe peanut butter/honey and my safe pretzel chips. I had to run through my entire day to determine how much physical activity and stress was likely to be in the rest of my day to figure out what I could (probably) safely eat for lunch.

It’s like this all day, every day. This math wouldn’t be hard except that it’s constant and unavoidable and controls my life.

The Sex Series – Part Three: Allergic reactions of the vagina and vulva

Most of what I said about kissing applies to genitally penetrating intercourse, too.  It is not uncommon for people to develop hives as a result of the vibration, pressure, heat and friction of intercourse. Swelling after sex, called postcoital edema, is also not unusual.  Sex is also a known trigger for asthma and rhinitis.  Several aspects of sex, including the heat and emotion, can activate the autonomic nervous system and cause release of mast cell mediators.  Importantly, studies have revealed that the allergic effects of sex are not due to the physical exertion (ie. exercise anaphylaxis).

While local reactions are more common, there is precedent for sex causing multisystem allergic response or anaphylaxis.  The person receiving the vaginal penetration is more likely to have anaphylaxis following sex, especially if they are strongly sensitized to food or medications.  Seminal fluid can contain food or drug allergens.  Aspirin and penicillin derivatives have been reported to cause allergic reactions from sex, called postcoital hypersensitivity. Transfer of pollens from the clothes or skin of the partner can also cause allergic reactions.

One product we have not yet discussed that can cause contact dermatitis and anaphylaxis is condoms. 25% of reactions to latex condoms cause hives over large portions of the body, angioedema and respiratory symptoms. There are latex alternative condoms, but many patients react to those as well.

Vaginally penetrating intercourse often causes microscopic tearing, mostly due to inadequate lubrication.  As a former sex educator, if you think you are using enough lubrication, you are not.  It is my personal experience that water based lubricants are better tolerated by most allergy patients for vaginal intercourse.  Silicone lubricant is popular because it’s not absorbed by the body and is therefore slicker, whereas water based lubricant often requires reapplication.  But that’s okay.  That’s why you get a whole bottle.

Contributing to the insufficient lubrication is the fact that most people don’t engage in long enough foreplay.  Foreplay provides a number of benefits: it increases naturally secreted vaginal lubrication, increases blood flow to the vagina and tells the cervix to get out of the way. 20 minutes of foreplay is often recommended as a rule of thumb in order to get the vagina in order before penetrating intercourse.

Moisture, friction and heat can cause the vulvar skin to break down. Estrogen plays a large role in keeping this tissue strong and undamaged.  Urine on the skin can cause contact dermatitis.  Malnutrition and history of genital infections can also contribute towards the reactivity of the tissue. It is also possible to be IgE positive for Candida albicans, a yeast that lives normally in the vagina.  Inflammation can upset the balance of the normal flora, resulting not only in vaginal infections but a literal allergy to Candida.

References:

Schlosser BJ. Contact dermatitis of the vulva. Dermatol Clin 2010: 28; 697-706.

Moraes PSA, Taketomi EA. Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000; 85: 253-267.

Chen WW, Baskin M. A 33-year-old woman with burning and blistering of perivaginal tissue following sexual intercourse. Annals of Allergy, Asthma & Immunology 2004; 93: 126-130.

Harlow BL, He W, Nguyen RHN. Allergic reactions and risk of vulvodynia. Ann Epidemiol 2009; 19: 771-777.

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

The Sex Series – Part One: Kissing and allergic reactions

The avenues by which a person can suffer symptoms as a result of sex are almost endless.  I am asked often about the mechanism by which mast cell patients can react to foreplay or intercourse. The reason it has taken so long to put this series together is not because of a dearth of information, but because there is so much.  The research on this topic is deep, if not always to the point: Why do some people react badly to having sex?

There are a number of reasons why sex can cause allergic symptoms, which explains why intimacy is often fraught with anxiety for mast cell patients.  So let’s start with the entry level: kissing.

It is widely accepted that kissing can transfer allergens via saliva, or contact between skin or oral mucosa.  Allergic reaction after kissing is not even especially unusual.  5-12% of IgE food allergic patients have had at least one reaction after kissing.  Peanuts, walnuts, and tree nuts are the most common offenders.  Rash around the mouth, hives around the mouth, flushing, angioedema of lips, mouth, tongue and throat, wheezing and hives all over the body have all been reported in this situation.  Usually symptoms present within minutes, but there are literature references to reactions developing up to three hours later.

In a group of 26 volunteers that ate peanut butter, the protein reached its highest concentration in saliva five minutes after consumption.  After an hour, the protein was undetectable.  Several methods for clearing the protein were tested.  Brushing teeth, rinsing mouth, or both, waiting an hour after consumption, and waiting an hour and then chewing gum, all reduced protein concentration by over 80%.  However, waiting one hour after eating was still the most effective way to clear the protein from the mouth.

Though much less common than transfer of food allergens, it is possible to transmit medications via saliva. In literature, all reports of this phenomenon involve ingestion of β-lactam antibiotics, including penicillin derivatives.  In these cases, the patients had symptoms of oral allergy syndrome with hives over large parts of the body.

The quality of the kissing is certainly a factor.  How deep is it?  How much hard? How much friction?  How wet?  Mast cell patients often react to physical stimuli like this.  It’s not hard to imagine a situation where the pressure and heat of kissing cause local mast cell degranulation.   I found a (non-scientific) article describing a woman with aquagenic urticaria who reacts to kissing because it’s wet.  For patients allergic to sweat, that could also cause a kissing reaction.

I feel like I should throw out there that you can react to allergens returned to the mouth by vomit.  Mostly because there isn’t really anywhere else to put it.  So it’s here.  The warning about vomit is in the kissing post.  How did this get to be my life?

BUT GUESS WHAT GUYS?!?!?!? Kissing can also be good for allergy patients.  One study reported that that kissing decreased wheal response (the formation of red swollen areas) was decreased 28-34% in patient allergic to dust mite and Japanese cedar pollen.  This patient group had allergic rhinitis and atopic dermatitis.  It didn’t decrease the response to injection of histamine, which means the benefit from kissing in this study is not directly blocking histamine.  Plasma levels of neurotrophins were decreased in these patients.  Neurotrophins have a complex relationship to mast cells, so it’s possible that neurotrophins block something that tells mast cells to release histamine.

I know everyone wants to know – how can I kiss safely? So hang in there, because it’s coming.  Along with the answers to all of the “embarrassing” sex questions I have ever been asked.

References:

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Maloney JM, et al. Peanut allergen exposure through saliva: assessment and interventions to reduce exposure. J Allergy Clin Immunol 2006; 118: 719-724.

Liccardi G, et al. Drug allergy transmitted by passionate kissing. Lancet 2002; 359: 1700.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.