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Mast cell mediator release mechanisms

There are many ways for mast cells to be activated.  Each of them involves a sequence of events involving several molecules.  These molecules change the next molecule in line in a way that causes it to perform a specific action.  It is hard to visualize and one of the harder concepts to understand about molecular biology.

I think of it like carrying the Olympic Torch to the Olympic Games. Before the Olympic Games, the Olympic Torch is lit in Greece.  Then a series of different people from all over the world carry the torch part of the way before giving it to another person.  Many, many people are involved, and the environment changes, but the torch always stays lit.  Finally, the very last person carries the torch into the stadium to light the Olympic Flame to open the Olympics.  Even though the people and environment changed, it’s still the same flame.

In the body, pathways are just like passing this Olympic torch. Instead of people carrying the flame and keeping it lit, molecules carry a message that they tell to the next molecule, and so on until the pathway ends.  The best known mast cell activation pathway is IgE activation.  IgE binds to a receptor on the outside of the mast cell.  The receptor knows that this means it has to degranulate.  It passes this message to a molecule, which passes the message down the line, just like the torch, until the mast cell degranulates.

Mast cells are well known for having many large granules that hold mediators until there is a signal to release. Granules are like pockets and mast cells stuff them full of premade mediators like histamine and tryptase. Mast cells actually sort mediators so that the granules are organized and mediators aren’t distributed randomly. The way mediators are stored together greatly affects the action of these molecules once they are released.

Large scale degranulation (sometimes called complete or anaphylactic degranulation) is the best known mast cell mediator release mechanism. In this kind of degranulation, granules swell and then lots of granules actually clump together to make a very large pocket. Then, this super pocket goes to the edge of the mast cell, the cell membrane, and pokes a hole to the outside.  The mediators in the super pocket are then released at once.  The granules and membrane have holes in them that will eventually be repaired. Following large scale degranulation, it takes about two days for normal mast cells to regranulate.

There is another kind of degranulation called piecemeal degranulation. This involves release of some mediators in a granule.  There is still a lot we don’t know about this process, but the general idea is that a regular granule puts some of its mediators into a tiny little bubble.  The little bubble then goes to the edge of the mast cell and slowly releases these mediators.  In piecemeal degranulation, the granules do not clump together to make one large granule, and there is no hole made in the membrane.  It is believed that some molecules help to push the mediators out of the cell but we don’t know what they are.

A number of mast cell mediators are not stored in granules and are instead made upon signals from specific pathways. Because these molecules aren’t stored in granules, it takes some time for them to be produced and released after mast cell activation. Lipid mediators, like prostaglandins and leukotrienes, are packed together and then transported across the membrane to the outside by other molecules.  Cytokines and chemokines are also produced on demand and then stored in small bubbles.  These small bubbles are then actively pushed out of the cell in a process called exocytosis.

References:

Moon TC, et al. Mast cell mediators: their differential release and the secretory pathways involved. Front Immunol 2014: 5:569.

Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol 2014: 14(7), 478-494.

 

Anaphylaxis and mast cell reactions

Author’s note: I am not a medical doctor. Anaphylaxis and use of epinephrine must be discussed with the managing provider to determine the best treatment plan for any individual patient.

 

Determination of mast cell reaction vs anaphylaxis

Anaphylaxis has a very complicated relationship with mast cell disease. Mast cell symptoms and reactions are inherent parts of mast cell disease.  All mast cell patients can reasonably expect to have some mast cell symptoms as part of their baseline.

Anaphylaxis is not an inherent part of mast cell disease. Anaphylaxis is a complication of mast cell disease.  Mast cell patients are at increased risk for anaphylaxis, but not all mast cell patients experience anaphylaxis.  In some studies, as many as 50% of mast cell patients had never experienced anaphylaxis.

The fact that anaphylaxis and mast cell reactions can have the same symptoms is probably the reason why it is difficult to separate the two. So for a minute, let’s stop talking about mast cell disease and consider a similar scenario that is better described.

  • Coronary artery disease (CAD) is the leading cause of death worldwide. It affects millions of people around the world. Everyone knows someone with coronary artery disease.  Probably multiple someones.
  • Patients with CAD have narrow arteries that interfere with blood flow to the heart. When they are diagnosed with CAD, their provider will tell them about symptoms they may experience daily as a normal part of their disease.  Their provider will also tell them about symptoms that they may experience that indicate the heart is not getting enough oxygen, like radiating chest pain, shortness of breath and nausea.  In these scenarios, the patient needs to take a med like nitroglycerin to try and stop the episode.  If that doesn’t work, the patient is at risk for a heart attack.
  • Radiating chest pain, shortness of breath and nausea are symptoms of CAD. Heart attack is not a symptom of CAD.  It is a complication of CAD.  It can also present with the same symptoms of radiating chest pain, shortness of breath and nausea.

Flushing, nausea, diarrhea and hives are symptoms of mast cell disease. (I’m just using these as examples, there are many others).  Anaphylaxis is not a symptom of mast cell disease.  It is a complication of mast cell disease.  It can also present with the same symptoms of flushing, nausea, diarrhea and hives.

These are the potential scenarios when a mast cell patient starts experiencing more severe symptoms than usual.

  1. The patient experiences flushing, nausea, diarrhea and hives. They don’t take rescue meds and the symptoms resolve. This is a mast cell reaction. This is not anaphylaxis.
  2. The patient experiences flushing, nausea, diarrhea and hives. They take rescue meds (not including epi here) and the symptoms resolve. This is a mast cell reaction. This is not anaphylaxis.
  3. The patient experiences flushing, nausea, diarrhea and hives. They may or may not take rescue meds (not including epi here). Either way, the symptoms do not resolve.   The amount of mast cell degranulation triggers a large scale reaction that initiates anaphylaxis. This is anaphylaxis and requires epinephrine. There are two possibilities here: it was anaphylaxis from the beginning, or it started as a mast cell reaction and became anaphylaxis. Either way, it requires epinephrine and other rescue meds.

It seems to me that when anaphylaxis occurs in mast cell patients as a sudden onset event that the symptoms seen are usually distinct from regular mast cell reaction symptoms. (This last sentence is based upon what I have experienced and what is reported to me by patients. There is no data on this.)

 

General notes on use of epinephrine

How do you know it is anaphylaxis? That’s the hard part. Mast cell experts feel differently about this. Most say to only use epi if you have trouble breathing or low blood pressure because then you know it is life threatening and thus anaphylaxis and not a mast cell reaction.

If you are having trouble breathing or low blood pressure (for adults, under 90 systolic), that is generally cited as the appropriate point to use epi. However, it is a conversation and decision that must be made with you and a doctor that knows you and your disease.

If you have had an episode before where you had severe symptoms and recovered without epinephrine, it is phenomenally unlikely that it was anaphylaxis.

If you think you may need epinephrine and are unsure, it is generally recommended to use your epipen. The reason for this is that epinephrine is pretty safe, despite how the movies depict it. The risk of using an epipen when you don’t need it is side effects of epinephrine use: rapid heartbeat, elevated blood pressure, anxiety, and generally not feeling great for a day or so. The risk of not using an epipen when you need it is death. People die from anaphylaxis with their epipens on them unused.

 

 

Meeting diagnostic criteria for anaphylaxis

As I reviewed in the previous post, there are many sets of diagnostic criteria for anaphylaxis. The one that is the most widely used in the WAO criteria published in 2006.  This set of criteria has been validated, meaning it was effective for correctly identifying patients experiencing anaphylaxis while excluding those who weren’t.  Even still, they note that about 5% of patients with anaphylaxis will not be covered by these criteria and to use discretion with this population.

The 2006 WAO criteria (shown below) are often used by emergency departments to determine whether or not epinephrine is needed. If the patient meets the criteria, epi is warranted.  This is one of the reasons why anaphylaxis is often considered synonymous with requirement of epinephrine.

 

2006 WAO Anaphylaxis Criteria
2006 WAO Anaphylaxis Criteria

Determining whether or not you have anaphylaxis when your blood pressure is not very low and you can breathe fine is not straightforward for mast cell patients. There are several charts that are often posted in mast cell groups that show four or five stages of anaphylaxis.  These charts are designed for people who do not have baseline allergic symptoms.  Mast cell patients have baseline allergic symptoms.

If you have mast cell disease and have flushing, nausea and hives regularly, that is not grade II anaphylaxis. That is mast cell disease.  Symptoms that are part of your normal baseline or reaction profile do not contribute to the overall assessment of anaphylaxis.  So let’s assume I have flushing, nausea and hives every day.  But then one day I also have diarrhea and tachycardia, which isn’t normal for me.  That is grade III anaphylaxis per the Ring and Messmer scale (shown below).  Whether or not you use epi at that point, assuming your blood pressure is not low and you can breathe okay, depends upon whether or not your doctor endorses the use of that scale.

 

Ring and Messmer Anaphylaxis Grading Scale
Ring and Messmer Anaphylaxis Grading Scale

 

Anaphylaxis vs anaphylactic shock

I often see people use anaphylaxis and anaphylactic shock interchangeably. They’re not the same thing.

Anaphylaxis is a severe, multisystem allergic reaction.

Shock is more properly called circulatory shock. It is a state arising from poor circulation such that tissues are not receiving sufficient blood supply.  Weak pulse, tachycardia, low heart rate, and mental status changes including loss of consciousness are all symptoms of shock.

Anaphylactic shock is circulatory shock caused by low blood pressure due to the vasodilation from large scale degranulation. By definition, it is blood pressure 30% below the patient’s baseline or below standard values (90 systolic for adults).  So if you aren’t experiencing circulatory shock, you aren’t having anaphylactic shock.

 

References:

Sampson HA, et al. 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 2006: 117(2), 391-397.

Brown, SGA. Clinical features and severity grading of anaphylaxis. Journal of Allergy and Clinical Immunology 2004: 114(2), 371-376.

Sampson HA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2005; 115(3), 584-591.

Ring J, et al. History and classification of Anaphylaxis. Chem Immunol Allergy 2010: 95, 1-11.

The definition of anaphylaxis

The term anaphylaxis is derived from Greek words for “against protection.” It was coined in over 100 years ago during some ill-fated experiments to immunize dogs to sea anemone venom. Instead of developing a tolerance, the dogs had progressively worsening reactions to the venom. This was the opposite of the intended protective effect and so anaphylaxis was named.  (Lieberman P, et al. Anaphylaxis –a practice parameter update 2015. Annals of Allergy, Asthma & Immunology 2015: 115(5), 341-384.)

 

The following were agreed upon a roundtable meeting for Anaphylaxis in Emergency Medicine, July 2011.

Working definition of anaphylaxis:

  • Anaphylaxis is a serious reaction that is rapid in onset and may cause death. It is usually due to an allergic reaction but can also be non-allergic.

Consensus statements:

  • The traditional mechanistic definition of anaphylaxis is not useful at the bedside.
  • Most acute episodes of anaphylaxis are managed by ED clinicians and not by allergists.
  • Anaphylaxis is underdiagnosed (and, hence, undertreated) in most pre-hospital care situations and EDs.
  • It is important for pre-hospital and emergency medicine providers to recognize that a patient can have anaphylaxis without shock.
  • Anaphylaxis causes significant morbidity and can be fatal.
  • Epinephrine should be the first-line treatment for all pre-hospital and ED patients with anaphylaxis.
  • There are no absolute contraindications to the use of epinephrine for anaphylaxis. Serious adverse effects are very rare when epinephrine is administered at the appropriate intramuscular doses for anaphylaxis.
  • Anaphylaxis is a long-term diagnosis, and management does not end with discharge from ED.
  • Outcomes data are needed.

Anaphylaxis has been defined several times with different criteria. I have selected definitions that I feel are demonstrative of the evolution of these criteria.  This list is not exhaustive.

The 2006 NIAID/FAAN criteria are the most frequently used to define patients to include in studies.  This data has also been validated with subsequent studies. (Sampson HA, et al. 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 2006: 117(2), 391-397.)

Definitions and criteria of anaphylaxis
Year Source Definitions and statements Diagnostic criteria
1945 Cooke RA. Allergy in theory and practice. Philadelphia, PA: W. B. Saunders Company; 1945:5. Defined anaphylaxis as “A special of particular immunologic type of induced protein (or hapten) sensitivity in man or experimental animals and may properly be considered as a subdivision of allergy.”
1970s Nonspecific; in text of book “Anaphylaxis and hypersensitivity reactions” edited by M Castells Defined anaphylaxis as “a systemic, immediate hypersensitivity reaction caused by IgE-mediated immunologic release of mediators from mast cells and basophils.”

Defined anaphylactoid reaction as “a similar reaction without evidence of IgE involvement.”

 
1998 Joint Task Force on Practice Parameters Defined anaphylaxis as “immediate systemic reaction caused by rapid, IgE-mediated immune release of potent mediators from tissue mast cells and peripheral basophils.”

Defined anaphylactoid reaction as “reaction that mimic signs and symptoms of anaphylaxis, but are caused by a non-IgE mediated release of potent mediators from mast cells and basophils.”
2003 World Allergy Organization (WAO) Expanded definition of anaphylaxis to include immunologic events (with or without IgE) and non-immunologic (contrast, vibration, temperature, etc).

Recommended term “anaphylactoid reaction” be abandoned and term “nonallergic anaphylaxis” used instead.
2004 Brown, SGA. Clinical features and severity grading of anaphylaxis. Journal of Allergy and Clinical Immunology 2004: 114(2), 371-376. Recommended grading system for generalized hypersensitivity reactions. Grade 1: Mild

Skin and subcutaneous tissues only

 Generalized erythema (redness/flushing), urticaria (hives), periorbital edema (swelling around eyes), or angioedema (swelling).

Can also be subdivided as with or without angioedema.
Grade 2: Moderate

Features suggesting respiratory, cardiovascular, or gastrointestinal involvement

 Dyspnea (difficulty breathing), stridor, wheeze, nausea, vomiting, presyncope (dizziness/about to pass out), diaphoresis (sweating), chest or throat tightness, or abdominal pain.
Grade 3: Severe

Hypoxia (low blood oxygenation), hypotension (low blood pressure), or neurologic compromise

 Cyanosis (turning blue), pulse oxygenation less than 92%, systolic blood pressure below 90 mm Hg (for adults), confusion, collapse, loss of consciousness, incontinence
2005 Sampson HA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol 2005; 115(3), 584-591. Recommended three specific scenarios that would identify anaphylaxis. Cautioned that these criteria are for classic anaphylaxis and may not cover non-immunologic anaphylaxis cases, such as exercise anaphylaxis.

Anaphylaxis is likely when any 1 of the 3 criteria are fulfilled.

 1 Onset of illness within minutes to hours with involvement of:

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue) and airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow)
Onset of illness within minutes to hours with involvement of:

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue) and low blood pressure or associated symptoms (low muscle tone, fainting)
2 Onset of illness within minutes to hours with involvement of two or more of the following after exposure to known allergen for that patient:

History of severe allergic reaction

Skin/mucosal tissue (hives, generalized itch, flush, swollen tips/tongue)

 

Airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow)

Low blood pressure or associated symptoms (low muscle tone, fainting)

In suspected food allergy: gastrointestinal symptoms (crampy abdominal pain, vomiting)
3 Onset of low blood pressure within minutes to hours after exposure to known allergen for that patient:

For adults, systolic blood pressure less than 100 mm Hg or decrease from baseline by 30% or more

For children, low systolic blood pressure for age or decrease from baseline by 30% or more

 

 
2006 Sampson HA, et al. 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 2006: 117(2), 391-397. Recommended three specific scenarios that would identify anaphylaxis. Cautioned that these criteria may only identify 95% of anaphylaxis cases.

 

Anaphylaxis is highly likely when any 1 of the 3 criteria are fulfilled.

These definitions have been used frequently to identify whether or not epinephrine is indicated to treat potential anaphylaxis.

 

These criteria have been validated, please refer to:

 

Campbell RL, et al. Evaluation of National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012; 129, 748-752.

 1 Onset of illness within minutes to several hours with involvement of:

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula) and airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow, low blood oxygenation)

Onset of illness within minutes to several hours with involvement of:

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula) and low blood pressure or associated symptoms of end-organ dysfunction (low muscle tone/collapse, fainting, incontinence)
2 Onset of illness within minutes to several hours with involvement of two or more of the following after exposure to likely allergen for that patient:

 

History of severe allergic reaction

Skin/mucosal tissue (generalized hives, itching, flushing, swollen lips/tongue/uvula)

Airway compromise (difficulty breathing, wheezing, bronchospasm, stridor, reduced peak expiratory flow, low blood oxygenation)

 

Low blood pressure or associated symptoms of end-organ dysfunction (low muscle tone/collapse, fainting, incontinence)

Persistent gastrointestinal symptoms (crampy abdominal pain, vomiting)
3 Onset of low blood pressure within minutes to hours after exposure to known allergen for that patient:

 

For adults, systolic blood pressure less than 100 mm Hg or decrease from baseline by 30% or more

For children, low systolic blood pressure for age or decrease from baseline by 30% or more
2007 Kroigaard M, et al. Scandinavian clinical practice guidelines on the diagnosis, management and follow-up of anaphylaxis during anesthesia. Acta Anaesthesiol Scand 2007: 51, 655-670. Assign severity grades for anaphylaxis. Grade 1 Generalized skin symptoms: flushing, hives, possible angioedema
Grade 2 Moderate multiorgan involvement with skin symptoms, low blood pressure, tachycardia, airway reactivity (cough, difficulty breathing)
Grade 3 Severe life threatening multiorgan involvement that requires specific treatment: collapse, tachycardia or bradycardia, arrhythmias, bronchospasm. Skin symptoms may not be present.
Grade 4 Circulatory or respiratory arrest
Grade 5 Death due to a lack of response to cardiorespiratory resuscitation
2007 Ruggeberg JU, et al. Anaphylaxis: Case definition and guidelines for data collection, anaphylaxis, and presentation of immunization safety data. Vaccine 2007: 25, 5675-5684. Both defined anaphylaxis and attached diagnostic algorithm for “level of diagnostic certainty”, a measure of how confident a provider could be that anaphylaxis was the correct diagnosis.

 

Anaphylaxis was defined as “a clinical syndrome characterized by sudden onset AND rapid progression of signs and symptoms AND involving multiple (2 or more) organ systems as follows.”

 Level 1 of diagnostic certainty

 

Highest level of certainty

 One or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness)
One or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting)
Level 2 of diagnostic certainty

 

Moderate level of certainty

 One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more minor criterion involving one or more system besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)

 
One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more minor criterion involving one or more system besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness)
One or more major cardiovascular symptom (low blood pressure, shock with at least 3 of 4 manifestations: tachycardia, capillary refill time >3 seconds, reduced central pulse volume, decreased level of consciousness or loss of consciousness) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) and one or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose)

 
One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more major dermatological symptom (hives or flushing, local or generalized) angioedema, generalized itching with rash) and one or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness)
One or more major respiratory symptom (bilateral wheeze, stridor, upper airway swelling, respiratory disease with 2 or more of the following: rapid respiration, increased use of accessory respiratory muscles, recession, cyanosis, grunting) and one or more major dermatological symptom (generalized hives or flushing, local or generalized angioedema, generalized itching with rash) one or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose)
Level 3 of diagnostic certainty

 

Low level of certainty

 One or more minor respiratory symptom (persistent dry cough, hoarse voice, difficulty breathing without wheeze or stridor, sensation of throat closure, sneezing, stuffy nose) and one or more minor criterion involving two or more systems besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)

 
One or more minor cardiovascular symptom (reduced peripheral circulation with at least 2 of 3 manifestations: tachycardia, capillary refill time >3 seconds without low blood pressure, decreased level of consciousness) and one or more minor criterion involving two or more systems besides cardiovascular or respiratory (generalized itching without rash, generalized prickle sensation, localized injection site urticaria, red and itchy eyes, diarrhea, abdominal pain, nausea, vomiting, mast cell tryptase elevation above normal limit)
2010 Ring J, et al. History and classification of Anaphylaxis. Chem Immunol Allergy 2010: 95, 1-11. Assigned severity grade based upon worst symptom Grade 1 Skin (itching, flushing, urticaria, angioedema)
Grade 2 Skin (itching, flushing, urticaria, angioedema may or may not be present

GI (nausea, cramps)

Respiratory (stuffy nose, hoarseness, difficulty breathing, arrhythmia) Cardiovascular (increase of over 20 bpm, systolic blood pressure decreased by at least 20 mm Hg)
Grade 3 Skin (itching, flushing, urticaria, angioedema may or may not be present)

GI (vomiting, defecation)

Respiratory (swelling in airway, bronchospasm, turning blue)

 

Cardiovascular (shock)
Grade 4 Skin (itching, flushing, urticaria, angioedema may or may not be present)

GI (vomiting, defection)

Respiratory (respiratory arrest)

Cardiovascular (circulatory arrest)
2013 Ito K. Diagnosis of food allergies: the impact of oral food challenge testing. Asia Pac Allergy 2013: 3(1): 59-69. Identified severity of anaphylaxis based upon grade of most severe symptom. Grade 1

Per primary source, grade 1 is NOT considered anaphylaxis.

 Skin (local itching, rash, hives, angioedema)

GI (oral itchiness, discomfort, lip swelling)

Respiratory (throat itchiness, discomfort)
Grade 2 Skin (systemic itching, rash, hives, angioedema)

 

GI (nausea, vomiting, diarrhea, transient colic)

Respiratory (mild nasal congestion, sneezing, single coughing)

Neurologic (loss of activity)
Grade 3 Skin (systemic itching, rash, hives, angioedema)

 

GI (repeated vomiting, diarrhea, persistent colic)

Respiratory (severe nasal congestion, repeated sneezing, continuous coughing, throat itching)

Cardiovascular (heart rate increased by 15 bpm or more)

 

Neurologic (anxiety)
Grade 4 Skin (systemic itching, rash, hives, angioedema)

 

GI (repeated vomiting, diarrhea, persistent colic)

Respiratory (choking sensation, hoarse voice, barking cough, difficulty in swallowing, wheezing, trouble breathing, turning blue)

 

Cardiovascular (arrhythmia, decreased blood pressure)

Neurologic (irritability, sense of impending doom)
Grade 5 Skin (systemic itching, rash, hives, angioedema)

GI (repeated vomiting, diarrhea, persistent colic)

 

Respiratory (respiratory arrest)

 

Cardiovascular (severe bradycardia, severe hypotension, cardiac arrest)

Neurologic (loss of consciousness)

The normal

In the spring of 2009, I realized I wasn’t hearing as well in my left ear. Shortly after that, I started having balance issues. Literally would just be walking and would tip over. I went back to see the same ENT and got a hearing test that confirmed that I had some hearing loss in my left ear. I was referred to a specialty hospital and diagnosed with Meniere’s Disease. They prescribed a blood pressure medication to decrease the pressure in my inner ear.

In September, I got another hearing test. My hearing loss was worse and now noticeable in both ears. I was rediagnosed with autoimmune inner ear disease which is a real thing but they very poorly understood. I tried several meds, including high dose steroids. By November, I was getting steroids injected into my eardrums and could no longer understand speech.

The panic was immediate and fierce. I obsessed over my hearing and what I could and couldn’t hear. The world became strange and threatening. I had never understood how much we use sound for. We use it to tell how far away things are. If they are moving. How fast they are moving. If someone is upset. How hot water is coming out of the tap. The size and structure of space.

The speed with which I stopped understanding speech was staggering. I had no idea how to function in the world with significant hearing loss. I didn’t know about video phones and deaf alarm clocks and doorbells that turn on a lamp when someone rings it. I didn’t know about hearing aids and cochlear implants and a million other things. And I didn’t know how to sign.

As soon as I realized my hearing was never coming back, I focused all my available energy on learning ASL. I learned a lot online and by watching ASL interpretations of music on Youtube. (Warning: A lot of resources labeled as ASL are not ASL. They are other sign languages or poor fabrications. ASL is not a signed code of English, it is actually not even based on English.) I learned about resources for late-deafened adults and groups to practice ASL. I made Deaf friends and learned about Deaf culture.

I got lucky and the injections preserved some hearing in my right ear. My left ear hears nothing. My hearing fluctuates in my right ear, mostly as a function of blood pressure. With normal blood pressure my hearing is not great, but it is much worse with higher blood pressure. This means that my hearing can change rapidly which is both disorienting for me and confusing for people around me. Fluctuating hearing loss is like a fast track to people think you’re making it up.

I had several hearing tests over the years and stopped getting them because I was accused of inventing my hearing loss due to its inconsistency. Less than a month before I was diagnosed with mast cell disease, a neurotologist told me I needed to see a psychiatrist because I was faking. I called her bluff and saw the psychiatrist.

Halfway through the appointment, he said, “I don’t know what you have but you have something. If you’re faking, you’re not doing it right. You’re working and adapting to the world around you.” He wrote a letter and no one ever questioned my hearing loss again. I haven’t had any more hearing tests and I never will. I will never try to get a hearing aid again.

A couple of weeks after that appointment, I was diagnosed with mast cell disease. Mast cells are involved in sensorineural hearing loss, mast cell disease is associated with auditory processing disorders and EDS is associated with conductive hearing loss. My hearing depends on reaction, blood pressure, medication, a million things. The reason it seemed so irregular was because it was. Like everything else that mast cell disease causes. It is less variable now that I am managing my mast cell disease.

It has been six years since I lost most of my hearing. It doesn’t affect my day to day life terribly anymore. There are sounds I haven’t heard in years and will likely never hear again. Music sounds different. Speech sounds different. I can lipread okay if I know what the context is and I can see the face of the person speaking. In the last few years, my hearing has stabilized enough that I can hear on the phone if there is no background noise. I don’t sign every day anymore so I’m not as fluid as I used to be, but my ASL is good enough to be understood and to understand. All my devices have long since been closed captioned. I sit in the corner in public places, my deaf ear to the wall. I sit at the end of the table during meetings so I can look at people when they talk. The white noise that surrounds me when background noise is high is no longer disorienting. It is just part of me.

Losing my hearing was the original wound. It was the first thing I lost that I never got back. Long before I was having pieces of me removed, I went to bed one night and woke up with hearing loss.

Last month, a nurse said to me, “I would have never known you have trouble hearing!” She exclaimed it, eyebrows high, like it was a compliment. It doesn’t feel like a compliment.

There are things about my life that I think I will never get over. I am having some really serious lower GI issues right now that were supposed to be alleviated by the last few surgeries. Just thinking about it is upsetting and scary. Like I can never accept these things as my normal. And if I can’t accept them, this fog of despair will just get closer and closer until it smothers me.

Six years ago, I was struggling to sign and understand speech. I thought I would never be able to accept having severe hearing loss as my normal.

But I did. I sing in ASL while I’m in the shower. This is my normal. I don’t know how yet but I’ll get over everything else. And then that will be my normal, too.

The effects of cortisol on mast cells: Cortisol and HPA axis (Part 1 of 3)

Things I’m not great at: Knowing how many posts I need to cover all the effects cortisol has on mast cells.  So this is the first of three posts on cortisol and mast cells.  Then we will get back to the tables breaking down the effects of hormones on mast cells.
Cortisol is a glucocorticoid steroid hormone with far reaching anti-inflammatory actions. It is the product of a very complex endocrine system called the HPA axis.  HPA stands for hypothalamus-pituitary-adrenal.  The hypothalamus is in the brain and the pituitary is a small structure on the edge of the hypothalamus.  The adrenal glands are above the kidneys.

The hypothalamus, pituitary and adrenal glands all release a number of hormones that affect many bodily functions. Briefly, the hypothalamus receives signals from the nervous system to make corticotropin releasing hormone (CRH).  CRH induces the pituitary to make adrenocorticotropin hormone (ACTH). ACTH induces the adrenal glands to make cortisol.

Cortisol is most well known as the stress hormone, although it has many other functions. It can be released as a response to inflammation or physical or emotional trauma.  In such instances, signals from the nervous system tell the hypothalamus that it needs to make CRH.  CRH triggers vasodilation and increased vascular permeability to allow immune cells move from the bloodstream to inflamed spaces in tissue.  CRH also triggers manufacture of ACTH, which then triggers manufacture of cortisol.

When cortisol levels are high in the adrenal gland, epinephrine can be made from norepinephrine. Cortisol is thought to regulate the enzyme that makes epinephrine at several steps in the process.  Epinephrine is also part of the stress response and participates in the fight-or-flight response.

The role for which glucocorticoids are most often prescribed is suppression of inflammation. Cortisol production is initiated very early in an inflammatory response. Cortisol counteracts vasodilation seen by many inflammatory mediators.  Cortisol also decreases vascular permeability so immune cells are not able to easily leave the bloodstream and move into tissues.  Cortisol also affects gene expression so that inflammatory products are not made as much and anti-inflammatory products are made more.  (This will be discussed in great detail when I cover how cortisol affects mast cells.)

A number of synthetic glucocorticoids, like prednisone and dexamethasone, have similar behaviors and functions. The medication hydrocortisone functions the most like cortisol in the body.  Synthetic glucocorticoids stay in the blood longer and are more bioavailable than cortisol.  The amount of cortisol produced by the body changes throughout the day in time with other functions.  Synthetic glucocorticoids cannot mimic these changes exactly and are thus inferior to cortisol.  Small changes in amount of glucocorticoid can have major effects.

References:

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Molecular and Cellular Endocrinology 2013: 380, 119-126.

Varghese R, et al. Association among stress, hypocortisolism, systemic inflammation and disease severity in chronic urticaria. Ann Allergy Asthma Immunol 2016: 116, 344-348.

Zappia CD, et al. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Scientific Reports 2015: 5.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 2011: 335(1), 2-13.

Interplay between mast cells and hormones: Part 2 of 8

Hormone Location released Major functions Interaction with mast cells Reference
Beta endorphin Pituitary Inhibits pain signaling In two studies, beta endorphin was shown to induce histamine release from mast cells; however, this phenomenon has not been seen by other researchers.

Sensation of pain activates mast cells and can also trigger endorphin release, so interplay between endorphins and mast cells is possible.

 Kimura T, et al. Intradermal application of nociception increases vascular permeability in rats: the possible involvement of histamine release from mast cells. European Journal of Pharmacology 2000: 407, 327-332.
Brain natriuretic peptide (BNP) Heart Reduce systemic vascular resistance and water, sodium and fat in blood, decreasing blood pressure

Decrease cardiac output

Vasodilator

Relax smooth muscle of airway

 BNP directly activates mast cells in a dose dependent fashion. Yoshida H, et al. Histamine release induced by human natriuretic peptide from rat peritoneal mast cells. Regulatory Peptides 1996: 61, 45-49.
Calcidiol/ Vitamin D3 (inactive) Skin Inactive form of vitamin D3 Vitamin D decreases IgE dependent mast cell activation and cytokine production in a dose dependent fashion.

 

 

 Yip KH, et al. Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation. Journal of Allergy and Clinical Immunology 2014: 133 (5), 1356-1364.
Calcitonin Thyroid Stimulates bone construction

Promotes retention of calcium in bone

 One report in 1994 noted that serum calcitonin was increased in a patient with SM. Yocum MW, et al. Increased plasma calcitonin levels in systemic mast cell disease. Mayo Clin Proc 1994: 69 (10), 987-990.
Calcitriol/ Vitamin D3 Kidney Promote absorption of calcium and phosphate in GI tract

Inhibit release of parathyroid hormone in kidneys

 Vitamin D decreases IgE dependent mast cell activation and cytokine production in a dose dependent fashion.

 

 

 Yip KH, et al. Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation. Journal of Allergy and Clinical Immunology 2014: 133 (5), 1356-1364.
Cholecystokinin Small intestine Release of digestive enzymes from pancreas and bile from gallbladder

Suppresses hunger

Stimulates vagus nerve

Decreases gastric emptying and GI motility

Unclear role in medication tolerance and withdrawal

 The form of CCK most predominant in intestine (CCK-33) stabilizes mast cells.

May have a role in preventing mast cell degranulation as a response to food.

 Vergara P, et al. Neuroendocrine control of intestinal mucosal mast cells under physiological conditions. Neurogastroenterology 2002: 14(1), 35-42.
Corticotropin releasing hormone (CRH) Hypothalamus Stimulate ACTH release from pituitary CRH binds to mast cell receptors CRHR-1 and CRHR-2 causing release of VEGF but not histamine, tryptase or IL-8.

CRH is also released by mast cells.

 Theoharides TC, et al. Mast cells and inflammation. Biochim Biophys Acta 2012: 1822(1), 21-33.
Cortisol and other glucocorticoids Adrenal gland (cortex) Breaks down fat in adipose tissue

Drives production of glucose, epinephrine and norepinephrine

Inhibits immune action and inflammation, protein production, and glucose transfer to muscle and adipose tissue

Cortisol has a wide range of other effects

 Glucocorticoids inhibit mediator production in several ways.

Decreases prostaglandin production by decreasing levels of COX-2, an enzyme that makes prostaglandins.

Decreases production of leukotrienes, prostaglandins and thromboxanes by increasing anti-inflammatory molecules.

Triggers release of annexin-1, an anti-inflammatory molecule that is also involved in the mast cell stabilizing mechanism of cromolyn.

Lowers bradykinin levels, decreasing swelling.

Directly interferes with production and secretion of cytokines.

 The role of Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil. International Immunopharmacology 2016: 32, 87-95.

Oppong E, et al. Molecular mechanisms of glucocorticoid action in mast cells. Mol Cell Endocrinol 2013: 380, 119-126.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Author’s note: I tried to hit the high notes here but cortisol has a massive range of effects on immune function, including mast cells, so the next post in this series will be dedicated just to cortisol and the effects on mast cells.

 

 

 

 

Fear of the dark

I was diagnosed with mast cell disease in 2012. By the time this diagnosis came, I was emotionally numb. I had been sick for years with terrifying and increasingly severe symptoms, had lost most of my hearing and repeatedly tested negative for dozens of things, rare and otherwise.

Less than a month before, a neurotologist who I will never forgive told me that I needed to see a psychiatrist because I was faking my hearing loss. I had stopped taking all my meds two weeks earlier because I was just done. I called my immunologist and told him that I no longer believed that this disease was killing me faster than the variety of risky meds I was on without a firm diagnosis.

I honestly just wanted it to be over. I didn’t want to kill myself and I didn’t want to die. But I wanted it to be over. I was sleeping through entire days, waking dripping with sweat and this acrid smell emanating from my pores, shaking and trying not to fall over when I finally got out of bed. I was in a truly unbelievable amount of pain and sleep was my only respite. I wanted to close my eyes and just…leave.

After I was diagnosed, I learned a lot about anaphylaxis and started learning about mast cells. I fixated upon anaphylaxis that occurred while sleeping with an unhealthy intensity. Despite not having serious breathing issues, I became convinced that I would stop breathing and die in my sleep. The oblivion that had been a comfort only a few months ago was now a sinister presence, watching from the dark corners of my bedroom when I turned out the lights. I would lay awake wondering if I would be aware of my death if I died, if I would stop breathing and be forever alone in some infinite darkness, until panic seized me.

A lot has happened in the years since. I have developed new, rational fears, like forgetting one of my medications while traveling (which I have since done), being labeled hysterical/unreliable by doctors, or being served food that I have explicitly stated as unsafe. Mast cell disease is unpredictable and the fact that I can’t always anticipate what will or will not make me react is a wellspring for many of my fears. The fact that something was safe the last hundred times doesn’t mean it will be this time.

Fear is important to self preservation. It is evidence of a primordial necessity of being scared. I was very scared of the dark when I was growing up, long before I knew that the dark could offer sanctuary to any number of terrible things. It is something inherited, a vestige of its utility thousands of years ago. Being fearless with a disease like mine is cavalier and dangerous. Every person, every place, every thing offers the possibility of triggering a reaction.

Fear is also a big reason why so many of us are diagnosed with anxiety or panic disorders before ultimately garnering a mast cell diagnosis. Mast cell mediators can cause a wide array of severe neuropsychiatric symptoms and our body’s response to allergic inflammation, including release of epinephrine, can bolster anxiety or panic. A psychiatrist once asked me what I was so afraid of like the things I was scared of were benign. After I told him, he responded, “Well, I guess I would be scared of those things, too.”

Fear does not ruin my life or control it. I have a complex relationship with fear. I compensate for the unpredictability of this disease by trying to anticipate all possible outcomes of a situation and building redundancies and failsafes into my personal management of this disease. I do a lot of yoga and meditate (less than I should) and walk a lot. I do visualization when I am very anxious, but to be honest, I’m still very high strung. I’m very high strung and I am about half as anxious as I used to be.

We are all of us trying to control a disease that we can’t fully control. That is upsetting and sobering and also liberating. I am getting better about doing things and going places where I can’t control things as much and trying not to compulsively explain to people who don’t know me what to do if I start shocking. I am trying to do things that scare me, like taking on additional responsibilities, taking formal classes and having recurring obligations beyond those that are essential to my life and health. Sometimes things go well and sometimes they don’t. I’m trying to be okay with that. I’m not always okay with that.

I don’t really remember what it was like before, when fear wasn’t a dark horizon in the backdrop of my life. And I’m tempted to say that I’m not scared as much anymore, but I don’t think that’s true. I’m not scared as much at this exact moment while I am writing this post. But tonight, I’ll shut off the lights, and I will still be scared of the dark.

Cloud of uncertainty

Winter is over. That can be hard to call for sure in Boston and I’m a bit superstitious about saying things like that aloud. But I’m ready to commit to the end of winter. Spring is here.

Springtime in Boston is so pleasant and joyful that I think about it in ridiculous hyperbole. The damp dark tones of thawing earth, the stubbornly cheerful flowers, the warm wind rushing around your face in its hurry. The way the moon shines silver on breaking waves and light creeps along the horizon earlier with each passing day. Walking to work in my low yellow heels and a light sweater instead of boots and the bulk of cold weather. The cool clarity of night air through open windows.

It’s a good thing I love all these things because season changes are rough. It is one of the few aspects of mast cell disease that seems universal. We don’t react well to change and so many things change with seasons. Pollen, foods, behaviors, activities, hobbies, temperature, humidity, obligations. I wake up drenched in sour sweat, my eyes burning when I open them in the morning, already nauseous. My neck and chest are cherry red with an occasional hive for variety. I’m having some word finding issues and some obnoxious but fleeting neurologic symptoms. So yea. It’s lucky I really like spring.

It has been a rough few weeks all the way around, work, masto, MastAttack, feelings. I have never been a person who counts days or months; I mark time by seasons. Last spring, I was recovering at home from lower GI surgery after eight days in the hospital. Two springs ago, I was recovering from a several days long anaphylactic episode that landed me in the hospital for five days. Three springs ago, I was starting a new job with a brand new ostomy.

These past several months have been difficult and sad in a way I can’t really articulate. There is a weariness and a sadness and a joy and an optimism that I wield like a weapon, even when I don’t think it will help. It is a physical stability with emotional trauma and pain and regret and living with my choices. It is not terrible. It is just hard. Some days it is so, so hard.

More and more I realize that the reason I have not really found a new normal as my disease progressed is because there is no normal with this disease. There is no consistency so there can be no lasting adaptation. I no longer have expectations for what I will feel like in any moment that isn’t the one I’m currently occupying.

You don’t adapt to unpredictability. You just try not to be consumed by it.

But I’m still glad it’s spring.

Thank you for helping my friend, Kristina Brightbill

I am deeply grateful for all the support this community has shown for Kristina, Lucas and the rest of the Brightbill/Daly family.

I am happy to report that Kristina is a semifinalist to win the wheelchair van! In three days, Kristina got almost 4000 votes. Rare disease community for the win!

I would also to thank the many people who offered financial or logistical support, software for speech rendered by eye movement, food for Lucas, prayers, good vibes and support. I am humbled to be part of this mast cell world, even when we all drive each other crazy.

I will keep you all posted on how this contest turns out.

Hope! We has it!

Kristina is a semifinalist!
Kristina is a semifinalist!

Patient questions: Why isn’t tryptase used to track SM progression in patients with SM-AHNMD?

Tryptase can be a useful tool for measuring progression of systemic mastocytosis. However, it is not used in patients with systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD). Patients with SM-AHNMD have systemic mastocytosis and also have another blood disorder that causes excessive proliferation of cells that aren’t mast cells. It is essentially having individual diseases that affect the bone marrow.

The reason tryptase is not tracked in patients with SM-AHNMD is because other proliferative diseases of bone marrow can increase production of mast cells. (Actually, proliferative diseases in most organs can cause increased production of mast cells). This is called mast cell hyperplasia, overproduction of mast cells. It is NOT the same as SM. A patient with no mast cell disease of any kind who has a blood disorder like chronic myelogenous leukemia or essential thrombocythemia could experience an increase in mast cells. It is not uncommon for people with conditions like this to experience allergic symptoms due to mast cell activation.

This can occur for a few reasons. The blood disorder might increase the amount of cells that could become mast cells. The blood disorder could cause increased release and production of molecules that encourage mast cell development. Mast cells are also part of the immune response and heavily involved in tumor biology. Proliferation of another cell type can be interpreted by the body as tumor formation so more mast cells can be made to address the “tumor”, whether or not it actually is a tumor..

A patient with SM-AHNMD may have a baseline tryptase before developing the second blood disorder of 30 ng/mL. (Just making up a number here). After diagnosis with the second blood disorder, a tryptase test could reveal an increase to 35 ng/mL. However, if this were the case, we wouldn’t know if the additional tryptase is coming from mast cells made by SM ramping up or as a side effect of the other blood disorder. Because we can’t tell, it isn’t used as an indicator of increased mast cell production as a direct cause of SM.

For patients with SM-AHNMD, other markers are used to track disease progression of SM. That includes checking for things like inappropriate blood cell counts and organ swelling and dysfunction (B and C findings).