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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

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).

Please help my friend, Kristina Brightbill

Last October was a nightmarishly dark time. My friend Seth had a catastrophic metabolic crisis a few days before his third birthday so severe that I honestly cannot believed that he survived. He was in the hospital in California trying to sort out effective and tolerated IV nutrition when he crashed. Seth is a mast cell kid with no safe foods. None.

As impossible as it sounds, Seth was not the only little boy at that hospital in California with no safe foods. There was another little boy there named Lucas, who also has mast cell disease. These little boys and their parents became very close friends, bonding over the absurdities and terror of having young children who can’t eat. Lucas’ mom, Kristina, was also a mast cell patient. When Seth was crashing, Kristina called me and we worried together.

At the time that Seth was having his metabolic crisis, Lucas was a year old and exclusively breastfed due to his frightening and prolific food reactions. Kristina had removed almost all foods from her diet in order to provide nutrition that could Lucas could tolerate. Eventually, she was only able to eat quinoa, organic cantaloupe and one brand of safe water. She herself was predictably experiencing physical issues from such a restricted diet. Her breast milk was Lucas’ only safe food and she sacrificed her health for his.

The week after we worried together on the phone about Seth, Kristina was preparing to take Lucas home to Florida after months admitted in California. On a Friday afternoon, she had anaphylaxis, and then she had a stroke. No one realized what was happening until it was too late. In a matter of hours, Kristina became a prisoner in her own body. The stroke was in her brainstem and she has locked-in syndrome.  She is 26 years old.

Kristina is completely aware and able to understand everything happening around her but cannot move or speak. She is able to communicate by blinking while someone points to letters and spelling words in this way. She continues to have ongoing health issues secondary to the stroke and mast cell disease. Her needs are very, very complex.

After months of inpatient care and stroke rehab, Kristina will be going home to be with her devoted husband, their son and her family and friends. Her home has required significant remodeling and she needs round the clock care to stay safe. Kristina also needs a vehicle that can transport her in her chair in order for her to be able to safely go home. As you can imagine, meeting all of these needs is a massively expensive and time consuming undertaking.

Parents of mast cell children often say that they would give anything to help their kids, that they would gladly lay down their lives to stop their children from suffering. Kristina literally gave everything she had to make her body a vessel capable of producing a food that her son could eat.

If you have ever been helped by this blog, or me, or anything I have written, please help my friend, Kristina.

Kristina’s family just found out about this contest to win a van that can transport her in her wheelchair. Please vote for her. Voting closes in two days but it is still worth a shot.  If the link doesn’t work, please cut and paste the following address into your browser:

http://www.mobilityawarenessmonth.com/entrant/kristina-brightbill-sarasota-fl/

If you are able and would like to donate there is an ongoing fundraiser for Kristina and Lucas, who will both need expensive lifelong care.  Please cut and paste the following address into your browser:

https://www.youcaring.com/kristina-brightbill-jedidiah-brightbill-lucas-brightbill-379577

Many thanks. Please keep this family in your thoughts/prayers/good intentions. There is always hope.

Patient questions: Everything you wanted to know about tryptase

I get a lot of questions about tryptase.

Tryptase is one of the most well characterized mast cell mediators and the first to be unique to mast cells. Serum tryptase is the most well known test for systemic mastocytosis and anaphylaxis. But mast cell patients sometimes test negative, complicating their lives and care.

There are a lot of reasons why mast cell patients test negative for tryptase. One reason is that a lot of the understanding of anaphylaxis hinged upon the ability of mediators to get quickly to the bloodstream to quickly spread to various organ systems. While this does happen, not all mediators move at the same speed. Tryptase is released from granules as large complexes with other mediators, like heparin. It takes time for it to dissociate enough to be active.

Tryptase also does a lot of things and breaks down lots of things. If there are things for it to break down in the immediate environment, it will still break them down whether or not you are having anaphylaxis. Eventually, the tryptase that wasn’t used up breaking things down gets to the bloodstream. This is why the ideal time to test for tryptase in blood is about 90-120 minutes after an allergic event/severe reaction/anaphylaxis. Following severe reaction/anaphylaxis, it can take about two weeks for tryptase to return to baseline.

The reason that most patients with systemic mastocytosis have high tryptase levels is because they have more mast cells and many mast cells secrete tryptase at rest. This means that even if they aren’t activated, they will still release tryptase regularly. The reason why baseline tryptase level is such an important marker for SM is because it distinguishes mastocytosis from anaphylaxis.

However, we have learned a lot about tryptase in the last several years, and it doesn’t seem like all mast cells secrete tryptase all the time. Mast cells are heavily influenced by their environment and the cells around them. Some mast cells make more tryptase than others and some release tryptase regularly and some don’t.

About 80-90% of SM patients have a baseline tryptase over 20 ng/ml. This means they tested over 20 ng/ml on two separate occasions when they had not recently had a severe event. But not all SM patients have elevated tryptase, but that doesn’t mean they don’t have more mast cells than usual. It is possible that their mast cells are concentrated in places in the body where tryptase will be used up before it gets to the bloodstream or that it will take too long to get there for the test to catch it. There is some evidence that tryptase testing is less reliable in overweight and obese women, and I’m sure that’s true. Some mast cells live in adipose tissue and that tissue is harder for large molecules to move through, like tryptase.

Our understanding of MCAS is that there is aberrant mast cell behavior without an abnormal number of mast cells. These patients generally have repeat negative biopsies and so the assumption is that they definitely don’t have SM. But tryptase is a crummy test and I think as a community we can’t really know if they have too many mast cells until we have more robust tests. I’m not saying MCAS patients have too many mast cells, but I’m saying I don’t really trust tryptase for detection of reaction/anaphylaxis in MCAS patients or, to be frank, in anyone.

So why do we still use tryptase if it’s a crummy test? It’s not a crummy test for everything. In particular, it is a very good indicator of disease progression (ISM to SSM to ASM) in patients who have a lot of mast cells. A steadily increasing tryptase level means that there is increased proliferation and can indicate moving to a state where organ damage is more likely. So it is helpful for those people. It’s not helpful for everyone else.

Tryptase testing is not affected in a meaningful way by any medications that I can think of. Mast cell stabilizers can decrease degranulation, but tryptase can also be released in other ways, and there has not been any demonstration that mast cell stabilizers are effective enough to affect this test. Antihistamines/other meds/steroids don’t affect tryptase level.

There was a consensus paper that came out several years ago in which it was posited that an increase in tryptase level of 2 ng/ml + 2% from baseline was indicative of mast cell activation and could be used in the diagnosis of MCAS. This is not widely agreed to in the US and the data supporting this has never been published so I personally understand the reluctance of providers to acknowledge this as a marker of mast cell activation.

The other big reason why mast cell patients may test normal for tryptase is that their reactions/anaphylaxis are not mediated by a pathway that triggers tryptase release like IgE does.  IgG activation and other pathways do not always demonstrate tryptase release.

I think I got everything. If you have more questions about tryptase, let me know.