A History of Mast Cell Activation Syndrome: Part 1

 

Criteria for mast cell activation syndrome in selected papers
Year Reference and criteria
1991 Roberts LJ, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol 96:19S-25S.
Called “idiopathic mast cell activation”

Meets all following criteria:

-Evidence of increased quantities of mast cell secretory products (histamine in plasma or urine; serum tryptase; prostaglandin D2; heparin)

-Does not meet criteria for systemic mastocytosis

2002 Jordan JH, Valent P, et al. Stem Cell Factor-induced Bone Marrow Mast Cell Hyperplasia Mimicking Systemic Mastocytosis (SM): Histopathologic and Morphologic Evaluation with Special Reference to Recently Established SM-criteria,Leukemia & Lymphoma 2002; 43(3):575-582.
-Acknowledges systemic form of mast cell disease that is distinct from systemic mastocytosis.

-Describes a case in which a patient received stem cell factor and developed symptoms and signs associated with systemic mastocytosis. Focal infiltration was seen in bone marrow but lacked other markers for SM.

-Criteria used to “discriminate between reactive MC hyperplasia and true mastocytosis with certainty.”

2005 Shibao C, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005;45(3):385-390.
Called “mast cell activation”

Meets all following criteria:

-History of facial or upper trunk flushing

-Urine methylhistamine >230 mg/g creatinine associated with flushing episode

2007 Sonneck K, Valent P, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome. Int Arch Allergy Immunol 2007;142(2):158-64.
Meets all following criteria:

-Severe hypotension following bee or wasp stings in patients with no cutaneous lesions

-Meets ≥2 minor criteria for systemic mastocytosis

2007 Akin C, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood 2007;110:2331-3.
Diagnosed in presence of one of the following minor criteria for systemic mastocytosis:

-D816V mutation

-Expression of CD25 by mast cells

Note: The paper describes the criteria as having “one or more minor criteria for systemic mastocytosis” but does not investigate presence of the other two minor criteria for systemic mastocytosis, 25% or more spindled mast cells in biopsy; or baseline serum tryptase of greater than 20 ng/ml.

2008 Butterfield JH, Weiler CR. Prevention of mast cell activation disorder associated clinical sequelae of excessive prostaglandin D2 production. Int Arch Allergy Immunol 2008;147:338-343.
Meets all following criteria:

-Elevation of serum tryptase, urinary 11b-PGF2a, or urinary n-methylhistamine

2009 Bonadonna P, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased tryptase levels. J Allergy Clin 2009;123:680-686.
Diagnosis of monoclonal mast cell activation syndrome if meets all following criteria:

-Unexplained recurrent anaphylaxis

-Absence of skin lesions

-Meets one (excluding raised tryptase) or two of the minor criteria for systemic mastocytosis.

2010 Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010: 126;1420-1427.
Meets all following criteria:

-Episodic symptoms with mast cell mediator release affecting ≥2 organ systems evidenced as follows: skin (urticaria, angioedema, flushing); gastrointestinal (nausea, vomiting, diarrhea, abdominal cramping); cardiovascular (hypotensive syncope or near syncope, tachycardia); respiratory (wheezing); naso-ocular (conjunctival injection, pruritis, nasal stuffiness)

-A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1- and H2- histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizer (cromolyn sodium)

-Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2.

-Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities

2011 Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Clin Immunol 2011;128(1):147-152.
Meets all following criteria:

-Episodic symptoms with mast cell mediator release affecting ≥2 organ systems evidenced as follows: skin (urticaria, angioedema, flushing); gastrointestinal (nausea, vomiting, diarrhea, abdominal cramping); cardiovascular (hypotensive syncope or near syncope, tachycardia); respiratory (wheezing); naso-ocular (conjunctival injection, pruritis, nasal stuffiness)

-A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1- and H2- histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizer (cromolyn sodium)

-Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2.

2011 Molderings GJ, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol 2011;4:10.
Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

Major criteria:

– Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

Minor criteria:

– Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies

– Mast cells in bone marrow express CD2 and/or CD25

– Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved

– Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  1. Tryptase in blood
  2. N-methylhistamine in urine
  3. Heparin in blood
  4. Chromogranin A in blood
  5. Other mast cell specific mediators (leukotrienes, PGD2)
2012 Alvarez-Twose I, et al. Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms. Int Arch Allergy Immunol 2012;157:275-280.
Mast cell activation syndrome predicted if REMA score <2:

+1 if male

-2 if female

+1 Absence of urticaria, pruritis, and angioedema

-2 Urticaria, pruritis, and/or angioedema

+3 Presyncope and/or syncope

-1 Baseline serum tryptase <15 ng/mL

+2 Baseline serum tryptase >25 ng/mL

2012 Valent P, Akin C, Brockow K, Butterfield JH, Carter MC, Castells MC, Escribano L, Schwartz LB, Horny HP, Metcalfe DD, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012;157:215-225.
Meets all following criteria:

-Typical clinical symptoms

-Increase in serum total tryptase by at least 20% above baseline plus 2 ng/mL during or within four hours after a symptomatic period

-Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn

Primary MCAS:

-Mast cells express CD25 and/or have the CKIT D816V mutation

-Patient has systemic mastocytosis or monoclonal mast cell activation syndrome

Secondary MCAS:

-Patient also has allergies or another condition that activates mast cells

Idiopathic MCAS:

-No explanation found for MCAS symptoms

Note: This paper states that it is possible to have both primary and secondary MCAS at once. “In some patients, the evaluation will show that both a primary MCAS and additional secondary MCAS (e.g. mastocytosis plus IgE-dependent allergy) are present.”

2013 Afrin LB. Presentation, diagnosis, and management of mast cell activation syndrome. In: David B. Murray (ed), Mast Cells. Nova Science Publishers, Inc. 155-229.
  Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

Major criteria:

– Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

Minor criteria:

– Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies

– Mast cells in bone marrow express CD2 and/or CD25

– Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved

– Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  1. Tryptase in blood
  2. N-methylhistamine in urine
  3. Heparin in blood
  4. Chromogranin A in blood
  5. Other mast cell specific mediators (leukotrienes, PGD2)
2013 Picard M, Castells M, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther 2013;35:548-562.
Meets all following criteria:

-Typical signs and symptoms of mast cell mediator release (affecting at least two organ systems): skin: flushing, pruritis, urticaria, angioedema; cardiovascular: hypotension; respiratory: wheezing, throat swelling; GI: diarrhea; naso-ocular: pruritis.

-Objective evidence of mediator release: elevated serum tryptase: 20% + 2 ng/mL above baseline; elevated 24-hour urinary histamine metabolites (methylhistamine); elevated 24-hour urinary prostaglandins (prostaglandin D2; 11b platelet derived growth factor 2a)

-Response to therapy that blocks mast cell mediator activity: H1 receptor with or without H2 blockers, ketotifen, cromolyn sodium, aspiring, and leukotriene receptor antagonists.

2013 Cardet JC, Castells MC, Hamilton MJ. Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep 2013;13(1):10-18.
Meets all following criteria:

-Presence of symptoms from at least two different organ systems: skin (flushing, urticaria, pruritus, dermatographism); gastrointestinal (abdominal pain and diarrhea); pulmonary (wheezing and shortness of breath); upper respiratory (nasal congestion or pruritus, throat swelling); cardiac (tachycardia, syncope or near-syncope); neurologic (concentration difficulties, headache).

-Patient response to medications that block mast cell mediators

-Increase in serum total tryptase by at least 20% above baseline plus 2 ng/mL during or within four hours of characteristic symptoms

Note: This paper also states that a 24-hour urine collection for the measurement of n-methylhistamine and prostaglandin D2, or its metabolite 11b-prostaglandin F2a should be obtained after the onset of symptoms.

2013 Valent P. Mast cell activation syndromes: definition and classification. Allergy 2013; 68:417-424.
Meets all following criteria:

-Clinical signs of severe recurrent (or chronic) systemic mast cell activation

-Biochemical evidence of mediator release, preferably 20% + 2 ng/mL elevation of tryptase

-Positive response to mast cell stabilizers and medication to counter mediator symptoms

Further characterization of MCAS:

Primary MCAS:

-Presence of CKIT D816V mutation; paper states that that “usually these mast cells express CD25”

-Meets all three criteria listed above

Secondary MCAS:

-Presence of underlying allergic or atopic disorder that demonstrates mediator release without clonal mast cells

-Meets all three criteria listed above

Idiopathic MCAS:

-MCAS criteria are fulfilled, but no underlying reactive disease, no allergen-specific IgE, and no clonal mast cells are detectable

-Meets all three criteria listed above

Note:

In this paper, mastocytosis with any type of mast cell activation is denoted SMSY where mast cell activation syndrome criteria are not satisfied

2014 Akin C. Mast cell activation disorders. J Allergy Clin Immunol Pract 2014:2;252-257.
Monoclonal mast cell activation syndrome when following criterion is met:

-Presence of “one or both” markers of clonality (CD25 and/or presence of CKIT D816V mutation)

-Fails to meet other criteria for systemic mastocytosis

Primary mast cell activation syndrome when following criteria are met:

-Meets criteria for idiopathic mast cell activation syndrome

-Mast cell activation in any form of mastocytosis

-Mast cell activation recorded as SMSY (Sy is for symptoms)

For secondary mast cell activation syndrome, meets following criteria:

-Meets criteria for idiopathic mast cell activation syndrome

-Symptoms caused by another condition triggering mast cell activation

For idiopathic mast cell activation syndrome, meets following criteria:

-Presence of symptoms that involve more than one organ system: naso-ocular and respiratory: naso-ocular, wheezing, conjunctival erythema, itching and watering; skin and soft tissues: urticaria, angioedema, itching; gastrointestinal: vomiting, abdominal cramping, diarrhea; cardiovascular: flushing, tachycardia, hypotension

-Favorable response to mast cell mediator targeting agents

-Elevation of a validated marker of mast cell activation during a symptomatic period

Note: This paper does not include spindling of mast cells as a marker of clonality. Spindled mast cells are included in diagnostic criteria of systemic mastocytosis but not used here for diagnosis for MMAS. Baseline tryptase over 20 ng/mL is also not here.

2014 Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3(1):1-17.
Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

Major criteria:

– Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

Minor criteria:

– Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies

– Mast cells in bone marrow express CD2 and/or CD25

– Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved

– Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

1.     Tryptase in blood

2.     N-methylhistamine in urine

3.     Heparin in blood

4.     Chromogranin A in blood

5.     Other mast cell specific mediators (leukotrienes, PGD2)

2014 Ravi A, Butterfield J, Weiler CR> Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11b-prostaglandin F2a.
Meets all following criteria:

-Presence of typical symptoms of mast cell activation

-Increased level of serum tryptase or 11b-prostaglandin F2a

2015 Pardanini A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk-stratification, and management. Am J Hematol 2015;90:251-262.
Diagnosis of “prediagnostic ISM” or “Monoclonal mast cell activation syndrome” if meets all following criteria:

– Meets one or two minor criteria for systemic mastocytosis

2015 Theoharides TC, et al. Mast cells, mastocytosis, and related disorders. N Engl J Med 2015;373:163-172.
Meets all following criteria:

-Presence of typical symptoms of mast cell activation

-Increase of serum tryptase by 20% + 2 ng/mL within four hours after acute onset of symptoms

2017 Afrin LB, et al. Characterization of mast cell activation syndrome. Am J Med Sci 2017; 353(3):207-215.
Mast cell activation disease is used here as an umbrella term that includes both MCAS and SM. Mast cell activation disease is diagnosed if both major criteria, or one major criterion and one minor criterion, are present. Following the diagnosis with mast cell activation disease, a bone marrow biopsy is used to narrow the diagnosis down to either SM or MCAS.

Major criteria:

– Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained)

– Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom)

Minor criteria:

– Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies

– Mast cells in bone marrow express CD2 and/or CD25

– Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved

– Evidence of a pathologically increased release of mast cell mediators by determination of the content of

1.     Tryptase in blood

2.     N-methylhistamine in urine

3.     Heparin in blood

4.     Chromogranin A in blood

5.     Other mast cell specific mediators (leukotrienes, PGD2)

2017 Akin C. Mast cell activation syndromes. J Clin Immunol 2017;140:349-55.
Meets all following criteria:

-Episodic multisystem symptoms consistent with mast cell activation

-Appropriate response to medications targeting mast cell activation

-Documented increase in validated markers of mast cell activation systemically (i.e., either in serum or urine) during a symptomatic period compared with the patient’s baseline values (serum tryptase, urinary histamine metabolites, urinary prostaglandin D2 or metabolites, urinary leukotriene E4)

2019 Valent P, Akin C, Butterfield JH, Horny HP, Schwartz LB, Metcalfe DD. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J Allergy Clin Immunol Pract 2019;x:x-x.
Meets all following criteria:

-Typical clinical signs of severe, recurrent (episodic) systemic mast cell activation are present (often in form of anaphylaxis) (definition of systemic: involving at least 2 organ systems)

-Involvement of mast cells is documented by biochemical studies; preferred marker: increase in serum tryptase level from the individual’s baseline to plus 20% + 2 ng/mL (other mast cell derived markers of mast cell activation (histamine and histamine metabolites, PGD2 metabolites, and heparin) have also been proposed, but are less specific compared with tryptase)

-Response of symptoms to therapy with mast cell stabilizing agents, drugs directed against mast cell mediator production, or drugs blocking mediator release or effects of mast cell derived mediators

About the upcoming series on “A History of Mast Cell Activation Syndrome”

Hey, MastAttackers,

About two weeks ago, there were some frantic posts about a recently published paper around criteria for MCAS and how this paper would change things/affect people. At that time, I told people I was working on a response and would get it out as soon as I could. I started working on it pretty much immediately.

What didn’t occur to me at the time was that it would be really difficult to explain the context and meaning around various sets of criteria without literally going through all the literature exhaustively and showing how different groups of researchers and clinicians define MCAS and how that has changed over time. As far as I can tell, this information had never been compiled in an accessible format. So I just did it myself, from 1991-2019.

This information forms the basis of a multipart series I’m posting on MastAttack entitled “A History of Mast Cell Activation Syndrome: Living Criteria and the Lives They Define.” In this series, I will discuss in very explicit terms how these various sets of criteria were devised and why – specifically, who did clinicians and researchers envision as the population who had MCAS – and what did MCAS mean to them at the time they defined it in that way. Additionally, I will include information on how clinicians intended to treat these conditions at the time they were defined – arguably the aspect of MCAS management that most affects safety and quality of life for patients.

I wrote this introductory “this is what’s coming your way” post instead of launching right into the meat of this series to set the tone for the discussions that I am sure (and hope) will ensue around these posts in the week to come. I hope that everyone will approach this with a sense of openness and fairness. I will try to do the same and will trust the community to let me know if I don’t meet that expectation.

I also want to be clear about the fact that there will be frank discussion of various treatments for MCAS patients, including the use of IV diphenhydramine, tyrosine kinase inhibitors, and other chemotherapy agents. Be respectful of the fact that many MCAS patients have severe and dangerous symptoms that require aggressive management. I know that information about this topic has been restricted in the past, including by me, for professional reasons. I am happy to be able to discuss this topic more openly now and look forward to making this information more accessible both for patients and for providers.

It is my sincere hope that as a community we can move away from the idea of “these criteria are the right criteria” and “these criteria are the wrong criteria” despite the fact that we all – including me – have a set of “pet criteria” that we think of as being most accurate. It’s not just unhelpful, it’s damaging both to patients and to the community, which is often perceived as disorganized and divided. By having a clear understanding of what these various criteria are, and what purpose they serve in various research and clinical groups, I believe it will be much easier to have meaningful conversations around the different forms of mast cell disease and how best to serve the people who live with these conditions.

Ask any questions you would like as the information in this series is shared (the MastAttack Facebook group is the best place to reliably get responses from me). References will be at the bottom as usual for my technical posts. I trust the community to fact check me and please let me know if I have made a mistake in anything shared so that I can correct it as quickly as possible.

While I have your attention, I would like to update you on a few other things as well. I think most people know that my health took a pretty serious downward turn about a year ago. Shortly after that, my father died. For obvious reasons, I was unable to continue working on a lot of ongoing MastAttack projects and could not keep up with consult requests or email questions. I appreciate your patience and understanding as I’m getting things sorted out again. I am happy to tell you that I will be wrapping up the 107 series in the next couple of months. I will share more specific information about other projects as things develop.

Thanks for your help and support. I have really missed being involved in the community and look forward to reconnecting.

Lisa

MastAttack response to the recent letter from the National Peanut Board

This post was written to directly stand against a letter recently published by the National Peanut Board (a real name that I did not make up). That letter can be viewed below and insists peanuts do not pose the risk many believe they do to allergic persons. I go through it line by line with the text from National Peanut Board prefaced with “Letter” and my thoughts prefaced with “My response.” As usual, sources are always cited.

****

Letter: It’s time to say goodbye to peanut allergies –

My response: Completely agree. Hooray! This guy for everything!

Letter: -not peanuts.

My response: Hmmm. Well, that took a jarring turn pretty quickly. That’s like saying it’s time to say goodbye to lung cancer, not cigarettes.

Letter: Breaking up is never easy. Today, a 50-year relationship comes to an end as Southwest Airlines stops serving complimentary peanuts on its flights. We’ve enjoyed our time together, but we have to tell our friends…it’s not us.

My response: Relationship drama does not belong on social media. Ten points from Slytherin.

Letter: You see, removing or banning peanuts from airplanes – or classrooms, or theaters or any public space – is a solution that is outdated and not rooted in today’s science.

My response: As a scientist, speaking on behalf of science everywhere, this is the stupidest thing I’ve ever heard. As if avoiding a potent allergen will ever be outdated. Give me a break. *rolls eyes*

Letter: Only somebody who unplugs their Walkman to check their beeper still thinks that location bans are the best way to prevent allergic reactions to peanut exposure.

My response: First of all, don’t hate. The 90’s weren’t that bad.

My response: Secondly, location bans are one piece of a complicated system that peanut allergic people utilize to find safe spaces and keep themselves out of danger. Location bans especially make sense in venues where a person can’t just leave if they find themselves confronted by a dangerous allergen. Like, I don’t know, a metal tube hurtling through the sky at warp speed?

Letter: While Southwest can do what they want to do – and we trust they’re doing it with good intentions – our job is to make sure the decision doesn’t cloud the extraordinary work being done by researchers, health professionals and allergy advocates.

My response: The extraordinary work being done is not in any way clouded by the fact that location bans are absolutely necessary in some situations. Although given the doozy that is the next paragraph, I would venture that the “problem” is that the author of this press release fundamentally misunderstands the current research findings. Hold onto your hats! This next paragraph of this press release is going to. Blow. Your. Mind. (And not in a good way)

Letter: Today, we know that peanut bans, while intended to protect those living with peanut allergies, don’t always work and create a false sense of protection.

My response: So because they don’t prevent every instance of peanut triggered anaphylaxis, we should just not have peanut bans anymore? Come on. Even the National Peanut Board has to realize how phenomenally asinine this statement is.

My response: Let’s say you are driving in a car that has four windows. Suddenly, it begins to pour. The rear passenger side window isn’t going up for some reason. Are you not going to close the other three windows to afford yourself some protection from the rain? Because this press release says they would just never even touch a window button again because when three of the windows roll up, the driver feels a false sense of security from the rain. That is how stupid this is.

My response: Anaphylaxis at school has become increasingly common.

  • “Most significant reactions in children are attributable to peanuts, fish, shellfish, egg, soy, wheat, tree nuts [and] milk.” (Sicherer 2010)
  • “Fatalities in school aged children in the United States have primarily been attributed to peanuts, tree nuts, milk, and seafood.” (Sicherer 2010)
  • “The Centers for Disease Control and Prevention recently reported an 18% increase in food allergy among school-aged children from 1997 to 2007; 1 in 25 children are now affected. Results of studies of children with food allergy indicate that 16% to 18% have experienced a reaction in school. Allergic reactions or treatment for anaphylaxis also occur in children whose allergy was previously undiagnosed (25% of cases of anaphylaxis). Fatalities were noted to be overrepresented by children with peanut, tree nut, or milk allergy.” (Sicherer 2010)
  • “In case series of fatalities from food allergy among preschool – and school-aged children in the United States., 9 of 32 fatalities occurred in school and were associated primarily with significant delays in administering epinephrine.” (Sicherer 2010)

Letter: A person will not have a life-threatening reaction by simply being in the same room as peanuts or peanut butter. You have to ingest the allergen.

My response: This is patently, verifiably false, and you should be ashamed of yourselves for saying it. You should be ashamed of OPENLY LYING about whether or not having peanuts nearby can kill someone. You should be ashamed that misinformation like this further endangers the lives of allergy patients around the world. You should be ashamed that an allergy patient might believe the words in this press release and injure themselves or worse. Where’s your false sense of security now?

My response: The American Academy of Asthma, Allergy, and Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) sit on a joint task force together for the purpose of developing a robust set of medical guidelines to protect patients with allergies. AAAAI and ACAAI both acknowledge that anaphylaxis can occur without ingestion of the trigger.

  • “Severe allergic reactions may be seen in some patients who only inhale or come in contact with food allergens.” (Sampson 2014)
  • “Some patients may experience symptoms on inhalation of a food allergen but not experience symptoms after ingestion of the same food allergen (eg, baker’s asthma).” (Sampson 2014)
  • “Therefore, it may be necessary to avoid food exposure by routes other than ingestion.” (Sampson 2014)
  • “In some cases, severe allergic reactions may be seen in patients who only inhale or come in contact with food allergens, thereby making avoidance even more difficult.” (Sampson 2014)
  • “Patients who are extremely allergic to peanuts might have a reaction at a ball game when peanut particles from husking are blown in the wind and inhaled by that individual and in airplanes when another passenger is eating peanuts.” (Sampson 2014)
  • “Transportation by various means also presents a risk of accidental exposure. Air travel has received the most attention, but long rail trips (especially in foreign countries) and cruise ships present their own set of risks that must be anticipated.” (Sampson 2014)

My response: Other groups also reported that anaphylaxis can occur without ingestion of the trigger.

  • “In some cases, severe allergic reactions may be seen in patients who only inhale or come in contact with food allergens, thereby making avoidance even more difficult.” (Chapman 2006)
  • “Allergic reactions that result from direct skin contact with food allergens are generally less severe than reactions due to allergen ingestion. Reactions that result from inhalation of food allergens are generally less frequent and less severe than reactions caused by either direct skin contact or ingestion. Exceptions to these generalizations are more likely in occupational environments and other settings in which food allergen sensitization occurred via either inhalation or skin contact.” (Chapman 2006) Author’s note: Please note that this was not tested on mast cell patients so reaction severity may vary.
  • “Anaphylaxis from non-ingestion exposure, such as contact with intact skin or being close to an allergen, is uncommon [but does sometimes occur].” (Lieberman 2015)
  • “Case reports and controlled studies in which foods are vaporized through heating have shown that reactions, primarily respiratory, can be elicited. These observations support limiting exposure to allergens being cooked.” (Sicherer 2010)

My response: Anaphylaxis to peanut can be life threatening.

  • “Peanut and tree nuts account for most fatal and near-fatal food allergic reactions in the United States.” (Chapman 2006)
  • “Peanut allergy affects approximately 0.6% of the general population and is the most common cause of fatal food induced anaphylaxis.” (Chapman 2006)
  • “In case series of fatalities from food allergy among preschool – and school-aged children in the United States, 9 of 32 fatalities occurred in school and were associated primarily with significant delays in administering epinephrine.” (Sicherer 2010)
  • “IgE-mediated food allergy is associated with an increased risk of death after accidental ingestion.” (Sicherer 2010)
  • “Although subsequent reactions are not necessarily more severe than initial reactions, they may be. For example, initial mild reactions to peanut may be followed by more severe reactions on subsequent exposures.” (Sicherer 2010)
  • “Clinical factors such as a history of asthma, previous reactions to trace exposures, and allergies to foods mentioned previously are potential risk factors for fatal anaphylaxis.” (Sicherer 2010)
  • “Food allergens are a frequent cause of severe anaphylaxis, particularly in patients with concomitant asthma and allergy to peanut, tree nut, or seafood. Such reactions may be biphasic or protracted. Food allergy should be considered in the differential diagnosis of patients who have idiopathic anaphylaxis.” (Sampson 2014)
  • “A study showed that peanut can be cleaned from the hands of adults by using running water and soap or commercial wipes but not antibacterial gels alone.” (Sicherer 2010)

Letter: We also know that introducing peanut foods to an infant as early as 4-6 months can reduce peanut allergy development by up to 86 percent.

My response: YOU GUYS, I FOUND THE ONLY TRUE STATEMENT ABOUT PEANUT ALLERGIES IN THIS ENTIRE PRESS RELEASE. But don’t get too excited because this only pertains to IgE mediated allergies, traditional allergies. There are a number of food allergies that are not mediated by IgE. If you have mast cell disease or eosinophilic GI disease or FPIES, the age when you introduce a food isn’t the driving issue in whether or not you tolerate it.

 

Sources cited

Chapman JA, et al. Food allergy: a practice parameter. Annals of Asthma, Allergy, and Immunology 2006;96:S1-S68.

Lieberman P, et al. Anaphylaxis – a practice parameter update 2015. Ann Allergy Asthma Immunol 2015;115:341-384.

Sampson HA, et al. Food allergy: A practice parameter.  J Allergy Clin Immunol  2014;134:1016-1025.

Sicherer SH, et al. Clinical Report Management of Food Allergy in the School Setting. Pediatrics 2010;126:1232-1239.

 

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 84

97. What is the progression of therapies to treat mast cell disease? What are the next steps if I’m not improving?

There are some general rules of thumb when adding new medications to a regimen in a mast cell patient.
Medication changes should be done one at a time. The reason for this is simple: if you get better, or worse, it will be harder to figure out which medication is the cause. Recommendations on how far apart to space changes vary, but most recommend 3-7 days.
Medications often contain dyes and inactive ingredients like lactose and alcohol that can cause reactions. Many patients take compounded medications to avoid these triggers. Bear in mind that compounding medications can be very expensive and many insurances will not cover it. You should also know that not all medications are able to be compounded.
In some instances, the likely benefit of a problem medication is enough that it is worth it to try and force tolerance. This should never be done without the supervision of a provider. Premedicating before taking a dose of the medication can help curb mast cell symptoms. Personally, I will premedicate before taking a new medication for three days. If I take it on the fourth day, when I’m not premedicated, and I react, I know that I’m unlikely to ever tolerate that med. There are also desensitization protocols that involve use of IV antihistamines, steroids, and sometimes, epinephrine.
• It is my experience that often many medications that would not typically warrant a taper down before stopping must be stopped gradually in mast cell patients to prevent reactions. For example, the general population does not need to wean off IV antihistamines. They can just stop taking it without a taper. But if a mast cell patient needed six doses of IV Benadryl, and they stop the medication cold turkey the following day, they usually react. Mast cell patients should change things slowly.
Some medications can take a while to achieve a beneficial effect. It is usually in the patient’s best interest to continue a med for long enough that they can feel confident in their assessment that a medication is or is not helping.

The following describes medication progression for overall management of mast cell disease. Please note that there are other medications that can be added for specific symptoms that are not described here. Please also note that this list is just a general guideline I find helpful.

1. Start baseline meds.

  • Start second generation H1 antihistamine, like cetirizine. Starting dose is usually one tablet 1-2 times a day.
  • Start H2 antihistamine, like famotidine. Starting dose is usually one tablet 1-2 times a day.
  • Start mast cell stabilizer, usually cromolyn. In adults, target dose is typically 200 mg four times a day. First generation H1 antihistamines, like diphenhydramine (Benadryl) are not typically used as baseline medication because they may have significant side effects, cause rebound reactions, or lose effectiveness as a rescue medication.
  • Many patients benefit from gradual dose increase in cromolyn. For reasons that are not clear, patients sometimes react to cromolyn before achieving some benefit. It can take up to four months for cromolyn to achieve full efficacy.

2. Start leukotriene blocker. Starting dose is usually one tablet at bedtime.
3. Start COX inhibitor, like aspirin. Starting dose is usually one baby aspirin (81 mg) daily. COX inhibitors interfere with production of prostaglandins.
4. Increase dose of H1 antihistamine started in step 1.
5. Increase dose of H2 antihistamine started in step 1.
6. Add another second generation H1 antihistamine to be taken along side the H1 antihistamine started in step 1. Loratadine and cetirizine are a common pair.
7. Add additional H1 antihistamine, like doxepin or cyproheptadine.
8. Start ketotifen. Starting dose is usually 1 mg twice a day. Ketotifen is both an H1 antihistamine and mast cell stabilizer. In the US, oral ketotifen must be obtained through a compounding pharmacy or imported from abroad via an FDA guidelines.
9. Increase dose of leukotriene blocker started in step 2.
10. Add first generation H1 antihistamine, hydroxyxine.
11. Start lipoxygenase inhibitor, like zileuton. Lipoxygenase inhibitors interfere with production of leukotrienes.
12. Increase dose of COX inhibitor started in step 3.
13. Increase dose of ketotifen started in step 8.
14. Take a short burst of corticosteroids, like prednisone. Corticosteroids suppress production of inflammatory mediators by mast cells.
15. Take a daily low dose of corticosteroids after a short burst at higher dose in step 14. Corticosteroids suppress production of inflammatory mediators by mast cells.
16. Start a benzodiazepine, like lorazepam.
17. Start Xolair, an anti-IgE biologic. It is unclear why Xolair helps mast cell disease when mast cell reactions typically occur without IgE involvement in this population.
18. Start regular infusion of IV fluids. This can help a lot with third spacing, fluids becoming trapped in places they aren’t supposed to, leading to swelling and functional dehydration.
19. Add therapies to block other inflammatory mast cell mediators, like interleukins or TNF. Enbrel is sometimes used in this capacity.
20. Add regular doses of IV push medications like diphenhydramine and famotidine.
21. Add continuous infusion of diphenhydramine (Benadryl) through IV line.
22. Start a tyrosine kinase inhibitor. Patients should receive regular bloodwork to monitor for organ damage or low blood cell counts.
23. Start untargeted chemo like interferon, cladribine, or hydroxyurea. Patients should receive regular bloodwork to monitor for organ damage or low blood cell counts.
24. Receive HSCT (bone marrow transplant). This option is ONLY available to patients who have malignant forms of mastocytosis and who have failed every other treatment option.

There are also a number of other changes that may help mast cell patients.
Remove obvious triggers.
Consider removing or limiting some foods. This is tricky because there are at least four different lists of low histamine foods and they all conflict. Removing lots of foods at once makes it much likelier than you will lose tolerance to them. I went strictly low histamine in 2014 and it was literally years before I could tolerate even small amounts of most of the foods I removed.
Adapt medication schedule so that triggering activities occur when medications are most available to your body. This includes things like taking antihistamines before eating or exercising.
Supplement things that many mast cell patients are deficient in. This includes vitamin D and magnesium.
• Start quercetin.
• If possible, low impact exercise can be helpful.
Manage your pain aggressively. Pain is a huge mast cell trigger.
• If you have a lot of environmental triggers, wearing a mast like a Vogmask is a good option.
• For patients who have severe GI involvement, bowel rest sometimes helps. Patients on bowel rest stop taking any food or drink by mouth and receive IV nutrition (TPN).
Avoid overtly stressful situations at all costs. I cannot emphasize this enough. Do not engage in upsetting situations if at all possible.

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Mastsisters

I love all my masto kids. But there’s something special about this little girl. The week after her second birthday, her mother, a total stranger to me, called me to convince me to be part of Addie’s team in her very complicated, very high stakes, very frightening, very literal fight for her life. I agreed. Addie was my very first case.

When our paths converged four and a half years ago, Addie was living on the edge of disaster every single day. Incidentally, so was I. We got our first PICC lines the same month. I started chemo two weeks after her mom called me. We were both in and out of the hospital with protracted anaphylaxis and scopes and procedures. We both sustained significant organ damage that year. Things were not good. But I always believed that if we could just stay alive that one day we would get better. Maybe not healthy. Maybe not well. But better. Better was the dream.

Today, we walked around Salem on a perfect breezy June day. We breathed in the salty ocean air. We looked for Halloween figurines in the small shops at Pickering Wharf. We squeezed through secret passages in dusty four hundred year old houses. We struggled to read the lettering on the smooth white faces of centuries old tombstones. We talked about school and safe foods and hospitals and ports. We ate things that would have put us in the ground when we first met.

This is not an easy life. It is never going to be easy. But there is something about looking back years later that makes you see this journey as worthwhile. We can eat food now. We aren’t admitted constantly. We are not shocking left and right. We are not always on the brink of anaphylaxis.

We made it. We are still here. We are still living in the happy moments and getting through the hard ones.

We are mastsisters. We are survivors. We are alive.

Me and Addie, Los Angeles, May 2015

Me and Addie, Salem, June 2018

Sensory memory

Sensory memory is the shortest. It lasts less than a second, usually; the memory of things you hear, echoic memory, might last a little bit longer. The things we see, hear, touch, taste, and smell all provoke a response by our nervous system. These tiny events are filtered almost immediately. Noticing everything would overwhelm our brain, both physically and figuratively. We only acknowledge things that are useful to short term memory; everything else is discarded before we even know it was there.

How many things do we see and hear and feel that our brain decides aren’t important? What if we wanted to see and hear and feel those things? What if it robbed us of these memories? I worried about this years before I understood the neurobiology of forgetting. I think that’s partly why I write: I don’t want to regret forgetting something, even if it’s not important.

My father died last month. He was diagnosed in January with a disease that would kill him. Right away, I hunted down memories of him. Hard copy photographs and pictures on our phones. Home videos from when we were growing up. Voicemails with his voice on them. Handwritten notes. Birthday cards. I started making videos of him so I could hear his voice and remember the way he moved. I journaled exhaustively, writing about my days with him in exquisite detail. I knew how easily those little pieces could be discarded and I didn’t want to lose any of it. It was too important.

All of this has had the weird side effect that I now cannot stop triggering sense memories. They just happen now. I can’t control them. I can’t choose not to pay attention. They are all so complete and so vivid. Splinters of moments that got caught in the void between the past and the present. Here but not here. Then but not then. Visible but untouchable.

In particular, I am overcome with memories from my childhood of us camping. From the ages of 4-14, my family camped every weekend from mid April to early October and for several weeks in the summer. I remember the long car rides to New Hampshire on Friday nights. Wearing my father’s blue jacket, standing in front of him around the campfire on a cool summer night. The smell of the damp earth every April on opening weekend. The sting of hitting the water after my father threw me into the air while we swam in the river. Sunny days at the end of summer when my father, my mother, my sister and I were the only people on the tiny beach. Making sand castles with moats around them. Day trips from the campground to Canobie Lake and Salisbury Beach and York Animal Kingdom.

And then the hard stuff, the memories I wish I never had to make: how soft his hair was under my hand when I tried to soothe him, the way his skin smelled at the end, how his chest rose and fell as he breathed. How it felt to wake up in a world where my father was not alive. How it was physically painful. How every day is still harder than the day before it. How it felt like I was suffocating when he died, like I’m dying. How it still feels like that.

How living in these memories is excruciating. But how losing them would be worse.

Riot in my heart

In 1995, my cousins moved in with us. One of my cousins shared a room with me. Every night, she would put on a mixtape of quieter alternative songs from bands like Alice In Chains, Nirvana, Bush, the Cranberries, Pearl Jam, Smashing Pumpkins and Red Hot Chili Peppers. In the daytime, she would blast louder music. It was the first I ever really connected with music. I liked the messy chaos and angst and obscure lyrics of alternative music. I think I burned a hole in Nirvana’s Nevermind album from listening to it so much in my discman.

A year or two later, one of my friends played me a Ramones album and I fell in love. I still love alternative but punk is the music of my soul. I am a punk. It was the first identity I found for myself and still one proudly wear today. I listen to the Misfits every morning and the Pogues, Generation X, Rancid, Bikini Kill, Operation Ivy, NOFX, and the Clash when I shower.

Punk gives me energy and motivates me. It makes me feel braver than I really am. I don’t wear ripped fish net tights under a plaid skirt with a band shirt and Doc Martens anymore. I don’t get in fist fights and go to shows in tiny shady venues or people’s basements. But I still have punk tendencies toward rebellion and dissent. It’s still in there. I still have a riot in my heart.

When life overwhelms, punk rock is the first thing I reach for. In 2013, I got a ton of bad news and was in so much bone pain that I was literally bedridden some days. I was scared and needed to make some very hard decisions about my health and my life. I wasn’t feeling very brave. I needed to reawaken the punk in me.

My hair was bright red for my senior year of high school. I couldn’t find a picture at the time but I wanted my hair to be that red again. A friend from high school is now a stylish. I asked her if she remembered what color my hair was and could she replicate it without a picture. She did and she could. In November 2013, we cut off eight inches of long light brown hair and painted the remaining hair fire engine red. Punk rock. And just like that, I found my courage.

This year has been so, so difficult. I could not have predicted how much energy I would expend taking care of someone who is dying. A lot of things in my life had to be abandoned for the time being so that I could focus on my family and my health, including a lot of my MastAttack responsibilities. I will resume them at some point.

I’m sitting here at 4am with bright red and purple hair, wearing an Operation Ivy shirt, listening to Rancid and the Misfits, hoping that it will give me the courage I need to survive this year.

Tyrosine kinase inhibitors in the treatment of mast cell diseases

Author’s note: The following post is my personal opinion and is based upon publicly available information and not upon any confidential information I have obtained as a result of my job. The ideas described below are directly attributable to me and not to my employer. I am not a medical doctor and this is not medical advice. This information should be used only to better inform yourself prior to speaking with your provider.

Tyrosine kinase inhibitors have been described in literature for over thirty years. The first tyrosine kinase inhibitor, imatinib, was approved by the FDA in 2001. Because it was the first effective therapy known for a fatal disease, chronic myelogenous leukemia, it was fast tracked through the FDA approval process and approved in two and a half months. In the years that followed, newer tyrosine kinase inhibitors were developed by various pharma organizations. The indications for these therapies expanded from CML to include several other diseases, including certain forms of systemic mastocytosis.

Tyrosine kinase inhibitors were developed with the intention of reducing the toxicity seen in older chemotherapy medications. They do this by targeting specific structures on diseased cells. For example, patients with chronic myelogenous leukemia have a genetic abnormality called the Philadelphia chromosome. This is the result of pieces of DNA getting switched around so that genes that aren’t normally next to each other end up stuck together. This forms a gene called BCRABL that tells cells to continually make new cells even when they aren’t needed. Imatinib targets BCRABL. The idea is that only the cancer cells have BCRABL so healthy cells wouldn’t be damaged.

In reality, it’s a lot more complicated than that. The biggest reason for this is that even though healthy cells don’t have BCRABL, they have other things that look like BCRABL. This is actually why imatinib can treat some cases of systemic mastocytosis: CKIT looks like BCRABL. And there are plenty of other proteins on plenty of other cells, some healthy cells, some diseased cells, that look like BCRABL or CKIT. This means that while tyrosine kinase inhibitors are much more targeted than older forms of chemotherapy, they aren’t so targeted that healthy cells don’t incur any damage at all. Sometimes that damage is serious. Sometimes it is irreversible.

In the mast cell sphere, imatinib was originally used for cases of aggressive systemic mastocytosis that did not have the CKIT D816V mutation. Over time, it was also used for other forms of systemic mastocytosis, including mast cell leukemia, systemic mastocytosis with associated hematologic neoplasm, and smoldering systemic mastocytosis. While imatinib was approved for use in people without the CKIT D816V mutation, there were trials on SM patients who did have the mutation. Published reports found it was less effective but did give benefit to some patients with the mutation. To be clear, the published data strongly points to imatinib being more effective in people without the CKIT mutation than in those that do. But there is some evidence that imatinib might have benefit even if you have the mutation.

I sometimes see people telling other patients that it is dangerous to use imatinib if you have the CKIT mutation. The danger for these people is that it might not work well for them. There’s no special risk beyond that. In fact, the current FDA licensing for imatinib is for patients without the CKIT D816V mutation OR patients in whom CKIT status is unknown. This means that sometimes people are put on it without genetic testing so it’s possible that some of the patients have the mutation.

I want to be so, so super clear about the next thing I say because it is so important that people know this. Imatinib, and other tyrosine kinase inhibitors, are chemotherapies. They are licensed as antineoplastic therapies, also known as chemotherapies. When it’s shipped to your house, it arrives there with the label “contains chemotherapy drugs” on the package. Patients taking it are supposed to be consented for chemotherapy so that they fully understand the risks. TKIs are, for sure, kinder, gentler, more targeted chemo drugs. But they are chemo. And they carry a lot of risks associated with chemotherapy.

I have seen patients describe these drugs as “extremely safe”, “harmless”, “unable to damage other cells”, or even “unable to kill cells.” Those ideas are patently false. These medications are not benign. They are serious. They can cause organ damage, especially liver damage. They can suppress bone marrow, resulting in low blood cell counts. They can cause clotting issues. They most certainly can damage other cells and kill cells, targeted and otherwise. There are hundreds of references describing the ways TKIs can do this, mostly by inducing apoptosis, making a cell kill itself. All of this information is publicly available.

The very fact that TKIs are chemo agents and can cause many of the associated issues is the reason why use of TKIs is controversial in the mast cell community. A lot of people believe that use of TKIs is only warranted in the aggressive forms of systemic mastocytosis that can cause organ damage and death. But there is another school of thought that posits that TKIs are appropriate for indolent SM and MCAS, specifically for cases where anaphylaxis is frequent and severe. They argue that these cases present enough risk to life that the benefits outweigh the risks. Still another group feels that TKIs are safe enough to use for control of non life threatening symptoms in patients with indolent SM and MCAS.

It is my personal opinion that there is benefit to trialing TKIs in patients with indolent SM and MCAS for whom disability or risk to life is significant. I think that you have a right to try unproven therapies when your life is at stake. But I also think that because of the risks, they should only be used when more conservative therapies have failed. The sole fact that they are chemo drugs shouldn’t preclude TKIs from consideration for severe cases of MCAS and ISM. Chemo drugs are prescribed in low doses to treat dozens of conditions, especially immune mediated disorders like autoimmune diseases. But I do think they should be a last resort. I do not personally feel that TKIs are appropriate for general symptom management in non life threatening cases.

My opinion can be summed up pretty cleanly as this: these drugs are serious and they should be reserved for serious cases until such time as we have actual data on how TKIs affect these patients. We need studies, not a handful of case reports, to really understand the risks for MCAS and ISM patients using these therapies. But when other treatments fail and there is risk to life, I think it is appropriate to consider TKIs in these populations.

Management of the peripartum period in a mast cell patient

I’ve been getting a lot of questions about pregnancy and delivery in mast cell patients. I had an interesting case a couple of years ago that I thought people might find illuminating. I contacted the patient and she had no problem with me sharing her case.

The case involved a pregnant mast cell patient experiencing both cardiovascular and mast cell driven complications of the pregnancy with significant risk of preterm delivery. I worked with the patient and her care team to develop a plan to minimize the risk of mast cell activation and anaphylaxis both before and after delivery. Mom delivered by Cesarean and had no complications during or after delivery. Baby also suffered no complications associated with birth.

This is some of the material I provided to her team.

Overview:

Mast cell disease is a group of proliferative and non-proliferative conditions that is hallmarked by severe allergic reactions and anaphylaxis to triggers by non-IgE pathways. Due to the the diverse role of mast cells in many processes, including allergy, immune defense, wound healing and reproduction, mast cell degranulation and activation is an ever present threat.

Premedication:

Mast cell patients are recommended to premedicate prior to any procedure, including non-invasive procedures, to suppress mast cell activation.

24 hours before:
50mg prednisone

1-2 hours before:
50mg prednisone
50mg diphenhydramine
150mg ranitidine
10mg montelukast

An IV protocol used by some patients in place of the oral meds at 1-2 hours:
50mg diphenhydramine
40mg famotidine
40mg methylprednisolone

Following procedures/medical events/anaphylaxis, some patients do best with a taper of antihistamines and steroids to suppress rebound reactions and biphasic anaphylaxis in the following days. An example of this regimen is:

Antihistamine support:
-50mg diphenhydramine IV every 4 hours for first 24 hours
-50mg diphenhydramine IV every 6 hours for next 48 hours
-50mg diphenhydramine IV prn thereafter

Corticosteroid coverage:
Corticosteroids play an integral role in modulating mast cell activation. In the days following procedures/medical events/anaphylaxis, some patients do best with a steroid taper. Please note that the reason for the taper is NOT to prevent adrenal insufficiency, but to provide adequate steroid coverage to suppress mast cell reactions at a time when a non-mast cell patient would safely tolerate an abrupt cessation of steroids.

There is no defined protocol, but many patients use a Medrol dosepak or seven day prednisone taper following anaphylaxis and do well with this protocol following other procedures/events.

Cardiovascular concerns:

In cardiac patients with mast cell disease, Kounis Syndrome (allergic angina/MI) is a risk. In this condition, patients experience angina/MI as the result of a histamine driven process. Mast cell rescue medications (diphenhydramine, famotidine, methylprednisolone) should be given along with appropriate management of cardiovascular symptoms (nitroglycerin, calcium channel blockers). Epinephrine can be used if appropriate.

Beta blockers are a hard contraindication for mast cell patients as they interfere with the action of epinephrine. Use of beta blockers is commonly cited as a risk factor for fatal anaphylaxis. ACE inhibitors are often not recommended due to interaction with the angiotensin/renin system in which mast cells actively participate.

Pain management:

Most opiates are not recommended for mast cell patients due to induction of mast cell degranulation. Fentanyl and hydromorphone are the ones most often used successfully and are the drugs of choice for acute pain management.

Literature findings:

Ciach K, et al. Pregnancy and delivery with mastocytosis treated at the Polish Center of the European Competence Network on Mastocytosis (ECNM). PLoS One 2016; 11(1): e0146924

  • Five women delivered via cesarean. In one patient, the cesarean was performed specifically because of concerns about vaginal delivery in a mastocytosis patient. In the other four cases, cesarean was performed because of preeclampsia; improper positioning of the fetus; lack of labor progression; and large size of the fetus’ head relative to the size of the uterus. In all of these cases, spinal anesthesia was used with no complications.
  • Twelve women delivered vaginally without complications. In two patients, an epidural was used for pain management. In three patients, medication (oxytocin) was used to induce uterine contraction.
  • Four patients experienced pregnancy complications in the second trimester. The complications were pregnancy induced hypertension and swelling of the extremities; deep thrombosis (blood clot formation); toxoplasmosis, an infection; preterm labor without delivery; and vaginal bleeding in the first trimester.
  • Four patients delivered early, at 26 weeks, 36 weeks, and 37 weeks. The woman who delivered at 26 weeks had preeclampsia and her baby died less than a month after delivery due to extreme prematurity. Twelve patients delivered full term. Three babies had low birth weight upon delivery.
  • Mastocytosis patients are at higher risk of complications that involve clotting. Mast cell patients often experience coagulation irregularities, such as blood clot formation.
  • There have been three cases reported in literature of mastocytosis patients who developed preeclampsia that required preterm delivery.
    In order to suppress mast cell reactions and anaphylaxis, patients were premedicated before delivery with antihistamines and corticosteroids. Another study on pregnancy in mastocytosis reported that even with premedication, some patients still experienced mast cell activation during or after labor.
  • Epinephrine, antihistamines and glucocorticoids (steroids) should be readily available during and after labor

Matito A, et al. Clinical impact of pregnancy in mastocytosis: A study of the Spanish network on Mastocytosis (REMA) in 45 cases. Int Arch Allergy Immunol 2011; 156: 104-111.

  • 22% (10) of patients delivered via caesarean. 78% (35) delivered vaginally.
    Nine patients required labor induction. Oxytocin was used in eight cases and dinoprostone was used in one case.
  • Premedication for mast cell activation with antihistamines and glucocorticoids was only given to 38% (17) of patients.
  • 82% (37) of patients received anesthesia. 32 patients received epidurals; 3 received local anesthesia; and 2 received general anesthesia.
  • 11% of patients had mast cell activation symptoms, including flushing and itching, during or just following labor.

Dewachter P, et al. Perioperative management of patients with mastocytosis. Anesthesiology 2014, 12): 753-759.

  • Mastocytosis symptoms can improve, worsen, or remain unchanged during pregnancy.
  • Anesthesia management of mastocytosis patients has not been well described, with 13 CM patients and 33 SM patients mentioned in literature since 2000.
  • In one instance, IV epinephrine was necessary following labor to manage low blood pressure and difficulty breathing in an SM patient.
  • Early use of epidural anesthesia is recommended for mastocytosis patients to manage pain as pain triggers mast cell degranulation.
  • Patients should continue their regular medications to manage mast cell disease until the day of surgery.