Anaphylaxis and mast cell activation syndrome (#ACAAI19 Twitter summary)

Dr. Ellis @DrAnneEllis: First up - Dr. Jay Lieberman - Idiopathic anaphylaxis - Prevalence and Presentations.

Lieberman: Prevalence of idiopathic anaphylaxis will vary - how far did researchers actually go to find a cause? what definition of anaphylaxis did they use? cohort based on ED presentation or outpatient allergy clinic?

Mayo/Rochester Data shows a rate of 15% of idiopathic anaphylaxis following their work up which included skin tests, serologic tests and occasionally challenges.

Rates of idiopathic anaphylaxis tend to be lower in the pediatric population - closer to 10%.

From the European anaphylaxis registry, rates of idiopathic anaphylaxis 3% in those less than 6yo, 4% in 6-12 yo 11% in 13-17 yo.

Lieberman - Recurring theme - the older you are, the more likely anaphylaxis will wind up being idiopathic, the younger you are, the more likely a clear trigger will be identified.

The NIH Idiopathic Anaphylaxis clinic (Carter and Metcalfe) - 9% were found to have Alpha-Gal allergy in one cohort of 70 patients.

Predictors of clonal mast cell disorder - Male, presence of syncope/presyncope and one other I missed :).

Kevin Parks MD ‏@kparksmd: Rate of idiopathic anaphylaxis increases with age. Lieberman data from TN suggests that 60% of adult anaphylactic presentations were idiopathic.

Urticaria/angioedema present in 100% of patients with idiopathic anaphylaxis in the Metcalfe data set (more than 300 patients).

Alpha-gal allergy now described all over the US and in international travelers who had tick bites in the US.

Dr. Ellis @DrAnneEllis: Next up we have Dr. Paul Greenberger "The Genetics, Biomarkers and Phenotypes of Idiopathic Anaphylaxis"

Serum tryptase may be elevated still at 5 h post onset of anaphylaxis; Peak is 0.5-1.5h.

Normal tryptase ranges - mode is 3-4, there are normal subjects however with a tryptase 15-19.
Systemic mastocytosis, chronic eosinophilic leukemia and FIP1l1-PDGFRA + neoplasms all have elevated tryptase levels.

Tryptase is a tetramer (mature Beta-Tryptase), stabilized by heparin; pro-tryptases have alpha and beta subunits, when you order a serum tryptase you are measuring the total (both pro-tryptases and mature tryptase).

Hereditary Alpha Tryptasemia (HaT) -there are inherited extra copies of TPSAB1 - more copies one inherits, the higher the blood tryptase, patients present with urticaria, flushing, hives, GI symptoms and rarely anaphylaxis.

TPSB2 gene can only make beta tryptase, TPSAB1 gene can produce both beta and alpha tryptase - Test for genotyping this can be ordered from Gene by Gene in Houston.

Hereditary alpha tryptasemia syndrome could be present in a subset of patients with mast cell activation syndrome BUT they do not have a clonal mast cell disorder.

Greenberger - things that occasionally explain IA: Is the allergic reaction more than 3h from ingestion of beef, pork or lamb? Consider alpha gal. Look for non-reported medication. Look for Bee Pollen consumption (usually pollen + mold).

Keep in mind non-organic disease as well (somatic symptom idiopathic anaphylaxis).

Greenberger's therapeutic/diagnostic trial of prednisone is 40-60mg QAM for 7 days then taper and stop after 3 months. Risk of doing this is leading patients to become steroid-dependent IA.

IA management -First line - Epinephrine auto injector, 2nd generation antihistamine, consider prednisone, 2nd line agents published with success - montelukast, oral cromolyn, ketotifen, Imuran, and Omalizumab.

Kevin Parks MD ‏@kparksmd: Greenberger: Tryptase peaks at one hour after onset of anaphylaxis but remains elevated up to 5 hours after onset. Don't hesitate to measure even if called by the ED after treatment.

Normal Tryptase usually under 10, but occasional patients have "normal" tryptase in the teens, possible alpha-tryptasemia without anaphylaxis. Measure tryptase between episodes!

Greenberger: undifferentiated somatoform-idiopathic anaphylaxis. develop a doctor-patient relationship to help them. avoid prednisone, epi. "This is not mast cell activation syndrome". THANK YOU DR GREENBERGER.

Dr. Ellis @DrAnneEllis: Last but definitely not least - Dr. Phil Lieberman "Overlap between mast cell disorders and anaphylaxis".

The history of mast cell disorders began with the description in the cardiac literature of a case - "Hyperadrenergic Postural Tachycardia Syndrome (POTS) - A Mast Cell Activation Disorder".

The first publication of an aberrant mast-cell population with clonal markers was from Akin and Metcalf but it was published in Blood. Not a paper we allergists read often!

Kevin Parks MD ‏@kparksmd: Lieberman: the hardest paper he has ever worked through peer review is on the topic of overlap of mast cell disorders and anaphylaxis. He's has been around a LONG time. This reflects the difficult current state of understanding of mast cell activation disorders.

Dr. Ellis @DrAnneEllis: The most cited description of mast cell activation syndrome - Castells' paper in 2011 JACI- lead author was a gastroenterologist given how many patients presented with recurrent abdominal manifestations and were discovered that way.

Mast cell activation syndrome(MCAS) series- 94% of patients had abdominal pain, 89% dermographic, 89% had flushing, 72% had all 3 symptoms. Px's additionally had headache, diarrhea, and memory/concentration difficulties. These "soft symptoms" make the diagnosis harder.

Mechanistic classification of disorders of mast cell activation: Primary (clonal) = systemic mastocytosis, MMAS. Secondary (non-clonal) - allergic disorders, chronic inflammatory/neoplastic, physical urticaria, chronic autoimmune urticaria. Idiopathic.

MCAS Proposed Criteria: 1. recurrent episodic symptoms consistent with mast cell activation in at least 2 organ systems. 2. Positive response to treatment with medication targeting mast cell mediators. 3. Biochemical evidence of mast cell activation (e.g.tryptase).

Tryptase during 'acute episode' must be 1.2 x the baseline tryptase plus 20% - to meet the MCAS criteria.

Differences between systemic mastocytosis and monoclonal mast cell activation syndrome (MMAS). MMAS is a disorder of mast cell activation rather than proliferation - KIT D816V mutation confined to a subpopulation, MC may be biphenotypic for CD25 expression.

80% of children with cutaneous mastocytosis and more than 90% of adults with systemic mastocytosis carry c-kit mutation - most common kit mutation is D816V in exon 17.

Patients with MMAS do not meet criteria for mastocytosis but may have 1 or both clonal markers (c-Kit D816V or CD25).

There are other mutations - novel disease-related alterations in kit gene transcripts (insertion of glutamine at position 252) described.

In MCAS - flushing more common, hives les common, angioedema perhaps less characteristic; nasal symptoms more common. Hypotension and Flushing top the list by far (95%).

Lieberman discussing a paper that I will actually be reviewing at the CAP session on Monday - JACI Jan 2018 Incidence of mast cell disorders in patients with idiopathic anaphylaxis.

Kevin Parks MD @kparksmd: Lieberman: MCAS criteria involves BIOCHEMICAL EVIDENCE - tryptase (preferred), urine N-MH, or PGD2. We need to lead on this. When we perpetuate a diagnosis of MCAS based on a syndrome without objective evidence, we are not helping patients.

I'm tweeting my question hoping for special treatment in a packed session: For Dr. Lieberman (dad) - how do we lead in our treatment approach to mast cell disorders to prevent MCAS from becoming the next IBS/fibromyalgia/POTS/EDS. Are we too late?

Lieberman (Jr) re: MCAS patients with no biochemical evidence: We have to be willing to recognize that some patients do not have an organic cause of their symptoms and be comfortable saying "I might not be the right specialist to help you".

Gailen Marshall with salient comment on supratentorial contributions to MCAS patients - we need to recognize the psychological component and be willing to improve our skill in communicating with patients.

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