Answer:
The serum tryptase correlates with mast cell burden and generally would not be expected to be greater than 20 ng/ml in cutaneous mastocytosis. However, this is a biological variable and cut offs provide statistical correlations but not absolute diagnosis. In a series of over 100 patients with cutaneous mastocytosis, the mean serum tryptase was 11.5 ng/ml and 14.9% had concentrations greater than 20 ng/ml (Kanamori). Furthermore, approximately 10-15% of subjects with systemic mastocytosis may have serum tryptase values below 20 ng/ml. Mast cell disorders require a clinical assessment in which the serum tryptase is only one component of the information.
In summary, I would encourage assessment for systemic mastocytosis as the serum concentration of 36 ng/ml exceeds the expected value. I would suggest you to repeat as I have seen significant variation in the values with commercial testing. However, even if the level decreases, I would assess for systemic mastocytosis with bone marrow examination for mast cell number and morphology and genetic testing for c-KIT abnormalities including D816V. I have also found the Mastocytosis Center at Brigham and Women’s Hospital in Boston to be a valuable resource in the evaluation of challenging patients.
Kanamori, Kelly Yoshimi, et al. "Clinical presentation and markers of cutaneous versus systemic mastocytosis: the mastocytosis center at brigham and women's hospital in Boston." World Allergy Organization Journal 8.Suppl 1 (2015): A141.
You may find this question from the archives of Ask the Expert of interest. Dr. Castells has comments in the response that I feel are very helpful.
Mast cell activation syndrome versus mastocytosis versus idiopathic anaphylaxis
Q: 4/30/2015
A 34 year-old Caucasian male who started having episodes of generalized hives around Thanksgiving of 2014. He then had a few episodes of anaphylaxis around December-Jan 2015. His tryptase was 10ng/ml which was checked a week after he had the last episode. I started him on a combination of H1 and H2 blockers which helped his symptoms to some extent but did have a few episodes of maculopapular rashes, angioedema, anxiety attacks, sometimes associated with confusion, however not as severe anaphylactic episodes as before. Repeat tryptase level was 5ng/ml. 24 hr Urinary levels of histamine, HIAA and metanephrines were within normal levels however the patient was on antihistamines at that time. VIP was also within normal limits. I added cromolyn sodium and that did help his symptoms further. He recently had an episode of macular rash, therefore I sent him for a punch biopsy with special stains for mastocytosis. The biopsy report was:
"The epidermis is intact. In the dermis, there is sparse perivascular infiltrate of lymphocytes with an interstitial infiltrate of variable numbers of neutrophils and eosinophils. Immunohistochemical stains were performed and compared to appropriate controls. Tryptase demonstrated a slight increase in mast cells."
Is his clinical presentation consistent with MCAS? He was unable to get a tryptase level during the attack for various logistical reasons. Should a Bone Marrow biopsy be done to rule out / in systemic mastocytosis?
A: I am not convinced that your patient has mast cell activation syndrome but would consider the possibility of idiopathic anaphylaxis. The general criteria for mast cell activation syndrome would include an increase in the baseline serum/blood tryptase to more than 11.5 ng/ml but less than 20 ng/ml or an increase of at least 30% of the basal tryptase during an episode. I do not think the histologic description of the skin biopsy would change my opinion as “slight increase in mast cells” is too nonspecific.
I would not recommend a bone marrow examination or c-KIT mutation studies. I agree with your treatment with high dose antihistamines and would consider adding a leuktotriene modifier. I would also provide epinephrine autoinjectors with instruction for use in flares associated with change in mental status or concern about hypotension. If the severity of the episodes increase, I would repeat the tryptase, try to get a tryptase during an episode and would consider alternative therapies utilized for idiopathic anaphylaxis, including oral corticosteroids. Omalizumab may improve idiopathic anaphylaxis but is off label.
I have included a couple of references you may find of value and a prior Ask the Expert question with additional references.
I have shared my opinion with Dr. Mariana Castells, Professor of Medicine Harvard University and Brigham and Women’s Hospital. Dr. Castells has responded.
“Mast cell activation syndrome MCAS is defined by compatible mast cell activation symptoms in at least 2 organ systems, the presence of elevated mast cell mediators at baseline or during acute episodes and the response to mast cell controller medications. The patient has clear symptoms of mast cell activation in 2 organs and he should have metyl histamine and prostaglandin metabolites PG11F2a in 24 hour urine and a KIT mutation for D816V in peripheral blood. Because 10-15% of patients with systemic mastocytosis have tryptase below 20 ng/ml systemic mastocytosis needs to be ruled out. If c-KIT mutation is positive a Bone Marrow Biopsy is indicated. Because of the continued presence of urticaria omalizumab may be indicated. In addition Ketotifen and sodium cromolyn are indicated for MCAS.
Here is the reference for MCAS. I hope this helps your management of this difficult patients
Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 128(1):147-52 e2. Epub 2011/05/31.”
In summary, I would treat as idiopathic anaphylaxis but with the elevated tryptase and Dr. Castell’s opinion, particularly the issue of 10-15% of patients with mastocytosis with tryptase less than 20 ng/ml, you may want to obtain urinary studies for histamine and Pg11F2a and c-KIT mutation on peripheral blood. If any of these are abnormal, then bone marrow would be suggested by Dr. Castells. My position is that if you are addressing the issue of anaphylaxis and the CBC is normal, I am not sure what you are going to do differently after the bone marrow. Follow up would be different though if your risk concerns are greater. The practice of medicine and allergy/immunology is an art based on science and there are many areas of grey art and not black and white science.
Akin C1, Valent Diagnostic Criteria and Classification of Mastocytosis in 2014. Immunol Allergy Clin North Am. 2014 May;34(2):207-218. doi: 10.1016/j.iac.2014.02.003.
Lee MJ, Akin C. Mast cell activation syndromes. Ann Allergy Asthma Immunol. 2013 Jul;111(1):5-8. doi: 10.1016/j.anai.2013.02.008. Review
Jones, Jeremy D., Samuel R. Marney, and John M. Fahrenholz. "Idiopathic anaphylaxis successfully treated with omalizumab." Annals of Allergy, Asthma & Immunology 101.5 (2008): 550-551.
Anaphylaxis without apparent cause
Q: 3/20/2015
64 yowf with solitary episode of hypotensive anaphylaxis. PMH: HTN, DM, melanoma. Meds: lisinopril, atenolol (both dc'd since), HCTZ, wellbutrin. Awoke well. Usual breakfast, same foods eaten regularly since. Lunch-beans, rice, sausage; eaten since w/o event. 1 hr later- diarrhea, abd pain. 4 hr later- pruritus, hives, lip swelling then SOB w/o wheezing, stridor, etc. Took Benadryl. In ER, hypotension, IM epi x3; needed Epi drip and glucagon. Stabilized next day then discharged following day. Abd CT showed "fluid in colon", given flagyl.
No other meds, alternative/herbal therapies, NSAIDs, latex, bee/fire ant/tick bites.
No symptoms of mastocytosis, carcinoid, pheo.
No diarrhea/travel/well water.
Exam noncontributory.
Normal CBC,diff,metabolic profile, tryptase, urine N methyl histamine, 5HIAA, Latex IgE, gal-alpha-gal IgE, food skin test panel,VIP. Total IgE 274. Urinary Metanephrines 8 (90-315), Norepinephrine 25 (122-676).
Aside from possibly a bone marrow biopsy to further evaluate mastocytosis, other diagnostic considerations/tests
A: I congratulate you on a very thorough evaluation of a very serious event. I cannot suggest any other diagnostic tests that would be appropriate at this time. I would be most concerned about idiopathic anaphylaxis (first episode so difficult to make this diagnosis) or alpha-gal/mammalian meat anaphylaxis despite the negative in vitro test. Dr. Cummins’ group utilize intradermal meat testing to assess this problem in addition to the in vitro test. Gelatin sensitivity has also been reported with mammalian meat sensitive individuals.
I would suggest the following. If another event occurs, I would repeat the tryptase. Even baseline levels less than 11.5 ng/ml may have mast cell activation syndrome and in these cases the tryptase during symptoms is 1.35 X greater than the baseline or 1.2 X baseline + 2 ng/ml (Clin Exp Allergy 2011;41:1777-83). I am not sure when the meat testing and alpha-gal testing were performed in relationship to the event, but I would consider repeat testing if testing was in close proximity (less than 4-6weeks). Although you indicate your patient has eaten the sausage dish, it is possible that the reaction is dose dependent and you may want to have him intentionally ingest a larger amount of the sausage.
Finally, you may consider testing for gelatin allergy with a commercial test available or you can perform skin testing with 1 tsp of Jell-O in 5 ml of normal saline (Kelso J et al. Adverse reactions to vaccines practice parameter 2012 update. J Allergy Clin Immunol 2012;130:25-43). I would not favor a bone marrow with the information provided.
Commins, Scott P., et al. "Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-a-1, 3-galactose." Journal of Allergy and Clinical Immunology 123.2 (2009): 426-433.
Morisset, M., et al. "Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1, 3-galactose." Allergy 67.5 (2012): 699-704.
Mullins, Raymond James, et al. "Relationship between red meat allergy and sensitization to gelatin and galactose-a-1, 3-galactose." Journal of Allergy and Clinical Immunology 129.5 (2012): 1334-1342.
I hope this information is of some help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI