Increase in serum tryptase with urticaria and tachycardia

My suspicion is your patient has either idiopathic anaphylaxis with a chronically elevated serum tryptase but without mastocytosis or hypertryptasemia with autonomic dysfunction and idiopathic urticaria. I think it would be helpful to have a serum tryptase in close proximity of an acute episode characterized by tachycardia and urticaria, as I would expect an increase if these events are anaphylaxis. However, the absence of an increase in serum tryptase does not exclude anaphylaxis.

A consideration would be to evaluate serum tryptase of primary family members as duplication of the tryptase gene, TPSAB1, is a dominant trait. I have attached a question from the Archives of Ask the Expert with Dr. Joshua Milner’s commentary. Dr. Milner has contributed to the understanding of familial hypertryptasemia, a condition associated with connective tissue disorders and dysautonomia (1).

I agree with the consideration of omalizumab with all of the above considerations (2,3).
In summary, I would suggest checking serum tryptase in the patient during acute episodes, serum tryptase of primary family members and genetic testing of the patient, which is available through commercial genetic testing, for the TPSAB1 gene to evaluate for duplication. I agree with a trial of omalizumab.

1. Lyons, Jonathan J., et al. "Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number." Nature genetics 48.12 (2016): 1564.
2. Maurer, Marcus, et al. "Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria." New England Journal of Medicine 368.10 (2013): 924-935.
3. Warrier, Priya, and Thomas B. Casale. "Omalizumab in idiopathic anaphylaxis." Annals of Allergy, Asthma & Immunology 102.3 (2009): 257-258.

9/28/2017: Elevated tryptase, urticaria and systemic inflammation
I have a 13 year-old male who presented to me with a case of chronic hives. He has a 6 week history of hives and has been treated with high dose antihistamines, H2 blockers and Singulair without benefit. The only medication that works is prednisone. During the initial workup his hives were biopsied and per the mother showed urticaria multiforme. Over the past 2 weeks, his symptoms have progressed and he has fevers up to 102, myalgias, nausea and vomiting when he comes off prednisone. He had labwork done and this was positive for only an elevated tryptase (23 - nml <11), Leukocytosis and an elevated CRP. The fevers and elevated tryptase are concerning for me. Would you have suggestions on what route to take for this child?

We sought the expert guidance of Dr. Joshua Milner. See his reply below:

"This is a very fascinating and difficult case. The key elements are a) a new-onset systemic inflammatory process, b) an urticaria-like rash and c) elevated basal serum tryptase. While a&b could be driven by an infectious/post-infectious, hematologic, or autoinflammatory/autoimmune process, c) is an interesting twist. Elevated serum tryptase is seen classically in acute anaphylaxis, mastocytosis, and some myeloid malignancies. More recently, increased copy number of the alpha allele at TPSAB1 – a gene that can encode alpha or beta tryptase – has been identified in most of the 4-6% of individuals in the population who have an elevated basal serum tryptase. This relatively common genetic trait and laboratory value appear to be associated with an increased risk for symptoms often associated with mast cell activation such as urticaria, flushing, itching and abdominal pain, as well as other GI, pain, autonomic, neuropsychiatric and connective tissue complaints.

Inflammatory processes like this patient’s were not mentioned in the initial descriptions of families with inherited tryptase elevations, but have rarely been observed by clinicians who care for these patients. Whether this association is causal or coincidental is a matter of active research. This points to the fundamental question—do patients with increased TPSAB1 copy number and previously undescribed or more severe symptoms require further work-up for their symptoms? This likely depends on the specific symptoms and what other more concerning underlying diagnoses might exist. In this case, there is value in determining whether the patient has increased TPSAB1 copy number. Checking BST in the parents could well clarify if one of them is a carrier—levels above 10 ng/mL are highly suggestive—and provide a temporary answer while waiting for a clinically available TPSAB1 genotyping, which cannot be accomplished with conventional next generation sequencing. A positive result argues that the tryptase elevation is genetically determined and not caused by an acute process. If the parent’s tryptases are normal, and the patient does not have increased TPSAB1 copy, it certainly raises suspicion that an acute process is driving the tryptase elevation and likely warrants a workup for what could be a myeloid-driven process. The lack of any response of the rash to high dose H1&H2 blockade, and positive response to prednisone argues against a simple mast cell activation issue, but given how little we know about these types of cases, one should have an open mind for multiple possibilities. It is difficult to predict a good treatment regimen, and hopefully, this is a reactive process which will resolve spontaneously at some point. However should it be prolonged, and should the workup not yield additional insight, alternatives to prednisone which could range from non-steroidal immune suppression to IL-1 blockade to JAK inhibition may have to be sought in conjunction with rheumatology and hematology colleagues as indicated."

Patricia McNally, MD, FAAAAI

I hope this information is of help to you and your practice.

All my best.
Dennis K. Ledford, MD, FAAAAI