Cause of Unexplained Anaphylaxis

Anaphylaxis is a severe life-threatening systemic hypersensitivity reaction caused by release
of mediators from mast cells and basophils, characterized by cutaneous, respiratory,
cardiovascular, or gastrointestinal signs and symptoms. The most common specific causes of
anaphylaxis are venom, drug, and food allergies (i.e. patients with specific anaphylaxis,
SA), When a causative factor is not identified in patients are said to have idiopathic
anaphylaxis (IA). Evidence of an underlying clonal mast cell disease has been found in about
I in 15 patients with IA in our studies and in about 1 in 12 patientswith venom induced
anaphylaxis in a European study. (1) The number of patients with anaphylaxis to foods or
drugs who have a clonal mast cell disease is not known and the number or patients with venom
induced anaphylaxis in the US with clonal mast cell disease has not been determined. Thus, a
more complete understanding of the prevalence of clonal mast cell disease in those
experiencing anaphylaxis and a better understanding of the associated laboratory
abnormalities and disrupted molecular signaling pathways will have a substantial impact of
the clinical management of patients who present with anaphylaxis.

This protocol thus focuses on determining the prevalence of clonal mast cell disorders in
patients with the anaphylaxis, whether unexplained (IA) or associated with exposure to an
antigen (SA), and attendant changes in the mast cell compartment. Subjects 13 - 70 years old
will be evaluated to correlate both clinical and laboratory features of anaphylaxis and to
identify genetic and molecular pathways that may predispose to these events. Subjects may
undergo bone marrow examination in addition to supporting laboratory studies when indicated.
We plan to enroll up to 200 subjects.

- INCLUSION CRITERIA:

- Subjects must be at least 13 years of age and no older than 70 years of age.

- Subjects with IA must have a diagnosis of anaphylaxis occurring in the absence of an
identifiable provoking agent or stimulus by a referral provider. Patient may carry
both the diagnosis of 1A and the diagnosis of SA.

- Subjects with SA must have a history of a severe reaction to a venom, food or, drug
confirmed when possible by relevant skin testing, challenge testing, RAST, immunoCAP,
or ELISA. within the past 36 months.

- Subject must have had a doctor s office or ER visit, or a hospitalization for
evaluation for anaphylaxis and have a history of involvement of the skin and/or
mucosal tissue (e.g., flushing, itching, hives, angioedema, tongue swelling), and at
least one of the following:

- Respiratory compromise (e.g., dyspnea, hoarseness-laryngeal edema,
wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia).

- Gastrointestinal symptoms of vomiting and/or diarrhea

- Reduced blood pressure and/or associated symptoms of end-organ dysfunction (as
evidenced hypotonia, hypoxia, collapse, syncope or incontinence).

- Letter of referral from prospective study participant's referring physician, or
similar primary provider - with copies of available medical evaluation and laboratory
studies

- Able and willing to consider a bone marrow biopsy and aspirate

EXCLUSION CRITERIA:

- Presence of conditions which in the judgment of the investigator or the referring
physician may put the subject at undue risk for travel (including frequent episodes of
IA not preventable by pre-medication, acute infection, severe thrombocytopenia
[minimum platelet count of 30,000], or significant cardiovascular disease)

- Any condition that - in the view of the principal investigator would make the subject
unsuitable for enrollment in this study

- Inability to provide informed consent

- Pregnancy