Cause of Unexplained Anaphylaxis

Studies in the Pathogenesis of Anaphylaxis

This study will explore the possible cause of unexplained, or idiopathic, anaphylaxis. Anaphylaxis is a rapid, life-threatening, severe reaction that occurs suddenly after contact with an allergy-causing substance, usually a particular food, drug or stinging insect. The allergen triggers mast cells to release several substances, including histamine. Histamine is responsible for many of the symptoms that may occur, such as flushing, hives, swelling of the palms and soles or tongue and vocal cords, nasal congestion, itching and tearing of the eyes, shortness of breath and wheezing, stomach pain, vomiting, low blood pressure, loss of consciousness, shock, and, rarely, death. Severe episodes of anaphylaxis are treated with epinephrine (adrenaline), followed by oral antihistamines and steroids. In more than half of cases of anaphylaxis, a clear cause is not identified. These cases are called idiopathic anaphylaxis. There is no cure or long-term preventive therapy for patients with recurrent episodes of idiopathic anaphylaxis.

People between 13 and 70 years of age who have idiopathic anaphylaxis, or have anaphylaxis that is caused by specific allergens such as food, venom, or drugs and medications may be eligible for this study.

Participants are evaluated at the NIH Clinical Center with the following tests and procedures:

• Medical history, physical examination and blood tests.
• Bone marrow biopsy. For this test, the skin over the hipbone and the outer surface of the hipbone itself are numbed with local anesthesia. Then, a needle is inserted into the hipbone and a small amount of bone marrow is drawn into a syringe. The needle also cuts a small core of bone marrow, which is removed for analysis.
• Other tests that may be needed for evaluation of the patient s condition.

Study Overview

• Status: Active, not recruiting
• Conditions: Idiopathic Anaphylaxis; Drug Anaphylaxis; Venom Anaphylaxis; Food Anaphylaxis

Detailed Description

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 - 75 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.

• Study Type: Observational
• Enrollment (Actual): 115

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Primary Clinical

Description

• INCLUSION CRITERIA:
• Subjects must be at least 13 years of age and no older than 75 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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Drug Anaphylaxis
Food Anaphylaxis
Idiopathic Anaphylaxis
Venom Anaphylaxis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective of this study is to determine if patients with anaphylaxis (IA or SA) have clinical & laboratory features that correlate with genetic or molecular abnormalities in their mast cell population including the presence o...	The primary objective of this study is to determine if patients with anaphylaxis (IA or SA) have clinical & laboratory features that correlate with genetic or molecular abnormalities in their mast cell population including the presence of clonal mast cell disease.	12/31/2028

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Explore abnormalities in signaling Evaluate growth and degranulation of mast cells grown in vitro. Identify patients with the D816V mutation	Explore abnormalities in signaling Evaluate growth and degranulation of mast cells grown in vitro. Identify patients with the D816V mutation	12/31/2028

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Melody C Carter, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the definition and management of anaphylaxis: summary report--second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006 Apr;47(4):373-80. doi: 10.1016/j.annemergmed.2006.01.018.
• Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006 Jul;97(1):39-43. doi: 10.1016/S1081-1206(10)61367-1.
• Patterson R, Hogan MB, Yarnold PR, Harris KE. Idiopathic anaphylaxis. An attempt to estimate the incidence in the United States. Arch Intern Med. 1995 Apr 24;155(8):869-71. doi: 10.1001/archinte.155.8.869.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2008

Study Registration Dates

• First Submitted: July 19, 2008
• First Submitted That Met QC Criteria: July 19, 2008
• First Posted (Estimated): July 22, 2008

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: November 19, 2025

More Information

Terms related to this study

• Keywords: Natural History; Anaphylaxis; Hives; Mast Cell; Bone Marrow; Tryptase; Antigen Specific
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Skin Diseases; Skin Diseases, Vascular; Skin and Connective Tissue Diseases; Urticaria; Anaphylaxis
• Other Study ID Numbers: 080184; 08-I-0184

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The initial hypothesis for this protocol has already been explored and published. The ongoing hypothesis generated with the expansion of the protocol is ongoing and once data collection is at a level for analysis, we will include in the IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No