Idiopathic Anaphylaxis Grand Rounds.

Idiopathic anaphylaxis (IA) refers to recurrent, life-threatening hypersensitivity reactions without identifiable triggers, representing a diagnostic and therapeutic challenge. We describe a 17-year-old girl presenting with recurrent episodes of flushing, pruritus, and respiratory symptoms, without consistent allergen exposure or cofactor involvement. Evaluation revealed elevated acute tryptase levels with a normal baseline, negative skin testing, and negative alpha-gal and KIT mutation analysis. The patient improved on daily cetirizine with no further reactions. IA remains a diagnosis of exclusion, requiring careful consideration of IgE-mediated allergies, cofactor-dependent anaphylaxis, clonal mast cell disorders, and systemic mimics such as neuroendocrine tumors or vasovagal syncope. We summarize current evidence on IA pathogenesis, epidemiology, differential diagnosis, and management. While antihistamines and corticosteroids are commonly used prophylactically, emerging data suggest anti-IgE therapy with omalizumab may offer benefit in refractory cases. Diagnostic workup should include serum tryptase measurement, trigger identification, and consideration of underlying mast cell disorders. Future research is needed to clarify the natural history, standardize diagnostic pathways, and evaluate long-term treatment strategies for this heterogeneous condition. CASE DESCRIPTION: A 17-year-old girl presented to the emergency department (ED) with a two-hour history of flushing, pruritus, and wheezing. The symptoms began after eating dinner, which included shepherd's pie and macadamia nuts, foods she had previously tolerated. There were no preceding exposures to medications, alcohol, or insect stings, and she did not engage in exercise prior to symptom onset. She reported three additional similar episodes. These were not consistently associated with eating, and there were no common foods or additives identified between episodes. There was no history of tick bite. There was no correlation between reactions and stage of her menstrual cycle. She did not have a personal or family history of atopy (atopic dermatitis, allergic rhinitis, asthma, IgE-mediated food allergy) or anaphylaxis. There was no history of spontaneous or inducible urticaria. She did not have a history of spontaneous flushing, pruritus, abdominal pain, diarrhea, presyncopal or syncopal episodes. She did not have a history of bony pain or fractures. At the time of the medical assessment in the ED, the patient's examination was notable for facial erythema and diffuse hives. Respiratory symptoms had resolved by the time of assessment. There were no cutaneous lesions suggestive of cutaneous mastocytosis. (Figure 1) The examination was otherwise unremarkable. She was given 2^nd generation antihistamines, and symptoms gradually resolved over several hours. The serum tryptase drawn two hours following symptom initiation was 17.2 mcg/L. A repeat level five days later was 3.2 mcg/L. During a follow up visit three months after ED presentation, skin prick testing (SPT) was negative to a variety of food and inhalant allergens including macadamia nut, wheat and beef. Serum IgE testing to galactose-alpha-1,3-galactose (alpha-gal) was negative, and qPCR analysis for the KIT D816V mutation in peripheral blood was negative. The patient was prescribed prophylactic cetirizine (20 mg daily) for three months, during which she experienced no further reactions. Given the clinical presentation, absence of identifiable triggers and the tryptase levels obtained at the ED and five days later, the patient was diagnosed with idiopathic anaphylaxis (IA).