Misdiagnosis of alpha-gal syndrome as non-celiac gluten sensitivity or lactose intolerance: A diagnostic blind spot for clinicians

Table 4 Clinical pearl summarizing alpha-gal syndrome for clinical practice, estimates may vary based on clinical presentation

Step	Action	Key decision-points/notes
Clinical suspicion[30,42]	Obtain detailed patient history (tick exposure, delay after mammalian meat ingestion, GI or allergic symptoms)	A high index of suspicion is required, especially in tickendemic regions or unexplained GI symptoms
	Note typical timeline: Ingestion of mammalian (non-primate) meat/products → delayed onset (approximately 2-6 hours) of symptoms (skin, GI, respiratory, cardiovascular)
Initial evaluation[41]	Physical exam (skin, airway, vital signs)	Because AGS can mimic other GI/food-allergy conditions, exclusion of more common diagnoses is prudent
	Consider other causes of symptoms (food intolerance, NCGS, lactose intolerance, IBS, conventional meat allergy)
Laboratory testing[40]	Order serum IgE specific to galactose-α-1,3-galactose (α-gal sIgE)	Typical cutoffs vary; e.g., > 0.1 kUA/L often used, but not strictly diagnostic of clinical allergy
	Understand that a positive test alone does not confirm AGS - must correlate with history and symptoms
Correlation of history + test + response[29]	Confirm delayed reaction after mammalian meat ingestion and positive α-gal sIgE	This triad (history + lab + diet response) is often used in practice to establish diagnosis
	Evaluate response to elimination of mammalian meat/products (clinical improvement)
Further evaluation/referral	If test is negative but suspicion remains high: Consider referral to allergist for intradermal testing, basophil activation test, or supervised food challenge (in experienced center)	Food challenge in AGS requires caution due to delayed onset and potential severity
	If significant allergic/anaphylactic signs (multisystem involvement) → allergy/immunology referral
Diagnosis and management plan[30,40]	If AGS is confirmed: Counsel on avoidance of mammalian meat/products (and possibly mammalianderived medications/biologics)	Although not strictly part of diagnostic algorithm, management planning is integral once the diagnosis is made
	Educate on tickbite prevention (to avoid further sensitization)
	Arrange appropriate follow-up and monitoring (including reconsidering re-introduction under guidance if IgE levels decline)

NCGS: Non-celiac gluten sensitivity; AGS: Alpha-gal syndrome; GI: Gastrointestinal; α-gal: Α-1,3-galactose; IBS: Irritable bowel syndrome.