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

Table 1 Tick species implicated in alpha-gal syndrome and their geographical distribution based on collection from available regional data

Tick species (common/scientific)	Typical geographic distribution/reported locations	Evidence/notes
Lone star tick - Amblyomma americanum[7]	Southeastern, mid-Atlantic, and parts of the Midwest United States; expanding northward and westward	Principal vector implicated in most United States AGS cases and in large surveillance studies
Sheep/deer tick - Ixodes Ricinus[16]	Europe (Sweden, France, Germany, Spain and other temperate countries)	Reported to carry α-gal-containing antigens and linked to sensitization in European case series
Paralysis tick - Ixodes holocyclus[14]	Eastern Australia (coastal New South Wales, Queensland)	Identified in Australian reports as associated with α-gal sensitization and tick-bite-related meat allergy
Asian longhorned tick – H. longicornis[17]	East Asia (Japan, Korea), parts of China; also detected in other regions	Salivary proteins with α-gal detected; case series from Japan and case reports implicate H. longicornis in sensitization
Amblyomma sculptum[18]	Brazil and other parts of South America	α-gal epitopes detected in saliva; experimental/serologic data support potential for sensitization
Amblyomma hebraeum/Rhipicephalus spp. (Africa)[19]	Sub-Saharan Africa (limited serologic detection; data sparse)	Serologic detection of α-gal in some parasites/ticks reported, but clinical case correlation and surveillance remain limited
Blacklegged/deer tick - Ixodes scapularis (and other Ixodes spp.)[8]	North America (northeast, upper Midwest); occasional recent case reports linking Ixodes spp. to AGS	Emerging reports suggest other Ixodes species may rarely be associated with α-gal sensitization in addition to Amblyomma spp.

AGS: Alpha-gal syndrome; H. longicornis: Haemaphysalis longicornis; α-gal: Α-1,3-galactose.

Table 2 Comparison between alpha-gal syndrome, non-celiac gluten sensitivity and Lactose Intolerance based on their diagnostic and pathophysiologic mechanisms

	AGS	NCGS	Lactose intolerance
Etiology	Mammalian products including beef, pork, lamb, venison and sometimes dairy/gelatin	Symptoms are triggered by gluten	Digestive problem caused by deficiency of the lactase enzyme
Onset	Delayed (typically 2-6 hours after eating the trigger food)	Within hours after consuming gluten	Within hours after dairy ingestion
Symptom manifestation	Hives, itching, swelling, nausea, vomiting, abdominal pain and diarrhea. Can potentially manifest as anaphylaxis	Abdominal pain, bloating, diarrhea, fatigue and headache	Nausea, bloating, abdominal cramps, gas and diarrhea
Immune mechanism	Allergic (type 1 hypersensitivity reaction)	Innate immune system	Digestive disorder involving lack of lactase enzyme
Diagnosis	Blood test for alpha-gal-specific IgE antibodies	Clinical diagnosis made by excluding celiac disease and wheat allergy but involving a positive response to gluten-free diet	Hydrogen Breath test and Lactose intolerance test

NCGS: Non-celiac gluten sensitivity; AGS: Alpha-gal syndrome.

Table 3 Multiple organ-systems affected by alpha-gal syndrome and associated symptom manifestation[35]

Organ system	Common signs & symptoms	Approximately of patients affected (%)
Cutaneous/skin	Urticaria (hives), pruritus, angioedema (lips, eyelids, tongue, throat)	56-80
GI	Abdominal pain, nausea, vomiting, diarrhea, bloating	47-69
Respiratory	Wheezing, cough, shortness of breath, nasal congestion	15-30
Cardiovascular	Hypotension, dizziness, syncope (especially in anaphylaxis)	10-25
Systemic/anaphylaxis	Multisystem involvement (≥ 2 organ systems), generalized reactions	50-75

GI: Gastrointestinal.

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.