Alpha-gal syndrome and what dermatologists need to know

Alpha-gal syndrome (AGS) is an emerging tick-associated allergic disease that is increasingly recognized across the United States. Although traditionally viewed as an allergy managed by allergists, dermatologists are often among the first clinicians to evaluate its most common presenting symptom: recurrent urticaria.(1) Because reactions typically occur several hours after food exposure, patients frequently carry a diagnosis of chronic spontaneous urticaria for years before AGS is uncovered.(1,2) In one case series, up to 64% of patients reported seeking urgent or emergent care for their symptoms.(3)

The CDC estimates that as many as 450,000 Americans may be affected, with more than 110,000 suspected cases identified between 2010 and 2022.(4,5) At the same time, the lone star tick, the vector responsible for most U.S. cases, is expanding beyond its historic southeastern range into the Midwest, mid-Atlantic, and Northeast.(5) However, in a 2022 national survey of 1,500 clinicians, 42% had never heard of AGS and another 35% did not feel confident diagnosing or managing it.(6) Awareness of AGS is increasingly important for dermatologists, who play a key role in recognizing its cutaneous manifestations and facilitating timely evaluation.

What is alpha-gal syndrome?

Alpha-gal syndrome is an immunoglobulin E (IgE)-mediated allergy to galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in all non-primate mammals but absent in humans and other primates. In the U.S., sensitization most commonly occurs following bites from the lone star tick (Amblyomma americanum), although other tick species have been implicated in different regions of the world.(7) Only a fraction of sensitized individuals go on to develop clinical AGS. Unlike classic food allergies, AGS reactions typically occur 2-6 hours after ingestion of mammalian meat or other alpha-gal-containing products, making the dietary trigger difficult to identify. The delay is thought to reflect the time needed to digest and absorb the alpha-gal-bearing glycolipids, which are processed more slowly than protein allergens.(1) In addition to beef, pork, lamb, and venison, some patients react to dairy products, gelatin-containing medications or vaccines, biologic agents such as cetuximab, and other mammalian-derived medical products.(1,8)

Risk factors for alpha-gal syndrome

AGS is a tick-borne disease concentrated in the South, East, and Central United States. As with other ticks, due to climate change and other factors, the tick’s range is continuing to expand northward and westward.(4,5) Individuals with frequent outdoor exposure, including hikers, hunters, forestry workers, landscapers, military personnel, and farmers, are at increased risk.(8) Recent CDC serosurveillance found that an estimated 24.0% of adults in the five U.S. states with the highest AGS prevalence had detectable alpha-gal-specific IgE antibodies, which may help identify regions with higher risk burden.(9) Most reported patients are adults and predominantly male; however, pediatric cases are likely underrecognized.(1) Prior tick exposure is reported by most patients, though the bite may occur weeks to months before symptom onset.(8)

Several factors modify risk and expression. A personal history of atopy increases the risk of developing AGS, whereas blood group B appears partially protective because its antigen closely resembles alpha-gal.(8) Alcohol, nonsteroidal anti-inflammatory drugs, exercise, and menses are thought to affect intestinal permeability and accelerate or intensify reactions.(8,10)

Cutaneous manifestations of alpha-gal syndrome

Cutaneous symptoms are the most common presentation of AGS and often prompt dermatologic evaluation. Patients classically develop delayed urticaria, with or without angioedema, several hours after consuming mammalian meat. Pruritus may also occur with or without visible skin findings.(1) A specific dermatologic sign of AGS is recall urticaria, which is a wheal that develops at the site of a prior tick bite.(11) Less well-characterized cutaneous features include chronic pruritus, isolated itching or edema of oral mucosa, and localized contact reactions to mammalian-derived products.(1)

AGS can also present with isolated gastrointestinal symptoms, flushing or generalized erythema, minimal or absent skin findings, or systemic anaphylaxis.(1) It is important to recognize that AGS reactions are heterogeneous, and patients may not react after every exposure.(1,3)

Differential diagnosis

Because of its delayed presentation, AGS can mimic a variety of dermatologic and allergic conditions.

• Chronic spontaneous urticaria produces near-daily hives unlinked to specific meals, whereas AGS hives follow mammalian meat by several hours and resolve on a restricted diet.(2)

• Mast cell activation syndrome can present with recurrent flushing, urticaria, and anaphylaxis, but lacks the consistent temporal tie to mammalian meat.(12)

• Other IgE-mediated food allergies react within minutes of exposure rather than hours later.(1)

• Idiopathic anaphylaxis is a diagnosis of exclusion.(13)

• Angioedema without urticaria, including ACE inhibitor-induced and hereditary angioedema, should be considered when swelling occurs alone.(1)

• Physical and cholinergic urticarias are triggered by heat, exercise, or pressure rather than food.

Dermatologists should consider AGS in patients with recurrent urticaria or angioedema, particularly when episodes occur overnight or several hours after evening meals, when there is a history of tick bites or outdoor exposure, or when symptoms improve with avoidance of mammalian meat.(1)

Diagnosis and treatment of alpha-gal syndrome

Diagnosis relies on a compatible clinical history together with detection of serum alpha-gal-specific IgE antibodies. Serum alpha-gal IgE is the gold-standard test, though there is no single threshold that is both sensitive and specific.(1,14) Because positive serology may occur in asymptomatic individuals, results should always be interpreted alongside clinical findings.(14) Referral to an allergist is appropriate when the diagnosis is uncertain or additional testing is needed, such as skin prick testing, intradermal testing, oral food challenge, or basophil activation testing.(1)

Prevention of alpha-gal syndrome

AGS is not an infectious disease and does not spread from person to person. Prevention focuses on avoiding tick bites through use of EPA-registered insect repellents, permethrin-treated clothing, protective clothing, prompt tick removal, and environmental tick-control measures.(4,8)

Control measures should be focused on limiting iatrogenic exposures, such as larger heparin boluses, gelatin-based products, or even monoclonal antibodies cetuximab, infliximab, and abatacept that carry mammal-derived excipients.(1,8) In procedures, mammalian-derived surgical materials, including catgut suture and gelatin hemostatic products such as Surgifoam, can trigger reactions and should be substituted in a patient with known AGS.(15) Porcine pancreatic enzymes and porcine prosthetic heart valves have likewise been implicated.(1) Several live vaccines contain gelatin, including MMR, varicella, zoster, rabies, and yellow fever, though the overall risk of reaction is low and gelatin-free alternatives or allergist-supervised skin testing can be used when concern is high.(8)

Management

There is currently no cure for AGS. Management centers on avoidance of mammalian meat and other alpha-gal-containing products that trigger symptoms, such as organ meat and pork-gut sausage casings.(1) Acute allergic reactions should be treated according to standard anaphylaxis guidelines, including intramuscular epinephrine when indicated. Patients at risk for severe reactions should be prescribed an epinephrine auto-injector and educated on tick-bite prevention.(1) Second-generation antihistamines (fexofenadine, cetirizine, or loratadine) are first-line for urticaria and pruritus; anti-emetics, antidiarrheals, or oral cromolyn solution help with prominent GI symptoms; and omalizumab has shown anecdotal benefit in refractory cases, though it is not FDA-approved for AGS.(1)

In some individuals, alpha-gal IgE levels and clinical reactivity decline over time if additional tick bites are avoided, and mammalian meat can be slowly reintroduced for some patients.(16) One published algorithm supports cautious, allergist-supervised reintroduction after 12 months of IgE monitoring and no interval reactions.(17) In 2020, the FDA approved alpha-gal-free “GalSafe®” pigs for food and medical use, which may eventually offer safer options for patients with AGS.(18)