Alpha-Gal Syndrome: Part II

By Zehra Naseem, MD, Aun Muhammad, MD, Arjun Chatterjee, MD and 
Alberto Rubio-Tapia, MD

Editor’s note: This is part two of a two-part series from the Cleveland Clinic Journal of Medicine (2025;92[5]:311-319) on diagnosing and managing and alpha-gal syndrome. Part I, which can be found here, covers the condition, associated symptoms and linked sources of the syndrome.

Alpha-gal syndrome is difficult to diagnose: the presenting symptoms can be vague, and reactions in sensitized individuals are delayed—typically happening late in the evening or in the middle of the night—or may not always occur, unlike other food allergies. Therefore, alpha-gal syndrome, especially gastrointestinal alpha-gal syndrome, may be underdiagnosed.

Alpha-gal syndrome is primarily identified through clinical evaluation and supported by laboratory testing. A history of tick bites, including larval tick bites (such as seed ticks) or “chigger” bites, and frequent engagement in outdoor activities can support a diagnosis of alpha-gal syndrome; however, tick bites are often painless, and around half of patients who develop a tick-borne illness don’t remember being bitten.¹

Serum IgE testing

An alpha-gal IgE level of 0.1 kU/L or greater confirms the diagnosis of alpha-gal syndrome, as it has a reported specificity of 92.3% and a sensitivity of 100%.¹ Laboratory testing for IgE antibodies against alpha-gal should be considered when clinical evaluation and patient history confirm two or more of the following:

• Timing: nighttime symptoms, starting with itching
• Ticks: history of tick bites, history of avid outdoor activities in tick-prevalent areas, prolonged irritation at the site of the tick bite
• Diet: consumes mammalian meats and high-fat dairy.

Diagnosis can be particularly difficult in patients who have reactions to mammalian products but test negative for alpha-gal IgE, which occurs in approximately 2% of patients referred for evaluation of alpha-gal syndrome.¹ Because patients with alpha-gal syndrome are also found to have elevated IgE antibodies against beef, pork and lamb, serum IgE testing for these alternative markers can help establish the diagnosis.²

Skin testing

Skin prick tests with mammalian meat extracts are unreliable because of false negatives and should not be used to establish an alpha-gal syndrome diagnosis.¹ The presence of IgE antibodies to beef can indicate a primary beef allergy, and IgE antibodies to pork (porcine and cat albumin) may signify pork-cat syndrome. Occasionally, skin testing for reaction to alpha-gal–containing drugs like cetuximab and basophil activation testing can be performed in those who test negative for alpha-gal IgE antibodies.

Oral food challenge

Although food allergies are generally diagnosed through food challenges, the delayed reaction characteristic of alpha-gal syndrome renders such challenges cumbersome and infeasible for routine clinical practice. However, if the initial serologic testing does not lead to a clear diagnosis, an oral food challenge may help.¹

Given the unpredictable nature of alpha-gal food challenges, discussing the risks and benefits with patients is essential. According to Commins,¹ 15% to 20% of patients with alpha-gal syndrome undergoing food challenges required epinephrine, emergency medical transport or both. As a result, alpha-gal food challenges should only be conducted by clinicians skilled in identifying and managing anaphylaxis, and should always be done in a controlled clinical environment where lifesaving treatments, such as epinephrine, are readily available.

These challenges should be performed when clinically appropriate in certain specific cases:³

• Unclear cause of an allergic episode and patient tests positive for alpha-gal IgE (≥ 0.1 kU/L) but continues to consume mammalian meat without any symptoms
• History of tick bites or significant exposure and patient tests positive for alpha-gal IgE and has been advised to avoid mammalian meat based solely on test results, despite not having symptoms
• Alpha-gal IgE level less than 2.0 kU/L in a patient who can tolerate high-fat ice cream made from cow’s milk and a small amount of pepperoni (about 12 g) without any reactions and has no history of tick bites for one year
• History of alpha-gal syndrome in patient who tests negative for alpha-gal IgE (< 0.1 kU/L) and has been followed over time
• Symptoms suggest alpha-gal syndrome but patient tests negative for alpha-gal IgE and additional diagnostic tests have been inconclusive

An oral mammalian meat challenge may be performed with two pork sausage patties (70 g) or three patties in patients weighing greater than 70 kg.¹ Pork is used for oral challenges due to its fatty composition, which increases the likelihood of allergic reactions.¹⁴ After an oral challenge, these patients must be monitored for up to six hours due to the risk of delayed reactions.

Management of alpha-gal syndrome

Currently, there is no cure for alpha-gal syndrome. The primary management strategy is eliminating foods and products that contain alpha-gal for a minimum of 30 days.⁵ Promising data show that extended avoidance of alpha-gal can lead to symptom resolution in many patients. According to a 2021 study of 16 patients with alpha-gal IgE antibodies, three-quarters reported significant improvement or resolution of symptoms after following a strict alpha-gal–free diet over a median follow-up of 13 months.⁶

Avoiding dairy products is not part of our standard recommendation because 80% to 90% of patients with alpha-gal syndrome do not have reactions to cow’s milk or cheese.¹ That said, published research and expert advice suggest that patients still symptomatic despite avoiding mammalian meat might benefit from eliminating dairy.⁷ Poultry, fish, and seafood, however, are safe for consumption because they do not contain alpha-gal.

Foods and products to avoid

Mammalian-derived products should be avoided. Gelatin, which is made from collagen in pig or cow bones, is present in foods such as marshmallows, gummy bears, and gelatin-based desserts, which should be avoided if previous allergic reaction episodes have occurred after exposure. Similarly, lanolin, collagen, and glycerin in personal care products are derived from mammals and should be avoided in instances of previous reactions. Because reactions have been reported with exposure to the monoclonal antibody cetuximab, it is reasonable to avoid it or to consult an allergist before starting this medication. Carrageenan, an additive made from seaweed and used to thicken and stabilize yogurt, nut milks and processed meat products, also contains alpha-gal and may provoke an allergic reaction.¹

Medical therapies

Medical therapy can be considered for patients with continued symptoms or with a high exposure risk.^1,5,8-10 Options include using long-lasting oral antihistamines such as fexofenadine or levocetirizine, which are effective for 22 to 28 hours after intake.⁹ An oral cromolyn solution may also be prescribed to stabilize mast cells, particularly to address gastrointestinal symptoms.¹¹ Moreover, for refractory cases, the anti-IgE monoclonal antibody omalizumab may be helpful.¹² In cases of severe allergic symptoms and anaphylaxis, patients must have access to self-injectable epinephrine for emergencies.

Alternative therapies to treat alpha-gal syndrome, such as acupuncture, currently have no scientific evidence to support their use.

Referral to an allergist

Managing alpha-gal syndrome extends beyond simple dietary restrictions and involves a multidisciplinary approach with gastroenterologists, dietitians, and allergists to ensure comprehensive patient care. An allergist referral should be placed when patients have symptoms such as facial or throat swelling, voice changes, breathing difficulties, hives or fainting after eating. These symptoms suggest a high risk of anaphylaxis and the need for epinephrine autoinjectors. Allergists can also assist with oral food challenges, especially when there is a potential risk of anaphylaxis.

Preventing tick bites

Primary prevention for alpha-gal syndrome involves avoiding tick bites and taking appropriate action if a tick is detected. Areas where ticks are common, such as tall grass, bushes, shrubs and leaf litter, should be avoided. Moreover, ankles and legs should be covered while hiking, ideally with clothes and boots treated with permethrin to deter ticks, and N,N-diethyl-meta-toluamide should be applied to the skin.^5,12

Tick checks should be conducted after outdoor activities in wooded areas. The lone star tick is considerably larger than the blacklegged tick, which is the vector for Lyme disease, making it much more visible. If a tick is found, it should be removed immediately with the help of tweezers, grasping the tick near its head or mouth to ensure complete removal without crushing. An antiseptic can then be applied to the area.

Advice for patients with alpha-gal syndrome

Patients with alpha-gal syndrome should be cautioned to prevent future tick bites, as repeated bites can sustain or increase alpha-gal IgE levels, which could exacerbate their allergy and symptoms.^14,15 Most patients (89%) who avoid tick bites tend to see a decline in their alpha-gal IgE levels.¹⁶ While the rate of decrease varies, and it is uncertain what level of reduction is necessary to restore tolerance, Commins¹ found that nearly 12% of patients tracked for more than five years had negative alpha-gal IgE titers (< 0.1 kU/L) and were able to reintroduce mammalian meat into their diets.

In addition, if patients with alpha-gal syndrome are still consuming red meat, they should be advised to use alcohol and nonsteroidal anti-inflammatory drugs with caution and to limit their consumption of fatty meats. It is also crucial to educate these patients about the potential risk of accidental exposure to alpha-gal through processed foods, restaurant meals, and inhalation of aerosolized alpha-gal from cooking bacon or beef products.

Research gaps and future implications

There is a lack of research on alpha-gal syndrome, and comprehensive studies are needed. Research should focus on evaluating the symptoms and immune responses in patients sensitized to alpha-gal through blinded food challenges with both alpha-gal–free and conventional mammalian meat, which would deepen our understanding of the clinical spectrum of gastrointestinal alpha-gal syndrome. Additionally, exploring the timeline to symptom resolution while following an alpha-gal–free diet and identifying factors that might further improve symptoms would be valuable. Investigating sensitized individuals who do not have symptoms, the mechanisms responsible for the spectrum of symptoms among patients with alpha-gal syndrome, and whether alpha-gal syndrome can cause chronic systemic inflammation and contribute to coronary artery disease could provide valuable insights into potential health consequences.

Moreover, further geographic studies on the regions where alpha-gal syndrome is prevalent should be conducted to identify individuals at a higher risk who might benefit from stricter preventive measures. Clear guidelines for risk stratification and desensitization protocols in patients with alpha-gal syndrome are also needed.

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