Alpha Gal Syndrome

Alpha Gal Syndrome – 17 Interesting Facts

Alpha gal syndrome is a condition characterized by allergic reactions to mammalian meat and other mammal-derived products caused by IgE sensitization to alpha-gal (galactose-α-1,3-galactose), an oligosaccharide expressed in cells and tissues of nonprimate mammals; in the United States, Europe, and Australia, tick bites are understood to be the major cause of this sensitization
Clinical history in AGS (alpha gal syndrome) classically involves onset of urticaria, with or without gastrointestinal symptoms, a few to several hours after ingestion of mammalian meat/animal products
Presentation may vary widely, and anaphylaxis is possible in severe cases
The diagnosis of AGS relies on a combination of compatible clinical history, supportive allergy test results (typically a positive serum alpha-gal IgE test result), and meaningful response to an appropriate avoidance diet⁴⁵³⁸
The major goals of treatment are to provide patients information so they can avoid alpha-gal exposure and adopt strategies to increase the likelihood that AGS is not long lived
Standard management considerations for AGS are generally similar to those for other types of food allergy and include⁴³⁹⁴⁷
Avoidance of triggers
Avoidance of alpha-gal (present in food and medications) is the cornerstone of AGS management
Avoidance of further tick bites can improve the natural history of AGS
Medications to prevent/control acute symptoms
Epinephrine is considered the gold standard for treating severe reactions, including anaphylaxis in patients with AGS⁸³
Food oral immunotherapy and biologics are emerging treatment modalities for Alpha Gal Syndrome⁴⁷
For symptoms that persist despite appropriate alpha-gal avoidance measures, alternative explanations should be sought⁵⁴
Many patients can outgrow their allergy over time and regain tolerance to mammalian meat over a period of several months or years, but this is not universal
It is common practice, especially among individuals who are motivated to expand their diets, to periodically monitor alpha-gal IgE levels and consider graduated introduction when levels have become undetectable (<0.1 IU/mL) or decreased significantly
Among patients with Alpha Gal Syndrome, the likelihood of achieving remission is also thought to be higher for those who avoid recurrent tick bites⁸¹
Because many clinicians are not familiar with Alpha Gal Syndrome, many patients benefit from care and follow-up provided by an allergist who has experience managing this condition

Alarm Signs and Symptoms

Patients with severe allergic reactions, including anaphylaxis, require prompt treatment with epinephrine; many patients will benefit from keeping an epinephrine autoinjector available for emergency use

Introduction

Alpha gal syndrome is a condition characterized by allergic reactions to mammalian meat and other mammal-derived products caused by IgE sensitization to the alpha-gal (galactose-α-1,3-galactose) allergen
- Individuals with IgE antibodies specific for the alpha-gal oligosaccharide are at risk for allergic reactions to beef, pork, lamb, and other mammalian meats¹
- Cutaneous and gastrointestinal symptoms are common, but reactions vary widely and can include severe anaphylaxis
- Mammalian meat allergy and red meat allergy are other terms used to describe this condition²
- Because dairy products, gelatin, and other foods and select medications sourced from mammals can also elicit reactions, this allergic disorder is now known more generally as AGS (alpha gal syndrome)³⁴⁵
- Because tick bites are strongly implicated as the major cause of IgE sensitization to alpha-gal, other authors have referred to Alpha Gal Syndrome as a tick-acquired meat allergy

Background Information

Alpha-gal is an oligosaccharide expressed in cells and tissues of nonprimate mammals and is structurally similar to the B-group (ABO) blood antigen⁶
Humans do not express alpha-gal but universally produce IgM, IgG, and IgA antibodies directed against alpha-gal⁷
Some individuals develop IgE antibodies to alpha-gal, with tick bites being the best understood risk factor⁸⁹¹⁰
The realization that IgE antibodies to alpha-gal were causally linked to allergic reactions to mammalian meat was first reported in 2009¹¹
Accordingly, many of the studies in the field have been cross-sectional and observational, and recommendations in the field stem in large part from expert opinion⁴⁵¹²

Epidemiology – How common is Alpha Gal Syndrome?

In the United States, Alpha Gal Syndrome is most common in parts of the Southeast, Midwest, and Coastal Atlantic in areas where Amblyomma americanum (the lone star tick) is established¹³¹⁴
There have been few systematic epidemiologic studies, but a recent CDC report estimates 96,000 to 450,000 AGS cases nationwide over the past 10 years¹³
Figure 1 illustrates the geographic distribution of suspected AGS cases in the United States based on commercial laboratory alpha-gal IgE test results collected between 2017 and 2022
Surveillance studies consistently show that in the US population, the prevalence of detectable serum IgE to alpha-gal is significantly higher than the prevalence of symptomatic AGS¹⁵¹⁶
Accordingly, at a community level, many individuals with alpha-gal sensitivity, particularly those with relatively low levels of alpha-gal IgE, can tolerate mammalian meat without any symptoms¹⁷¹⁸¹⁹
AGS is most often diagnosed in adults, but children can also have the syndrome²⁰
Some studies show that rates of alpha-gal sensitization are higher among males than females, but overall, there is not a clear sex bias in AGS cases²¹²²²³
Potential effects of race on Alpha Gal Syndrome need more systematic study, but in cohorts and case series in which race has been reported, AGS (or sensitization to alpha-gal) is predominantly diagnosed in White individuals¹⁰¹⁶²³

Cases are per 1 million population per year

Etiology – What causes Alpha Gal Syndrome?

Across North America, Europe, Asia, and Australia, tick bites are thought to be the major cause of IgE sensitization to alpha-gal²⁴²⁵
- In the United States, the tick most associated with AGS is Amblyomma americanum⁸¹⁴²⁶
- Outside the United States, other species of tick are implicated, including Ixodes ricinus in Europe and Ixodes holocyclus in Australia²⁷
In less industrialized areas of the world, alpha-gal sensitization has been linked to helminths and other endoparasites, but the prevalence of symptomatic AGS in these areas has received little study²⁸²⁹³⁰

What are the Risk Factors?

Tick bites are the best understood risk factor for acquiring Alpha Gal Syndrome. Accordingly, forest workers, hunters, landscapers, gardeners, owners of outdoor pets, and hikers are at increased risk^17182731
Some studies indicate that tick bites that itch for a prolonged period (days or longer) are strongly associated with Alpha Gal Syndrome.¹⁰¹⁶ This likely reflects a local allergic reaction in the skin that promotes the development of IgE against alpha-gal present in tick saliva³²
Individuals who have type B or AB (ABO blood group) blood have been proposed to be at reduced risk for developing Alpha Gal Syndrome, but this is not seen in all studies, and it is clear that individuals with type B or AB blood can still become sensitized¹⁰³³³⁴
Males and individuals who have atopy showed increasing likelihood of alpha-gal sensitization in some, but not all, studies²¹²²
Individuals who have asthma and/or atopy may be more likely to have AGS-related respiratory symptoms³⁵
Among individuals who are IgE sensitized to alpha-gal, temporally associated cofactors such as use of NSAIDs, exercise, and alcohol ingestion can increase the likelihood and/or severity of a reaction on exposure to alpha-gal³

Diagnosis

Approach to Diagnosis

Figure 2. Suggested diagnostic and management algorithm for alpha-gal syndrome.AGS, alpha-gal syndrome; GI gastrointestinal; IgE, immunoglobulin E.

Clinical history of Alpha Gal Syndrome (alpha-gal syndrome) classically involves onset of urticaria, with or without gastrointestinal symptoms, a few to several hours after ingestion of mammalian meat/animal products
Presentation may vary widely in terms of timing and severity; some reactions occur in less than 2 hours, and anaphylaxis is possible in severe cases
Because there is often a delay of several hours before symptom onset, many patients do not appreciate the connection to mammalian meat ingestion
Allergic symptoms do not occur with every exposure to alpha-gal, also making the link difficult for patients to appreciate
AGS should be considered in patients with unexplained urticaria and/or gastrointestinal symptoms of abdominal pain, heartburn, nausea, vomiting, and diarrhea who live in AGS-prevalent areas and routinely consume mammalian meat and/or dairy products³⁶³⁷
Physical examination findings are typically unremarkable/nonspecific at the time of evaluation (patients are rarely seen while acute symptoms are active)
Allergy testing (serum alpha-gal IgE, skin testing) is critical to support the diagnosis⁴⁵
Oral food challenge, which is a preferred diagnostic test in the evaluation of many food allergies, is less practical for Alpha Gal Syndrome diagnosis because of the need for prolonged observation⁴
Meaningful response to an alpha-gal avoidance diet supports diagnosis; an avoidance diet has both diagnostic and therapeutic functions for patients with Alpha Gal Syndrome³⁷
A suggested approach to the diagnosis and management of AGS is summarized in Figure 2

Diagnostic Criteria – How is this condition diagnosed?

The diagnosis of Alpha Gal Syndrome relies on a combination of compatible clinical history, supportive results of allergy testing (especially elevated alpha-gal IgE titer), and meaningful response to an appropriate avoidance diet⁴⁵³⁶
Because the serologic prevalence of detectable alpha-gal IgE in community surveillance significantly exceeds the prevalence of symptomatic mammalian meat allergy,¹³¹⁵ a positive alpha-gal IgE test result in the absence of compatible clinical history is not adequate for a diagnosis of Alpha Gal Syndrome⁴⁵

Workup

History

The classic presentation of Alpha Gal Syndrome (alpha-gal syndrome) involves the onset of urticaria, with or without gastrointestinal symptoms, approximately 2 to 6 hours after ingestion of mammalian meat or other mammal-derived food products¹⁰³⁸
Some individuals have isolated gastrointestinal symptoms in the absence of cutaneous symptoms, most often cramping pain but also heartburn, nausea, diarrhea, or vomiting¹⁹³⁹⁴⁰⁴¹
Other symptoms that have been occasionally described in case series or case reports include joint pain, headaches, and fixed rashes¹⁰⁴²⁴³
Midnight anaphylaxis has sometimes been used to describe AGS, as many severe reactions occur late at night or early in the morning when a patient has already been asleep⁴⁴
Anaphylaxis is often defined as allergy symptoms affecting 2 or more body systems, which occur after a known exposure to a relevant allergen. Some studies have reported that upwards of 60% of patients with Alpha Gal Syndrome report symptoms consistent with anaphylaxis according to this definition⁴⁵
Many reactions seem to be precipitated in the setting of alpha-gal exposure concurrent with cofactors such as alcohol consumption, exercise, and use of NSAIDs⁴⁶
- The relevance of these cofactors is not unique to alpha-gal allergy and likely reflects a decrease in the allergen dose threshold required to elicit a reaction⁴⁷
Reactions in patients with Alpha Gal Syndrome are not necessarily reproducible on every exposure, which can complicate both diagnosis and management
Patients who receive parenteral medications that contain alpha-gal, such as the monoclonal antibody cetuximab, can have rapid-onset reactions⁴⁸

Physical Examination

The presence of urticaria can be a helpful sign, but urticaria is rarely present during a physician visit when Alpha Gal Syndrome is suspected
Physical examination findings are typically unremarkable at the time of evaluation, since patients rarely present while acute symptoms are active

Laboratory Tests

Measurement of serum alpha-gal IgE is typically the diagnostic test of choice⁴⁵³⁶
- Any positive test result (assay cutoff ≥ 0.1 IU/mL) can be indicative of Alpha Gal Syndrome in the appropriate clinical context, although many individuals, especially those with relatively low levels of IgE (eg, < 1 IU/mL) often do not report appreciable allergic reactions¹⁷³¹
  - Of note, this is not unique for alpha-gal, as population-based studies of common food allergens such as cow’s milk, egg, and peanut have revealed similar discrepancies between rates of IgE sensitization to these foods and symptomatic food allergy⁴⁹
  - Individuals who are sensitized to alpha-gal (as evidenced by positive serum alpha-gal IgE) but who have never had an allergic reaction to mammalian meat or other mammalian products are generally not described as having Alpha Gal Syndrome
- A negative alpha-gal IgE test result (ie, < 0.1 IU/mL) makes an AGS diagnosis very unlikely, but if preclinical probability remains high, then skin testing can provide additional assurance to exclude the diagnosis
- There is no single alpha-gal IgE level that has both high sensitivity and high specificity for predicting symptomatic AGS. Risk of symptomatic Alpha Gal Syndrome increases with higher alpha-gal IgE levels; cutoffs of 0.59 IU/mL and 2 IU/mL have been proposed by 2 separate groups as having optimal performance characteristics¹⁶¹⁹
- Many laboratories will run an alpha-gal panel that also includes beef, pork, lamb, and/or cow’s milk; but these IgE tests add little to the initial workup if clinical suspicion of Alpha Gal Syndrome is strong
- Positive test results for beef or pork IgE in the absence of detectable alpha-gal IgE can suggest other forms of meat allergy

Diagnostic Procedures

Skin testing
- Measurement of serum alpha-gal IgE is usually adequate for an Alpha Gal Syndrome evaluation, but occasionally, skin testing may provide additional information to help confirm or rule out the diagnosis. One example would be a patient who has high preclinical probability of having AGS but negative alpha-gal IgE serology
- Skin prick testing using commercial beef, pork, or other mammalian meat extracts can aid in diagnosis; however, the sensitivity of skin prick testing for Alpha Gal Syndrome is relatively low and should not be relied on to rule out Alpha Gal Syndrome.¹¹ Some centers use cetuximab for skin testing, as this monoclonal antibody expresses abundant alpha-gal⁴⁵⁴⁵
- Intradermal testing has much higher sensitivity but should only be carried out if the skin prick test result is negative to mitigate the risk of a testing-related reaction⁵⁰
  - The combination of negative blood IgE test and negative intradermal skin test results effectively rules out Alpha Gal Syndrome
  - A positive intradermal test result in the setting of an appropriate clinical history is suggestive of AGS, even if a blood test result was negative
- Prick-to-prick testing using freshly cooked meat has also been reported but is not standardized¹¹⁵¹
- Serious allergic reactions are uncommon with skin testing but remain possible, particularly with intradermal tests. Accordingly, skin testing should only be undertaken by clinicians experienced with skin testing who are prepared to treat anaphylaxis
Oral food challenge
- An oral food challenge involves gradually administering increasing oral doses of a suspected food allergen until allergy symptoms develop or a predetermined dose threshold is reached
- Because of the potential for serious allergic reactions, including anaphylaxis, an oral food challenge should be performed under the supervision of a clinician familiar with managing possible complications and adverse effects
- Although an oral food challenge can be an important diagnostic test for many food allergies, it is less practical and infrequently performed for patients with AGS because of the need for very prolonged observation and the inconsistency of reactions

Diagnostic Tools

Response to alpha-gal avoidance⁴⁵³⁶
- A favorable response to a mammal-restricted diet plays an important role in clinching an Alpha Gal Syndrome diagnosis
- Alternative explanations or concomitant conditions should at least be considered when patients continue to experience symptoms despite eliminating mammalian meat and other mammalian products from their diets

What are the Differential Diagnosis?

During workup for AGS (alpha gal syndrome), there are several other disorders to consider (Table 1)
In adults, particularly in areas where tick bites are common, AGS is the most common cause of mammalian meat allergy; however, there are other causes of allergy to mammalian meat¹⁰⁵²
- Primary beef allergy is seen more often in young children than in adults, but occasional cases of IgE antibodies to beef proteins such as bovine serum albumin (containing the allergen Bos d 6) or immunoglobulin (containing the allergen Bos d 7) have been reported
- Individuals with cat allergy can become allergic to pork owing to IgE cross-reactivity between cat allergen (Fel d 2) and pork allergen (Sus s 1). Typically, these diagnoses and the relevant IgE testing are worth pursuing only in situations when there is a convincing history of mammalian meat allergy but the alpha-gal IgE test result is negative
Chronic urticaria, idiopathic anaphylaxis, and irritable bowel syndrome are other diagnoses that can occasionally be confused with AGS or exist concurrently with Alpha Gal Syndrome

Table 1. Differential Diagnosis: Alpha gal syndrome

Condition	Description	Differentiated by
Primary beef allergy	Urticaria or other allergy symptoms after consuming beef in setting of positive IgE response to beef test	Symptom onset is typically more rapid (occurs before 2 hours), and alpha-gal IgE test result is negative (or level is lower than the beef IgE)
Pork-cat syndrome	Urticaria or other allergy symptoms after consuming pork (and sometimes beef) in an individual with cat allergy	Alpha-gal IgE test result is negative, whereas pork and cat IgE test results are positive. Component testing will reveal IgE response to cat allergen (Fel d 2)
Chronic urticaria	Frequent episodes of urticaria and/or angioedema that persist > 6 weeks	These patients will not routinely have detectable alpha-gal IgE or respond to a mammal-free diet
Idiopathic anaphylaxis	Recurrent anaphylaxis in absence of identified allergenic trigger	These patients will not routinely have detectable alpha-gal IgE or respond to a mammal-free diet
Irritable bowel syndrome	Chronic gastrointestinal symptoms for which other identifiable causes have been excluded	These patients will not routinely have detectable alpha-gal IgE or respond to a mammal-free diet

Treatment – How is Alpha Gal Syndrome treated?

Approach to Treatment

The major goals of treatment are to provide patients information so they can avoid alpha-gal exposure and adopt strategies to increase the likelihood that AGS (alpha-gal syndrome) is not long lived
Standard management considerations for alpha-gal syndrome are generally similar to those for other types of food allergy and include:⁴³⁷⁴⁵
- Avoidance of triggers
  - Avoidance of alpha-gal (present in food and medications) is the cornerstone of Alpha Gal Syndrome management
  - Avoidance of further tick bites can improve the natural history of AGS
- Medications to treat acute reactions
- In select cases, patients who do not strictly avoid dairy and other products with relatively low amounts of alpha-gal may use medications to control symptoms
Food oral immunotherapy and biologics are emerging treatment modalities for AGS⁴⁵
Comprehensive discussions of food allergy and anaphylaxis management are beyond the scope of this Clinical Overview, which focuses on Alpha Gal Syndrome-specific considerations
A suggested approach to the diagnosis and management of Alpha Gal Syndrome is summarized in Figure 2

Nondrug and Supportive Care

Alpha-Gal Avoidance

General considerations³⁴⁵¹²³⁷
- In alpha-gal–sensitized individuals, reaction risk is related to the amount of alpha-gal present in a given food or product
- Awareness of relative amounts of alpha-gal present in foods or medicinal products can be helpful for risk stratification, as many patients can tolerate alpha-gal when present in relatively small amounts
- For example, mammalian meat and organ meats, which are abundant sources of alpha-gal, are much more likely to elicit reactions than foods such as low-fat dairy products that contain less alpha-gal
Mammalian meat and organ meats
- The mainstay of Alpha Gal Syndrome management is to avoid mammalian meat and organ meats. Beef, pork, lamb, and venison are the best-known mammalian meats consumed in the United States, but others such as bear, bison, and goat should equally be expected to express alpha-gal and elicit reactions⁵⁷
- Organ meats such as kidneys and liver also express abundant amounts of alpha-gal and should be avoided⁴⁵⁸
Dairy products and gelatin
- Many patients with Alpha Gal Syndrome can tolerate dairy products such as cow’s milk and cheese and also gelatin without severe reactions, likely reflecting amounts of alpha-gal lower than those present in mammalian meat and organ meats³⁷
- However, a subset of patients may experience urticaria or other symptoms related to dairy products and gelatin, and avoidance of these is recommended for these individuals. Foods containing gelatin can include jelly beans, marshmallows, puddings, and desserts such as Jello.
Other foods and food products⁴
- Mammal-derived fats including lard (pork fat), tallow (solid beef or mutton fat), and suet (semi-solid beef or mutton fat) are used in some cooking and can trigger AGS reactions. Some fried foods, as well as broth and gravy, are often overlooked as potential sources of alpha-gal
- Sausage prepared using natural casings derived from pig intestines should be avoided. In some cases, this can include chicken or turkey sausage
- Carrageenan is a seaweed-derived polysaccharide that has galactose-α-1,3-galactose linkages and is commonly used in the food industry. The relevance of carrageenan as an Alpha Gal Syndrome trigger is not well understood, but it may contribute to reactions in a minority of patients
Medications
- Alpha-gal is present at varying levels in some medications and medical products
- The monoclonal antibody cetuximab expresses alpha-gal and can lead to severe anaphylaxis in individuals with alpha-gal sensitivity⁴⁸
- Antivenom, heparin, and pancreatic enzyme replacement are mammal derived and may cause reactions in some patients with Alpha Gal Syndrome
- Products that may be mammal derived but with less clear evidence of the presence of alpha-gal include magnesium stearate and glycerin. Most patients do not need to avoid these, but some patients report a reduction in cutaneous or gastrointestinal symptoms by avoiding products that contain them
- Considerations for specific medications/medical products, including whether they should be withheld, are summarized in Table 2

Table 2. Medications and medical products that contain or could contain alpha-gal and their relevance to alpha-gal syndrome.

Medication/product	Description	Important features and recommendations
Cetuximab	An mAb produced in mouse SP2/0 cells used to treat carcinoma; alpha-gal expressed in Fab domain	Symptom onset is rapid; reactions can be severe and can occur in sensitized individuals who have tolerated mammalian meat. Desensitization can be carried out for patients with AGS who need cetuximab.⁵⁹ Alpha-gal may be expressed in other mAbs and fusion proteins (eg, infliximab, abatacept), but levels are lower than in cetuximab and reactions to these have not been widely reported.⁴⁶⁰ Cetuximab can be used in diagnostic skin testing⁴⁵⁴⁵
Snake antivenom	Products such as CroFab are sheep-derived polyclonal antibody fragments used to treat toxic snake envenomation; these products contain alpha-gal⁶¹⁶²	Antivenom can activate basophils from patients with Alpha Gal Syndrome in vitro, but in vivo reactions in patients with AGS do not appear to be common.^61626364 Given the risk/benefit ratio, antivenom should not be withheld from patients with Alpha Gal Syndrome who are otherwise appropriate candidates, but close monitoring is advised⁴⁵
Pancreatic enzyme replacement	Pancrelipase and other commercially available products are porcine- derived enzymes used to treat pancreatic enzyme insufficiency and express alpha-gal⁶⁵⁶⁶	Reactions to pancreatic enzyme replacement products have been reported, but most of these are not severe. Pancreatic enzyme replacement is likely tolerated by most patients with Alpha Gal Syndrome⁵⁵⁵⁶
Thyroid replacement	Mammalian-derived thyroid extracts such as Armour thyroid carry alpha-gal⁶⁷	Synthetic alternatives such as levothyroxine do not have alpha-gal and are likely safer for patients with AGS⁴⁶⁸
Bovine/porcine heart valves and vascular grafts	Bioprosthetic valves and vascular grafts from pigs and cows contain alpha-gal⁶⁷⁶⁹	Acute reactions to bioprosthetic valves have been rarely reported.⁷⁰ The risk of early degeneration of biological valves and grafts remains mostly theoretical, as systematic investigation has been lacking⁷¹⁷²
Heparin	Heparin is a polysaccharide anticoagulant often sourced from pig intestines. Alpha-gal may be present as an impurity in some lots of heparin	Reactions to low-dose heparin used for deep vein thrombosis prophylaxis are rare in patients with AGS, but reactions appear more common for high-dose heparin infusions used in some cardiovascular interventions.⁷³⁷⁴ To date, a role for preoperative testing and premedication has not been widely adopted⁷⁵⁷⁶
Gelatin-containing vaccines	Gelatin-containing vaccines such as varicella and MMR vaccine have low levels of alpha-gal⁷⁷	Reactions to gelatin-containing vaccines in patients with AGS appear to be very rare, but there have been case reports.⁷⁸⁷⁹⁸⁰ Strict avoidance is likely not necessary, but administration with caution is advised¹²

Caption: AGS, alpha gal syndrome; CroFab, Crotalidae polyvalent immune Fab (ovine); mAb, monoclonal antibody; MMR, measles, mumps, rubella.

Tick Avoidance

Management also involves education about the role of tick bites in promoting Alpha Gal Syndrome
Patients who avoid subsequent tick bites are more likely to experience a decrease in alpha-gal IgE levels and, accordingly, are thought to be more likely to outgrow their allergy⁸¹
Length of avoidance appears to correlate with likelihood of remission; patients able to avoid tick bites on a long-term basis (1-2 years or more) are more likely to tolerate successful reintroduction of red meat into their diets⁴⁵
Tick avoidance measures, including the application of permethrin to clothes and shoes, is generally advised for those who reside in tick-endemic areas and have frequent exposure (https://www.cdc.gov/ticks/avoid/).

Drug Therapy

For patients with Alpha Gal Syndrome, drugs are mostly used for management of acute reactions
- Diphenhydramine (25-50 mg PO 3-4 times daily) can be used as needed for mild symptoms resulting from alpha-gal exposure (inadvertent or otherwise)⁸²
Epinephrine autoinjectors are used in the management of serious food allergies and are commonly prescribed for patients with AGS.⁵ Epinephrine is considered the gold standard for treating severe reactions including anaphylaxis in patients with AGS⁸³
- In the outpatient setting, patients are often prescribed fixed-dose epinephrine autoinjectors. These are weight based: 0.3 mg is the dose for adults and children weighing 30 kg or more, and 0.15 mg is the dose for children weighing 15 to 30 kg. Toddlers weighing less than 15 kg can be treated with dosing of 0.01 mg/kg, although injectors containing less than 0.15 mg may not be available⁸⁴
- Dosing should be repeated every 5 to 15 minutes if symptoms are ongoing
- Patients should generally seek formal medical evaluation if they have used epinephrine outside the medical setting
- Some experts recommend prescribing epinephrine autoinjectors to all patients with AGS, but other clinicians will take into account prior history and patient preferences as part of shared decision-making. For patients who have not had anaphylaxis or severe symptoms, it may be reasonable to forego epinephrine autoinjectors in some cases⁸⁵
Some patients with AGS who continue to consume dairy products (or other products with relatively modest amounts of alpha-gal) may benefit from taking medications to prevent mild symptoms related to AGS⁵
- Oral antihistamines such as fexofenadine (60-180 mg PO twice daily), levocetirizine (2.5-5 mg PO twice daily), and cetirizine (5-10 mg PO twice daily) are OTC and can be taken routinely to address symptoms including frequent pruritus or urticaria⁸⁶⁸⁷⁸⁸⁸⁹
- Oral cromolyn (100-200 mg PO twice daily 20-30 minutes before meals) is an option for patients with gastrointestinal symptoms that do not completely respond to an avoidance diet or who have ongoing low-level alpha-gal exposure in their diet. Dosing can be up to 4 times a day before meals, but many patients respond to twice-daily dosing.⁴ Some patients report benefit from using cromolyn before going to restaurants where inadvertent exposure to occult sources of alpha-gal can be hard to control
- In select cases, oral corticosteroids, antiemetics, antispasmodics, and antidiarrheals have been described as being helpful⁴⁵
Biologic therapies are under investigation for management of food allergy
- International food allergy management guidelines published in 2022 indicated that there was insufficient evidence at the time to make a recommendation regarding monoclonal antibodies for treating food allergy but stated that clinicians could consider the anti-IgE monoclonal antibody omalizumab for selected patients, such as those with recurrent anaphylaxis despite food allergen avoidance⁹⁰
- Omalizumab has not been well studied specifically in AGS but received FDA approval in February 2024 for use in food allergy more generally.⁹¹ It is not a cure but has been shown to decrease the risk of reactions in individuals with food allergies who react to low-level exposures⁹²
- Omalizumab is approved for management of IgE-mediated food allergy in patients aged 1 year and older to reduce allergic reactions that may occur with accidental exposure to allergens in foods and to be used in conjunction with food allergen avoidance⁹¹
- Omalizumab dosing is 75 to 600 mg subcutaneously every 2 or 4 weeks, with dosing based on weight and baseline serum total IgE per manufacturer guidance⁹¹
- There is currently limited guidance on use of omalizumab in AGS treatment, although among patients prescribed omalizumab for the treatment of chronic urticaria who had concomitant AGS, a small uncontrolled series suggested reduction in AGS symptoms in patients with accidental exposure⁹³

Treatment Procedures

Food oral immunotherapy
- Oral immunotherapy is an approach to management of food allergy that uses progressively increasing oral doses of food allergen to increase the threshold dose of allergen that triggers symptoms and achieve allergen desensitization⁴⁵
- Oral immunotherapy, in which mammalian meat is gradually reintroduced in a graded fashion in a controlled setting, has been described in a few reports and may be effective in treating Alpha Gal Syndrome⁹⁴
- A recent case series from Turkey provides further support for this possibility, although it was notable that interval tick bites could nonetheless lead to a loss of tolerance⁹⁵

Persistent or Recurrent Disease

For symptoms that persist despite appropriate alpha-gal avoidance measures, alternative explanations should be sought⁵³
- In this case medication and management plans should focus on the other potential diagnoses
- For example, patients with AGS who have recurrent urticaria despite an appropriate alpha-gal diet may have chronic spontaneous urticaria and benefit from scheduled high-dose antihistamine or omalizumab therapy

Admission Criteria

Admission may be necessary for Alpha Gal Syndrome-related severe reactions, including anaphylaxis, that do not rapidly respond to emergency measures

Follow-up

Monitoring

Alpha-gal IgE levels are often dynamic and can wane over time in many individuals⁸¹
It is common practice, especially among individuals who are motivated to expand their diets, to periodically monitor alpha-gal IgE levels and consider graduated introduction of alpha-gal–containing products when levels of IgE have become undetectable (<0.1 IU/mL) or decreased significantly. Follow-up testing has been suggested at 6- to 12-month intervals⁴⁵³⁶
If patients can tolerate high-fat dairy products such as ice cream and their IgE levels have dropped significantly, then it may be reasonable to have conversations about the risks/benefits of cautiously trying small amounts of mammalian meat⁴⁵
These patient-physician discussions can vary depending on a patient’s motivation to reintroduce mammalian meat and also on the severity of their prior reactions. With appropriate precautions in place (eg, diphenhydramine, an epinephrine autoinjector, awareness of a household adult), many patients go on to successfully reintroduce mammalian meat Into their diets
Meat challenges in the allergy clinic are occasionally carried out in some centers, but because of the delayed and idiosyncratic nature of reactions in patients with AGS, these challenges have limitations⁴⁵

Complications

Alpha Gal Syndrome can present with severe reactions, including anaphylaxis
- Reported rates of anaphylaxis vary widely depending on the criteria used for diagnosis and the population studied
- However, among patients with an established diagnosis who are on an avoidance diet, severe reactions are uncommon
- This is because exposure to small amounts of alpha-gal (eg, by accidental exposure) is rarely adequate to cause severe reactions

Prognosis

The natural history of Alpha Gal Syndrome is variable
Many patients can outgrow their allergy over time and regain tolerance to mammalian meat over a period of several months or years, but this is not universal. Currently, there is no diagnostic test that can predict the course of Alpha Gal Syndrome
The trajectory of alpha-gal IgE is often used to determine whether the allergy is waning. If the alpha-gal IgE level becomes undetectable, it is very likely that Alpha Gal Syndrome is in remission and reintroduction of mammalian meat will be successful⁴
A significant decrease in alpha-gal IgE from the level at the time of diagnosis could also suggest clinical remission; however, information about specific levels or cutoffs associated with remission is limited⁴

Referral

Patients with a straightforward Alpha Gal Syndrome diagnosis who respond well to a mammal-free diet can often be managed by a primary care clinician
Because many clinicians are not familiar with Alpha Gal Syndrome, many patients benefit from care and follow-up provided by an allergist who has experience diagnosing and managing this condition
Patients with atypical presentations or those who do not respond to a mammal-free diet can especially benefit from consultation with an allergist
Some patients with AGS have been observed to develop concomitant allergic disorders, such as chronic spontaneous urticaria or eczema, which do not respond to changes in diet. These patients should be treated with measures (including appropriate referrals, if necessary) targeting their specific presentation

Screening and Prevention

Tick bites are the best understood instigator of alpha-gal IgE sensitization. Accordingly, avoidance of tick bites is expected to mitigate the risk of developing alpha-gal syndrome⁸¹
In addition, among patients with Alpha Gal Syndrome, the likelihood of achieving remission is thought to be higher for those who avoid recurrent tick bites⁸¹

References

1.Platts-Mills TAE et al. On the cause and consequences of IgE to galactose-α-1,3-galactose: a report from the National Institute of Allergy and Infectious Diseases Workshop on Understanding IgE-mediated mammalian meat allergy. J Allergy Clin Immunol. 2020;145(4):1061-1071.