Disclaimer- The posts in this series are intended to improve awareness of this important and potentially deadly disease. I am not an Allergist or Immunologist and I am not offering any medical advice. Please consult with your own physician or health care provider for that. An educated patient and their family are the best advocates for their health care.

What is alpha gal syndrome?

Alpha-gal syndrome (AGS) is an IgE-mediated allergic reaction to galactose alpha-1,3-galactose (alpha-gal), an oligosaccharide present on the cells of all non-primate mammals, which occurs several hours after consuming beef, pork, other non-primate mammalian meats, or non-primate mammalian-derived products. The delayed onset, 2-6 hours after ingestion, distinguishes it from typical food allergies. It has been estimated that there are about 450,000 people affected in the United States. While initially recognized in patients presenting with skin reactions (urticaria/hives and angioedema) and anaphylactic shock, about 40% of patients present solely with gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, and vomiting without predominant skin, respiratory, or circulatory symptoms. Sensitization occurs through tick bites (particularly the Lone Star tick in the United States). The Lone Star tick’s life cycle is shown below. It bites humans in all three stages larva, nymph and adult.

The proposed mechanism, shown below, involves absorption of alpha-gal bound to fat in glycolipids, which are incorporated into chylomicrons that enter the circulation approximately 2 hours after ingestion. The chylomicrons are processed into smaller particles over the next several hours. These particles, LDL, are small enough to cross capillaries, enter tissues and subsequently bind to IgE antibodies on the surface of mast cells in the gastrointestinal tract, skin or other tissues. This triggers mast cell degranulation and release of histamine and other mediators that act on sensory nerve endings, intestinal smooth muscle, and mucous glands.

In the United States, most cases are reported within the geographic range of the Lone Star tick shown below, extending from southern Maine west to Iowa and south to Texas and Florida.

Initial studies

Dr. Thomas Platts-Mills and colleagues at the University of Virginia were instrumental in characterizing AGS, with key discoveries published in 2009 and 2011 that established the link between tick bites and IgE-mediated non-mammalian meat allergy. The 2009 report (link) described a novel form of delayed anaphylaxis to red meat related to IgE antibodies against galactose-α-1,3-galactose (alpha-gal). This was followed by a landmark study in 2011 by Commins and colleagues (link), which provided direct evidence linking tick bites to the development of AGS. The authors reported that IgE antibodies to alpha-gal increased 20-fold or greater following tick bites in three patients, and established a strong correlation between a history of tick bite/s and IgE levels to alpha-gal. The authors identified Amblyomma americanum (the Lone Star tick) as the primary vector in the United States. This was the first example of an ectoparasite response giving rise to an important food allergy. Evidence that ticks bites are the causal agent is summarized in the table below.

Clinical Presentation

The clinical presentation of AGS includes variable symptom severity ranging from skin reactions (hives/urticaria) to life-threatening anaphylactic shock.

Symptoms typically occur 2 to 6 hours after consuming mammalian meat, though the delay can range from 3 to 8 hours. This delayed onset creates diagnostic challenges, as the syndrome can be easily confused with chronic spontaneous urticaria, mast cell activation syndrome, inflammatory bowel disease or irritable bowel syndrome (IBS). Beyond red meat, alpha-gal is present in visceral organs, dairy products, gelatin, and certain pharmaceuticals derived from non-primate mammals or containing inactive ingredients from non”primate mammals. A significant fraction of patients experience isolated gastrointestinal symptoms without classic allergic manifestations. In a cohort of 124 seropositive patients from the Mayo Clinic, 47% presented with gastrointestinal symptoms, with a higher proportion being female compared to those without GI involvement. These patients are sometimes misdiagnosed with IBS. The American Gastrointestinal Association notes that certain clinical presentations should increase the clinical suspicion for AGS especially patients that awaken from sleep with gastrointestinal distress, which corresponds with the typical 2-6 hour delay from alpha-gal ingestion to reaction. There is also significant reaction variability even within an individual patient to the same exposure.

Risk factors

People living in or who have lived in the Southeast (NC, SC, Georgia, Florida), mid-Atlantic (Maryland, Virginia), Midwest (including Arkansas, Missouri, Oklahoma, Kansas), and the East Central United States (Kentucky, Tennessee) where Amblyomma americanum (the Lone Star tick) is endemic are at primary risk, see maps below. The Lone Star tick is thought to be unique in that it may be the only tick that bites humans in all three of its life cycle phases (larval, nymph, and adult), which may explain why it is the principal cause of sensitization in the United States.

Geographic risk extends internationally to Australia, South Africa, Western Europe, and Japan, where AGS has been reported, though the specific tick vectors differ by region.

In addition to geographic considerations, specific demographic, immunologic and other characteristics have been found in case-control studies that identify high-risk populations for the development of AGS. Demographic factors that increase risk include middle-aged adults and individuals of White race. The syndrome shows relatively equal sex distribution, though some studies report a slight female predominance, and females with AGS may be more likely to develop gastrointestinal symptoms than males. Intrinsic immunologic and genetic factors also influence AGS susceptibility. Patients with B blood type are at lower risk of AGS than those with type A or O (Odds ratio (OR)- 0.4- 95% confidence interval 0.18-0.88), link. This may occur because the alpha-gal epitope and the type B blood group antigen are similar, see figure below.

A history of childhood allergies (Odds ratio (OR)- 1.99- 95% confidence interval 1.02-3.89), family history of AGS (Odds ratio (OR)- 8.33- 95% confidence interval 2.99-27.38) or other food allergies (Odds ratio (OR)- 2.70- 95% confidence interval 1.47-4.98), and a history of severe reactions to insect bites or stings (Odds ratio (OR)- 3.14- 95% confidence interval 1.81-5.47) are all associated with higher risk (link). Patients with a history of four or more tick bites have dramatically elevated odds of developing AGS (Odds ratio (OR)- 33.05, 95% confidence interval 9.92-155.12) as do those who experience severe reactions at tick bite sites (Odds ratio (OR)- 7.93, 95% confidence interval 3.74-16.8). The risk also increases with increasing numbers of tick bites. Individuals spending 17 or more hours per week outdoors in wooded areas are also at increased risk (Odds ratio (OR)- 5.58, 95% confidence interval 2.56-12.19), link. A high percentage of affected patients report a history of at least one tick bite (86%). An elevated alpha-gal-specific IgE level can be seen in as many as a third of asymptomatic controls with tick exposure, suggesting that a tick bite is necessary but not sufficient for the development of clinical disease. Undoubtedly, host susceptibility factors play a role in who does or does not develop symptoms. In summary, people with outdoor exposure or occupations, a history of multiple tick bites and an exuberant skin reactions to them are at higher risk for developing AGS. Therefore, prevention of tick bites is the most modifiable risk factor.

Diagnosis

Diagnosis relies on demonstrating alpha-gal-specific IgE antibodies in serum combined with a compatible clinical history and improvement on a mammalian-restricted diet. Some affected patients will have an alpha-gal-specific IgE level less than 1.0 IU/ml but their ratio of specific to total IgE is >1% because their total IgE levels are low. One problem with diagnosis is that provider awareness of AGS remains limited. In a 2022 survey of family practitioners, general practitioners, internists, pediatricians, nurse practitioners and physician assistants across the country published in the Morbidity and Mortality Weekly Report from the CDC, reported that 42% of U.S. healthcare providers had never heard of AGS, and among those familiar with it, fewer than one-third knew how to diagnose the condition (link). In addition, another study estimated that in 5% of cases the wrong test was ordered. These knowledge gaps contribute to significant underdiagnosis.

Management

Management centers on strict avoidance of mammalian meat and internal organs, as well as potentially other mammalian-derived products depending on individual reactivity patterns. In one study, 22 of 40 patients reported symptom resolution with dietary avoidance during a mean follow-up of 27 months, 7 were eventually able to reintroduce a regular diet. Importantly, tick bite prevention is essential, as IgE levels can decrease over time in the absence of repeated tick exposure, and AGS may wane in many patients who avoid further sensitization. Many experts recommend that patients carry epinephrine auto-injectors for emergency management of potential anaphylactic reactions. Dietary sources of alpha-gal warrant careful attention. Many experts recommend a tiered approach to management, shown in the figure below. They recommend that symptomatic patients avoid mammalian meat, innards, and organs, as well as hidden sources including mammal-derived gelatin in desserts and yogurts, lard in biscuits, pork casings in poultry sausages, beef broth, and fatback or bacon in vegetable dishes, and anything fried in lard or beef tallow (tier 1). Approximately 20% of patients experience persistent symptoms despite avoiding these foods and require additional avoidance of dairy products, particularly whole milk, ice cream, heavy cream, and soft cheeses (tier 2). If symptoms persist then a more comprehensive examination of all potential exposures is required (tier 3). Other potential triggers could include: lotions, cream and soaps- glycerin; natural flavors- may be of a mammalian source; added enzymes; guar or xanthum gums; rosemary extract; carrageenan is derived from edible red seaweed and contains alpha-gal, it is often added to rotisserie chicken as a filler (carrageenan is widely used as an aid in food processing, gelling, thickening, and stabilizing. It is added to many products such as beer, wine, cheese, organic fruit, nut milk, lunch meats, and yogurt. A very small percentage of patients with AGS, 1-2%, react to it); vitamins added to food may be derived from mammalian sources; canned tuna may be contaminated by dolphin, a mammal, trapped in the nets; and some fish eggs. Consultation with allergists or immunologists is often recommended when selecting pharmaceuticals and medical products for AGS patients, as comprehensive lists of all alpha-gal-containing products are not readily available. Alpha-gal-free alternatives are in development, including medical devices from specialized manufacturers. Other treatments have been used in small numbers of patients including omalizumab, dupilimab, and oral immunotherapy.

The two tables below list specific foods and medications and their relative risks.

Prevention of tick bites

Temperature sensitivity of Lone Star ticks

Lone star ticks (Amblyomma americanum) generally become inactive below approximately 40°F. Adult ticks show minimal to no questing activity below this temperature range, while nymphs and larvae may have slightly different thresholds. However, during unseasonably warm winter periods Lone Ster ticks may exhibit activity. The greatest risk of being bitten by Lone Star ticks exists from early spring through late fall. Nymph and larval Lone Star tick activity is highest from late July to early September. Outdoor exposure risk diminishes with sustained temperatures below 40°F, though vigilance during warm winter days in endemic areas remains important. Between 2010 and 2022, over 110,000 suspected cases of AGS were identified in the United States, with the highest case counts in Arkansas, Kentucky, Missouri, and Long Island, New York- all areas with substantial Lone Star tick populations. From January 2017 through December 2022, a total of 90,018 persons (30.5% of those tested) had an elevated alpha-gal-specific IgE, with the number of people testing positive increasing from 13,371 in 2017 to 18,885 in 2021. This increase may be due to an expanding tick population, increased clinical awareness and testing, or both. Suspected cases were identified predominantly in counties within the southern, midwestern, and mid-Atlantic regions. Allergists in these regions manage the majority of cases, with many providers treating more than 100 patients each. The epidemiology of AGS may shift further north due to climate change. With global warming, tick density is increasing and their geographic range is expanding.

Preventing tick bites

A multi-pronged approach including habitat avoidance, protective clothing, chemical repellents, and post-exposure tick checks has been recommended. Ticks live in grassy, brushy, or wooded areas. The study below in Oklahoma reported the habitat where two species of ticks are most likely to be located.

When outdoors, walking in the center of trails when possible has been has been recommended. Light-colored clothing with long sleeves and long pants makes it easier to see ticks before they attach to skin. Tucking pants into socks creates a barrier at the ankles, which is particularly important since nymphal lone star ticks quest near the ground. To prevent tick bites I follow the recommendations discussed in the previously posted University of Virginia community update (link). I use DEET or picardin on exposed skin per the manufacturer’s recommendation. I treat my shoes, pants, and socks, with products containing 0.5% permethrin from Sawyer per their recommendations. I apply permethrin (0.5%) to clothing and shoes outside wearing an N-95 mask and gloves and allow them to dry for at least one day prior to use. Permethrin should only be applied to clothing and gear, not directly to skin. Permethrin-treated clothing can kill ticks. Above the area where my pants are tucked into my socks I wrap double sided scotch tape to catch crawling ticks. Before I get in the car for the trip home I roll a lint roller over my pants and shirt front and back to catch ticks I cannot see. I shower as soon as I get home. This provides an opportunity to wash off unattached ticks and conduct a thorough tick check. If ticks are found, I promptly remove them using clean fine-tipped tweezers inserted between the tick body and the skin. I place my clothes directly into a plastic trash bag until I can wash them, separately from other laundry..

Prevention in those with AGS

Patients already affected by AGS are recommended by experts to be especially vigilant to avoid further tick bites. Repeat bites have been shown to increase alpha-gal-specific IgE levels and may increase the likelihood/severity of a reaction following alpha-gal consumption. The only intervention that can decrease alpha-gal-specific IgE levels is to avoid future tick bites, making the prevention of tick bites important for patients with AGS.

Evidence for Effectiveness

A 2-year randomized, placebo-controlled, double-blinded trial among 82 outdoor workers in Rhode Island and southern Massachusetts demonstrated that factory-impregnated permethrin clothing reduced tick bites by 65% in the first year and 50% in the second year, for an overall 2-year protective effect of 58%. In this study participants experienced high occupational exposure to blacklegged ticks (Ixodes scapularis), and the sustained protection over two years demonstrates the durability of the factory-impregnated permethrin treatment. No treatment-related adverse outcomes were reported during the 2-year study period. This trial focused on blacklegged tick exposure. It appears that factory-treated permethrin clothing maintains activity longer than self spraying, probably because factory treatment involves placing the garment in a closed bag filled with permethrin solution, which likely soaks into the fabric better.

From the Sawyer website- “Sawyer recommends 3 ounces of formula per garment. It does not matter whether the garment is a size small or extra large; you are seeking the molecules in 3 ounces of the formula to protect you. If you are treating your socks, they count in the overall application as well and the formula used is part of the 6 ounces needed to treat an outfit. Applying less than 3 ounces per garment will lead to unsatisfactory results. The more permethrin molecules in the area the greater your overall protection. Treating your shirt and pants is much more effective than just treating one of the garments. Also treating your back pack significantly adds to the protection from your shirt and pants. While ticks usually find you at the ankle level (be sure to treat the socks and pants) they can also climb bushes and find you at a higher level so be sure to treat your shirt as well if you are around bushes and concerned about ticks.” “Odorless after drying, Sawyer Permethrin Fabric Treatment can be used to treat a variety of fabrics like clothing, gear, and tents. A successful application of this insect repellent treatment is effective against mosquitoes and ticks for 6 weeks or 6 washes.”

Next- The Complex Immunology of the Alpha-gal Syndrome