Among the litany of conditions that can result from a tick bite, a severe allergy to red meat and other products containing alpha-gal sugars is growing in prevalence but not widely understood, even among healthcare professionals. A new review details the current state of scientific knowledge on alpha-gal syndrome. The lone-star tick (Amblyomma americanum), pictured here, is most commonly associated with alpha-gal syndrome, but in fact cases show up on every continent except Antarctica, and they aren’t all associated with lone star ticks. The review lists at least 12 tick species linked to alpha-gal syndrome all over the world. Most come from two groups: Amblyomma and Ixodes. (Photo by Lauren Bishop, CDC Public Health Image Library)

By Melissa Mayer

Melissa Mayer

About 30 million years ago, primates had a problem: A prehistoric pathogen probably exploited sugars made by the primates’ own bodies to evade the primates’ immune systems. So, primates adapted, halting production of the sugar, known as “alpha-gal,” and instead cranking out antibodies against it.

This evolution enabled better defense against that ancient pathogen as well as modern illnesses like malaria and bacterial sepsis. It may have made it tougher for some viruses to jump from other mammals—who all still make alpha-gal—to primates like us.

But evolution doesn’t give free lunches.

The trade-off for the immune system upgrade is an incurable and potentially life-threatening tick-borne allergy—alpha-gal syndrome, which is the subject of a recent review published in March in the Journal of Medical Entomology.

Not Just a Southern Story

Melissa Nolan, Ph.D, MPH

“Alpha-gal” is the shorthand term for the sugar molecule galactose-α-1,3-galactose, which can be found on cells and tissues of all mammals except humans and other primates. It is also produced by ticks and several other parasites. A tick bite can cause a human body to develop antibodies to alpha-gal and, in some cases, become hypersensitive, or allergic, to it. This hypersensitivity can then be triggered by consumption of red meat or other products that contain alpha-gal. Severe allergic reactions can be life-threatening.

In the United States, alpha-gal syndrome is often framed as a quirky Southern problem: a lone star tick (Amblyomma americanum) bite that leaves its victims allergic to red meat.

But cases show up on every continent except Antarctica, and they aren’t all associated with the same species of tick. The review lists at least 12 tick species linked to alpha-gal syndrome all over the world. Most come from two groups: Amblyomma and Ixodes.

That raises important questions about the role Ixodes ticks might play in transmission in North America.

“I have some suspicions that people are probably getting alpha-gal from Ixodes scapularis—the Lyme disease tick—here, but we just don’t have enough research on it,” says Melissa Nolan, Ph.D, MPH, associate professor of epidemiology and biostatistics at the University of South Carolina’s Arnold School of Public Health and senior author on the review article. “We have patients that are coming in and getting diagnosed with new-onset alpha-gal in the winter months, when our Ixodes are very active, but we don’t see as much lone star activity.”

And the allergy might extend beyond ticks.

The review notes cases of alpha-gal syndrome without known tick exposures and highlights the possibility that alpha-gal could be carried in the saliva or venom of other vectors—like mites (chiggers), tsetse flies, wasps, fire ants, and hookworms.

Researchers working in the lab of Melissa Nolan, Ph.D, MPH, associate professor of epidemiology and biostatistics at the University of South Carolina’s Arnold School of Public Health, examine ticks in glass vials as part of the lab’s work to conduct tick surveillance in the field. Nolan and colleagues have recently published a review in the Journal of Medical Entomology that details the current state of scientific knowledge on alpha-gal syndrome, a severe allergy to red meat and other products containing alpha-gal sugars that can result from a tick bite. (Photo courtesy of Melissa Nolan, Ph.D, MPH)

Researchers working in the lab of Melissa Nolan, Ph.D, MPH, associate professor of epidemiology and biostatistics at the University of South Carolina’s Arnold School of Public Health, examine a drag cloth as part of the lab’s work to conduct tick surveillance in the field. Nolan and colleagues have recently published a review in the Journal of Medical Entomology that details the current state of scientific knowledge on alpha-gal syndrome, a severe allergy to red meat and other products containing alpha-gal sugars that can result from a tick bite. (Photo courtesy of Melissa Nolan, Ph.D, MPH)

A Diagnostic and Research Puzzle

If pinpointing the allergy’s culprits is tough, so is nailing down the disease itself. It’s difficult to define what counts as alpha-gal syndrome, because the symptoms may be inconsistent or delayed, showing up hours after consuming an allergen. Some people test strongly positive for alpha-gal antibodies but don’t have symptoms. Others hover just below the testing threshold but have severe reactions—sometimes triggered by something as subtle as meat grilling next door.

Plus, alpha-gal syndrome is underdiagnosed because it isn’t widely known, even among healthcare providers. The authors say that, in two published surveys, between two-thirds and three-quarters of providers in the United States showed major knowledge gaps about the condition.

“Some of the work that we’ve done, in addition to this paper, is showing evidence that there’s just really low physician awareness—so we don’t even have doctors thinking about it,” says Nolan. “We have some really interesting evidence to show that a third or half of people that come in with a tick bite as a chief complaint, half of them come in with alpha-gal symptoms, but they’re not actually getting diagnosed.”

It may take years for patients to receive an alpha-gal syndrome diagnosis. That’s a problem because the main treatment is eliminating sources of alpha-gal. That means avoiding not only red meat and dairy but also vaccines, antivenoms, and medications made with components derived from mammals—like the gelatin that encases many prescription and over-the-counter medications. It also means being careful with alcohol and exercise, which can make reactions worse, and knowing the symptoms of life-threatening allergic reactions like anaphylaxis.

“It really is a complete lifestyle change,” says Nolan.

There are some clues for future research—like the tantalizing fact that people with blood type B have a lower risk of developing alpha-gal syndrome, likely because B-group sugars resemble alpha-gal.

Right now, alpha-gal syndrome sits at the crossroads of evolution, shifting ecosystems, and medical blind spots. The authors say it’s a complicated condition that requires experts from many fields—medical entomology, parasitology, ecology, immunology, medicine—to come together and bring fresh insights “from the field to the bench to the bedside.”

Melissa Mayer is a science writer and the human behind Washington State University’s science cat, Dr. Universe. Email: [email protected].