“I just laid down on the bathroom floor and called for my husband . . . A minute or two later, I felt the itching on my hands and then on my feet, and I looked around, and it was everywhere—hives, just intense itching. We decided it was time to go to the emergency room.”—JOANNE, alpha-gal allergy sufferer

Have you ever heard of alpha-gal syndrome?

I hadn’t, until I met with a friend earlier this month in Chapel Hill, and she told me she had been diagnosed with this unusual syndrome. Alpha-gal syndrome is an allergy to red meat that a person develops after a lone star tick bites him/her and transmits a sugar molecule called alpha-gal. I’m serious! The sugar is the allergen.

Joanne, whom I quote above, had a full-blown allergic reaction in October 2016 after eating “two very small ribs.” First, she had severe gastrointestinal distress; then the hives came. She was 65.

Alpha-gal is not a tick-borne disease; it’s a tick-borne allergy. If you’ve never heard of it, either, it may be because alpha-gal syndrome, which is characterized by a delayed allegic reaction after eating red meat, has only recently been identified. Also, many people who have the allergy don’t know they have it.

Just eating a hamburger or a few spare ribs can bring on a full-body case of intense hives or a severe bout of nausea, vomiting, and diarrhea, or even life-threatening anaphylaxis in people who, like Joanne, have been eating hamburgers and spare ribs all of their lives without incident.

I told my friend Linda I always knew she was an alpha gal. This alpha-gal, however, is short for galactose-alpha-1,3-galactose, which allergist and immunologist Dr. Scott Commins, of the University of North Carolina Dept. of Medicine, described in a Sept. 12, 2017 UNC podcast as “a carbohydrate or sugar that has two galactose sugars linked in an alpha-1-3 linkage.”

Dr. Commins is an associate professor in UNC’s Division of Rheumatology, Allergy, and Immunology and Thurston Arthritis Research Center. He is also a nationally recognized expert in alpha-gal syndrome. The UNC allergist trained as an allergy and immunology fellow in the University of Virginia lab where, and when, the first alpha-gal allergy cases were identified and studied.

Although scientists in Georgia reported in the late 1980s upon what were most likely 10 cases of alpha-gal allergies caused by tick bites, they did not publish their findings, nor did the Georgia Allergy Society or the U.S. Centers for Disease Control and Prevention follow them up. It was not until 2009, when the U.Va. research team, led by Thomas A.E. Platts-Mills, M.D., Ph.D.,  published a report of 24 cases of “delayed anaphylaxis to red meat,” occurring after tick bites, that alpha-gal syndrome gained research traction.

Interestingly, before they made the tick bite-red meat-allergic reaction connection, Dr. Platts-Mills and his colleagues grappled with what Dr. Commins calls in the “Alpha-Gal Allergy—with Dr. Scott Commins” podcast the “cancer side of alpha-gal.”

Starting in 2004, more than 20 percent of the patients who were receiving intravenous infusions of the cancer drug, cetuximab, in clinical trials developed sudden-onset alpha-gal syndrome and experienced anaphylactic-type reactions. A few fatalities occurred. Most of the affected patients lived in the southeastern United States, which, it turned out, not coincidentally, is a hotbed region for ticks. (I’ll return to the cancer story later.)

ALPHA-GAL SUGAR AND TICKS

Chemists and those inclined toward chemistry will understand what Dr. Commins means by an alpha configuration. The rest of us need know only that alpha-gal sugar, which coats some proteins, is present in non-primate mammals, such as cows, sheep, pigs, and even dogs and cats, but we humans don’t have it. We can make an immune response to alpha-gal sugar, however—producing what are known as IgE (immunoglobin E) antibodies— if we eat foods that are derived from species that have it.

While most of us who are non-immuno-compromised eat these kinds of animal products without becoming reactive to the alpha-gal sugars in them, some of us become reactive, i.e., allergic. Those who do react produce a novel IgE response that is different from typical IgE responses directed toward protein allergens. (Allergies are caused by exposure to substances called allergens or, more generally, antigens. Most food allergies are caused by protein allergens, such as peanuts, not by sugars.)

Much of Dr. Commins’s research is focused on why some people react to alpha-gal, while others don’t.

My friend Linda, who lives in the woods, became potentially allergic after she was bitten by a lone star tick, which carries alpha-gal molecules from the blood of the animals it commonly bites.

Linda is outdoorsy and tick-savvy. She covers her arms and legs and wears boots when she’s out in her woods, and she checks herself for ticks regularly. She knew that she had been bitten by a lone star tick, which also transmits unwelcome diseases, and told her primary-care physician during a subsequent checkup about it. Her doctor did a screening blood test and diagnosed her with alpha-gal, before Linda, who is largely a vegetarian, had experienced any symptoms. She had never heard of it.

Since her diagnosis, my friend has avoided eating beef, pork, and lamb—“anything essentially that has hooves and walks on four legs,” Dr. Commins says, adding venison, bison, and buffalo to the list—or anything that may be cooked in a stock with these meats and has felt fine. Dr. Commins also discourages ice cream consumption.

According to the UNC medical professor, only a “small fraction” of people who test positive on an alpha-gal blood test actually develop allergic responses after eating red meat. That’s good news.

Contrary to what you may assume, lone star ticks do not come from Texas. They are named for the white, star-shaped spots on their backs (see above) and primarily live in the southeastern United States. Only the females transmit alpha-gal sugar and disease. With warmer winters prolonging tick seasons, lone-star-tick populations are starting to spread farther north and west. Like many of their tick “cousins,” they travel on deer.

In the podcast, Dr. Commins cautions that lone star ticks should not be assumed to be the only cause of alpha-gal syndrome. The allergy exists in Australia, Europe, and parts of Asia where the lone star tick does not.

Most people with alpha-gal syndrome do not know they have alpha-gal until they become ill, which typically does not occur, according to Dr. Commins, until four to six weeks after a tick bite, at which point the patient may have forgotten about the bite, if he/she even noticed it.

Besides the lapse in time between a tick bite and allergic symptoms, there is a two- to six-hour delay between the eating of red meat and the development of an alpha-gal reaction. These delays make alpha-gal easy to overlook.

To diagnose alpha-gal, Dr. Commins says, a physician relies on two-fold proof: 1) a clinical history; and 2) a positive blood test.

CLINICAL HISTORY: SYMPTOMS

Because the red-meat allergic reaction doesn’t start until an average of three or four hours after eating a hamburger or a steak, most alpha-gal allergy sufferers are stricken during the night when they are asleep. One explanation for the hours-long delay, Dr. Commins says, is that the digestive process for fat takes that long. In contrast, most allergic responses to food, such as peanuts or eggs, are immediate.

The alpha-gal allergic reaction often begins with intense itching, particularly on the palms and soles of the feet. It then spreads to the rest of the skin.

“We have patients tell us repeatedly that their hands begin to itch and turn red,” Dr. Commins explains. “Then they often get systemic hives all over their skin. [The process usually] starts with skin and itching and hives and redness, perhaps swelling, then [patients] often tell us that they feel light-headed, so we think their blood sugar is dropping. Often there is a gastrointestinal component to this as well—so really severe abdominal cramping, diarrhea, nausea, vomiting—all the hallmarks of an anaphylactic allergy reaction.”

In a Sept. 19, 2017 University of North Carolina Dept. of Medicine podcast that Dr. Commins did with Joanne, one of his alpha-gal allergy patients, the allergist says that he worries when two organ systems—the skin being one—are involved in the reaction.

If a patient just has hives, then he or she can probably manage the reaction with an antihistamine, such as Benadryl®. It there is second organ system involved—typically, the gastrointestinal system and/or the cardiovascular system (blood-pressure changes)—then Dr. Commins advises the patient to call 911 or go immediately to the emergency department of a local hospital. The reaction can be life-threatening.

Joanne, who is a Duke University professor, describes waking up around 2 a.m., feeling nauseated and having extreme and sudden “gastrointestinal distress.” Her face was flushed and very hot. After having severe diarrhea, she started feeling itching on her hands and feet, “and I looked around,” she says, “and it was everywhere—hives, just intense itching.”

She went to an emergency room with her husband and was treated for anaphylaxis: “They gave me some fluids. They gave me maybe two Benadryl tables, and then just observed me, and after a while I was fine.”

The emergency physicians did not diagnose Joanne with alpha-gal. Instead, they referred her to her primary-care physician, who happened to be at UNC. She did some computer research and came up with the possible alpha-gal diagnosis, which the physician herself had never made. Armed with the tentative alpha-gal diagnosis and with the knowledge that, as a gardener, she received many tick bites, Joanne pretty much diagnosed herself, through Internet research, before she saw Dr. Commins.

Joanne had eaten red meat her whole life, without any difficulties. She had even eaten meat every night for several consecutive nights before the consumption of those “two very small ribs” that induced her allergic distress and brought her to the bathroom floor.

HYPERSENSITIVITY & CETUXIMAB

Judging from her symptom description, Joanne probably did not experience anaphylaxis.

According to the online Mayo Clinic, anaphylaxis, which is a severe hypersensitivity induced by exposure to an allergen, is characterized by:

*Difficulty breathing

*Rapid, weak pulse

*Dizziness or lightheadedness

*Drooling and inability to swallow

*Full-body redness and warmth (flushing)

Anaphylactic “shock” occurs when there is a sharp drop in blood pressure, along with breathing difficulties, hives, and itching. Such shock can be fatal.

“Hypersensitivity reactions are a classic side effect of cetuximab,” write French researchers in a 2014 oncology journal article in which they report upon three cancer patients in Normandy, France, who developed life-threatening symptoms with cetuximab treatment, one of whom died. (See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116358/.)

Elsewhere, they write that “Hypersensitivity reactions are a classic side effect of monoclonal antibodies.”

In 2004, when ImClone and Bristol Meyers Squibb were investigating the monoclonal antibody, cetuximab, in clinical trials for treatment of metastatic colorectal cancer, they did not know about this “classic side effect.” Early in their studies, however, it became clear that the antibody was causing hypersensitivity reactions, primarily in patients in a group of southern U.S. states. (Very roughly speaking, monoclonal antibodies are one type of substitute antibodies formed in a lab and used in cancer immunotherapy.)

Cetuximab was produced in a mouse cell line, not in human cells. According to Dr. Commins, patients who received this intravenous medication reacted “on the order of one in five or one in four on first infusion.”

“These reactions . . . developed rapidly and symptoms often peaked within 20 minutes following or during the first infusion of the antibody and occasionally proved fatal,” write Drs. Commins, Platt-Mills, and John W. Steinke in a 2015 article, “The Alpha Gal Story: Lessons Learned From Connecting the Dots.” Because of marketing delays, it was not until 2006 that the true severity of the reactions became obvious.

Eventually, the U.Va. researchers deduced that the mouse cells—mice being one of the species that make alpha-gal—were “decorating” the cancer drug with alpha-gal sugar, so that when the medication was given to people who were alpha-gal allergic, they reacted.

At the same time, Dr. Commins says in a podcast, Dr. Platt-Mills and he were seeing patients in the U.Va. Asthma and Allergic Disease Center who were not on cancer drugs, but were telling us, “Hey, doc, I think I’m allergic to beef (or pork, or lamb) but it doesn’t happen every time, and it happens in a delayed way.”

Dr. Platt-Mills had developed a blood-screening test for alpha-gal allergy to use in the cancer-drug context. He and Dr. Commins applied it to clinic patients with a meat allergy, and “that opened the Pandora’s box,” Dr. Commins says. A CDC map of the incidence of Rocky Mountain Spotted Fever in the United States and, ironically, Dr. Platts-Mills’s own experience with a tick bite and a meat-eating allergic reaction helped the researchers to make the eventual causative connection.

Both the clinical-trial cancer patients and the walk-in clinic patients who experienced allergic reactions had been bitten by lone star ticks. Amazing.

THE GOOD NEWS

The best news about alpha-gal syndrome is that it appears to be a transient allergy, not a life-long immune response. Besides taking Benadryl upon the appearance of symptoms, Dr. Commins recommends using EpiPen or epinephrine auto-injector, which is used for other allergies. Epinephrine is the same as adrenaline.

In an excellent July 2018 New York Times Magazine article about alpha-gal, Dr. Commins suggests that an enzyme in the tick’s saliva may work as an immunological adjuvant, essentially telling the bite victim’s immune system to see alpha-gal as a threat that warrants an allergic reaction.

If he is correct about the enzyme being “what it is about the tick that creates this risk,” then the development of an allergy shot that uses this salivary component may not be that far off. An allergy shot would desensitize people with alpha-gal and prevent future allergic reactions.

In the meantime, you know the tick drill: Cover up and tuck in; use insect repellant on your exposed skin, clothing, and gear; keep your dog on a leash; tick-proof your yard by clearing brush and leaves; and check yourself, your children, and your pets for ticks.

Ticks are rarely higher than knee-high–contrary to the myth that they fall from trees–but they have an unnerving habit of crawling up your skin, once they’re aboard.

Ann, 8/31/18

UNC podcast with Dr. Scott Commins, Sept. 12, 2017:

https://www.med.unc.edu/medicine/news/chairs-corner/podcast/alpha-gal

UNC podcast with Dr. Commins and Joanne, Sept. 19, 2017:

https://www.med.unc.edu/medicine/news/chairs-corner/podcast/alpha-gal-patient