EXPERT ANALYSIS FROM THE 2015 AAAAI ANNUAL MEETING

HOUSTON (FRONTLINE MEDICAL NEWS) – In central Virginia, where IgE-mediated delayed allergic reactions to red meat have become the most common cause of anaphylaxis in adults, physicians have taken to looking for what they call the ‘Mossy Oak sign.’

“If a patient shows up in a blaze-orange cap and hunter’s camouflage fatigues, an allergy fellow will tell me, ‘There’s a positive Mossy Oak sign in room 2,’ and I know that probably means the patient has delayed anaphylaxis to alpha-gal,” Dr. Scott P. Commins said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Alpha-gal is short for galactose-alpha-1,3,-galactose, an oligosaccharide present on thyroglobulin and other tissues in nonprimate mammals. It’s not normally present in humans, but when a lone star tick (Amblyomma americanum) that has fed on a nonprimate mammal bites a human, the alpha-gal is transferred, eliciting serum IgE antibodies.

Mossy Oak is a popular brand of hunter’s camouflage clothing. A positive Mossy Oak sign is useful in clinical practice because a patient who presents to a medical clinic dressed in hunting regalia is someone who spends a lot of time outdoors in the woods and fields where ticks lurk. He’s also typically someone who enjoys eating red meat. And whether it’s venison, beef, pork, lamb, goat, or bison, it contains alpha-gal. The result, in a patient who’s been primed via tick bite, can be a life-threatening anaphylactic or urticarial reaction arising 3-6 hours later, explained Dr. Commins, an allergist at the University of Virginia, Charlottesville.

He and his coinvestigators have played a central role in the still-unfolding story of this novel disease involving late-onset anaphylaxis to mammalian meat. Dr. Commins was the lead author of the paper that first described the syndrome ( J. Allergy Clin. Immunol. 2009;123:426-33 ), as well as a subsequent paper that established the lone star tick as the culprit, making this syndrome the first known example of a response to an ectoparasite giving rise to a serious form of food allergy ( J. Allergy Clin. Immunol. 2011;127:1286-93 ). More recently, the investigators have shown that alpha-gal-specific IgE does not cause or worsen asthma ( Am. J. Respir. Crit. Care Med. 2012;185:723-30 ).

In a wide-ranging talk, Dr. Commins addressed the diagnosis and management of delayed anaphylaxis to red meat. He also touched upon some provocative emerging issues, including the possible risks posed by placing a porcine heart valve or bioprosthetic ligament in a patient with serum IgE antibodies to alpha-gal.

The investigators stumbled upon the phenomenon of tick-transmitted delayed anaphylaxis to red meat while they were trying to unravel the explanation for the markedly regional occurrence of IgE-mediated hypersensitivity reactions to the chimeric monoclonal antibody cetuximab (Erbitux) previously reported in the oncology literature ( J. Clin. Oncol. 2007;25:3644-8 ). Dr. Commins and his colleagues realized that the same southeastern and south-central states where reactions to the initial infusion of cetuximab were concentrated were the states where the lone star tick abounds.

Incidentally, scientists at the Centers for Disease Control and Prevention follow the lone star tick closely because it is the primary vector for ehrlichiosis. CDC researchers say the tick’s range is steadily expanding and now includes 28 states, with New York’s Long Island a hot spot.

There is no public health requirement to report serum IgE-mediated delayed reactions to red meat, so the exact number of affected patients is unknown. But it’s clear that many thousands of individuals are affected, and estimates are being revised upward as the novel syndrome becomes more widely known. The disorder is common in Europe and Australia as well.

Classically, IgE-mediated anaphylactic reactions occur within 5-30 minutes after exposure to the offending agent. Thus, the 3- to 6-hour delay in symptom onset in patients with a reaction to the alpha-gal in red meat is remarkable; the explanation for the time lag remains unclear.

Dr. Commins and others have shown that individuals with serum IgE antibodies to alpha-gal also typically have serum IgE antibodies to cat, dog, beef, and pork, but not to egg, peanut, chicken, fish, or house dust mite.

Diagnosis of IgE-mediated urticarial or anaphylactic reactions to mammalian meat is made on the basis of the presence of serum IgE antibodies to alpha-gal. Dr. Commins recommended considering the diagnosis and ordering the blood test in the setting of new-onset anaphylaxis in a patient who enjoys hunting or other outdoor activities in a state where the lone star tick is found, particularly if the symptoms occur at night, hours after a big meat-heavy meal. A history of recent or persistent tick bites is an obvious clue.

“Also, it’s striking how many patients develop palmar erythema and itching during an episode. Not all report it, but when they do it’s usually a pretty good giveaway that they might have IgE to alpha-gal,” according to the allergist.

He added that it’s entirely reasonable to order a screening test for IgE to alpha-gal in patients in lone star tick–abiding states whose anaphylactic reactions seem to occur randomly without an apparent trigger.

Dr. Commins and his coinvestigators have assembled a database of roughly 500 of their patients with IgE to alpha-gal, about half of whom have a history of atopy. The investigators have found that an individual’s atopic status has no bearing on IgE antibody titer or the severity of the delayed reactions. Moreover, neither the alpha-gal IgE antibody level, the ratio of alpha-gal-specific IgE to total IgE, nor IgG antibodies correlate with reaction severity, he continued.

Based upon their study of 45 affected children, Dr. Commins and coworkers concluded that the clinical presentation and serum IgE pattern are the same as in adults ( Pediatrics 2013 May [doi:10.1542/peds.2012-2585]). Since that publication, however, the investigators have realized there is a subgroup of affected teenagers who present with GI symptoms, he added.

Turning to disease management, Dr. Commins said he advocates an avoidance diet that eliminates mammalian meats, rich desserts, and super-premium ice cream.

“I also counsel patients to avoid broths, gravies, and anything that might be a mystery sauce,” he said. “You’d be surprised at how many people with alpha-gal order chicken at a Mexican restaurant thinking that they’re doing the right thing and end up reacting. I don’t know exactly why it happens, so I just say ‘avoid mystery sauces.’ Dairy and cheese are actually fairly well tolerated, although soft cheeses, like brie, can cause a reaction.”

Reactions are inconsistent, and symptoms can vary from episode to episode. Cofactors are a concern, with exercise and alcohol tending to make patients more sensitive to an alpha-gal exposure. The degree of risk posed by vaccines containing gelatin constitutes an emerging and unresolved issue.

“We’ve heard of several reactions to the shingles vaccine because of the gelatin, and the MMR vaccine is also on the radar,” Dr. Commins said.

Implantation of porcine bioprosthetic heart valves in patients with serum IgE antibodies to alpha-gal has been associated with reports of early valve failure; all bioprosthetic valves contain alpha-gal unless they’ve been decellularized. In addition, Dr. Commins is familiar with a case at another university in which three separate attempts to place a bioprosthetic ligament during repeated arthroscopic knee surgeries failed in a patient who had a “screamingly high” level of IgE to alpha-gal.

“I think this bioprosthesis issue is yet to be resolved,” he added.

One audience member, a Texas allergist, said she has a lot of trouble convincing her patients who are avid hunters to give up eating red meats. Dr. Commins said he faces the same issue.

“There is a recalcitrant group that just wants to eat a side of beef every day. I tell them if you’re not going to be on an avoidance diet, at least avoid the fattier cuts and don’t eat tremendous amounts. We believe that the antigen is possibly a glycolipid. Those cuts of meat that are high in fat are the ones patients tell us over and over again give them the worst reactions,” he said.

“The inconsistency of the allergic reactions keeps some patients from taking this disease seriously,” the allergist added. “What eventually happens for some patients is they end up having a really bad reaction. And then that convinces them.”

He monitors affected patients’ alpha-gal IgE levels over time. If and when the IgE becomes negative, he recommends a food challenge test. The patient comes in at 8 a.m., eats three pork sausage patties, and spends the day under observation at the clinic, walking the stairs periodically since exercise is a cofactor. If the challenge goes off without a hitch, the patient is free to go home at 4 or 5 p.m. In the past, that was the patient’s ticket to clearance to safely eat a big meat meal with alcohol, but Dr. Commins has pulled back of late from that recommendation.

“We believe that additional tick bites can make the allergy come back. So if someone passes a challenge in October and then the following spring gets more tick bites, you may have set them up to have a reaction because you’ve told them they can eat meat again. So the utility of a negative food challenge is unclear unless you’re pretty confident a patient is not going to have more tick bites,” he explained.

Dr. Commins reported receiving research grants from the National Institutes of Health to conduct his studies on delayed anaphylactic reactions to red meat. He serves on speakers bureaus for Genentech and Teva.

bjancin@frontlinemedcom.com

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