Becoming allergic to meat turns your life upside down. Known as alpha-gal allergy, the condition dictates what you can eat, wear, how you relax, and even which medicines are safe. Is research finally starting to catch up?
It is early morning in early summer, and I am tracing my way through the woods of central North Carolina, steering cautiously around S-curves and braking hard when what looks like a small rise turns into a narrow bridge. I am on my way to meet Tami McGraw, who lives with her husband and the youngest of their kids in a sprawling development of old trees and wide lawns just south of Chapel Hill. Before I reach her, McGraw emails. She wants to feed me when I get there:
“Would you like to try emu?” she asks. “Or perhaps some duck?”
These are not normal breakfast offerings. But for years, nothing about McGraw’s life has been normal. She cannot eat beef or pork, or drink milk or eat cheese or snack on a gelatine-containing dessert without feeling her throat close and her blood pressure drop. Wearing a wool sweater raises hives on her skin; inhaling the fumes of bacon sizzling on a stove will knock her to the ground. Everywhere she goes, she carries an array of tablets that can beat back an allergy attack, and an auto-injecting EpiPen that can jolt her system out of anaphylactic shock.
McGraw is allergic to the meat of mammals and everything else that comes from them: dairy products, wool and fibre, gelatine from their hooves, char from their bones. This syndrome affects some thousands of people in the USA and an uncertain but likely larger number worldwide, and after a decade of research, scientists have begun to understand what causes it. It is created by the bite of a tick, picked up on a hike or brushed against in a garden, or hitchhiking on the fur of a pet that was roaming outside.
The illness, which generally goes by the name ‘alpha-gal allergy’ after the component of meat that triggers it, is a trial that McGraw and her family are still learning to cope with. In much the same way, medicine is grappling with it too. Allergies occur when our immune systems perceive something that ought to be familiar as foreign. For scientists, alpha-gal is forcing a remapping of basic tenets of immunology: how allergies occur, how they are triggered, whom they put in danger and when.
For those affected, alpha-gal is transforming the landscapes they live in, turning the reliable comforts of home – the plants in their gardens, the food on their plates – into an uncertain terrain of risk.
Alpha-gal is familiar to many scientists because it is responsible for an enduring disappointment: its ability to trigger intense immune reactions is the reason that organs taken from animals have never successfully been transplanted into people. The puzzle was why the drug recipients were reacting to it. To have an allergic reaction, someone needs to have been primed with a prior exposure to a substance – but the trial recipients who reacted badly were all on their first dose of cetuximab.
Team members scrutinised the patients and their families for anything that could explain the problem. The reactions appeared regional – patients in Arkansas and North Carolina and Tennessee experienced the hypersensitivity, but ones in Boston and northern California did not. They investigated parasites, moulds and diseases that occur only in pockets of the USA.
"The researchers wondered – if the mystery reactions shared a footprint with a disease, and ticks caused the disease, could ticks be linked to the reactions too?"
Then Dr Christine Chung, a Nashville researcher recruited to the team, stumbled on an intriguing clue. Almost one in five of the patients enrolled at a cancer clinic at her hospital had high levels of IgE to alpha-gal. But when she checked those patients’ near neighbours, treating them as a control group – that is, people who lived their lives in the same way, but did not have cancer and had no reason to have received the drug – almost one in five had antibodies to alpha-gal as well.
Almost a decade later, that correlation still makes Platts-Mills chuckle. The alpha-gal reaction “had nothing to do with cancer,” he says. “It had everything to do with rural Tennessee.”
If tick bites had sensitised them, then the alpha-gal reaction might be a food allergy as well as a drug reaction. But the connection was speculative, and cementing cause and effect would take one final, extraordinary coincidence.
As it happens, Platts-Mills likes to hike. One weekend he took off across the central Virginia hills, tramping through grassy underbrush. He came home five hours later, peeled off his boots and socks, and discovered his legs and feet were speckled with tiny dots. They looked like ground pepper, but they were dug into his skin – he had to use a dull knife to scrape them off – and they itched something fierce. He saved a few, and sent them to an entomologist. They were the larval form of lone star ticks.
This, he realised, was an opportunity. As soon as the work week started, he had his lab team draw his blood and check his IgE levels. They were low to start with, and then week by week began to climb. Platts-Mills is English – his father was a Member of Parliament – and in the midst of having his IgE tracked, he went to an event at the Royal Society of Medicine in London. “And at that point,” he says cheerfully, “I ate two lamb chops and drank two glasses of wine.”
This international company is banning meat at work
The lone star tick doesn’t receive much attention in the USA. It’s the black-legged tick, Ixodes scapularis, that has the dubious honour of being the most well-known, as it’s the carrier of Lyme disease, which causes an estimated 300,000 cases of illness in the USA each year.
The lone star tick doesn’t transmit Lyme disease, but is the vector for other serious illnesses, including Q fever, ehrlichiosis, Heartland virus, Bourbon virus and tularaemia, an infection so serious that the US government classifies the bacteria that cause it as a potential agent of bioterrorism.
While Lyme clusters in the north-east and the northern Midwest, the diseases carried by Amblyomma stretch from the coast of Maine to the tip of Florida, the Atlantic to the middle of Texas, and the southern shores of the Great Lakes all the way to the Mexican border.
And that range appears to be expanding. “The northern edge of where these ticks are abundant is moving,” says Dr Rick Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies, north of New York City. “It is now well-established further north, into Michigan, Pennsylvania, New York and well up into New England.
“Climate change is likely playing a role in the northward expansion,” Ostfeld adds, but acknowledges that we don’t know what else could also be contributing.
It’s a universal complaint among tick scientists that we don’t know as much about ticks as we should. Tick-transmitted illnesses are more common in the USA than mosquito-borne ones – according to the CDC’s most recent accounting, in 2017 tickborne diseases were 2.6 times more common than when the agency began counting in 2004 – yet it’s mosquitoes that receive the most public health attention and funding, from national surveillance programmes to local mosquito-control campaigns. (In fact, the CDC was founded in 1942 because of mosquito-borne disease; its original title was the Office of Malaria Control in War Areas.)
What is known about where ticks live, what they feed on, and how they are affected by changes in land use and climate has mostly been assembled out of the findings of scientists fighting for scarce research funding.
It’s impossible to talk to physicians encountering alpha-gal cases without hearing that something has changed to make the tick that transmits it more common – even though they don’t know what that something might be.
The lone star tick is a sturdy, stealthy predator. It isn’t picky about conditions – it tolerates the damp of Atlantic beaches, and its western expansion only stopped when it ran up against the Texas desert – and it’s content to feed from dozens of animals, from mice all the way up the tree of life.
One aspect of its epidemiology is becoming clear, though. The allergy isn’t only caused by the lone star tick.
In Australia, Van Nunen (who is now a clinical associate professor at the University of Sydney School of Medicine) couldn’t understand how her patients’ tick bites solved the mystery of their meat allergy. But she could see something else. The beaches that fringe the coast north and south of Sydney are rife with ticks. If bites from them were putting people at risk of a profound allergy, she felt compelled to get the word out.
In 2007, Van Nunen wrote up a description of 25 meat-allergic patients whose reactions she had confirmed with a skin-prick test. All but two had had severe skin reactions to a tick bite; more than half had suffered severe anaphylaxis. That abstract formed the basis of a talk she gave later that year to an Australian medical association, which was then indexed – but not published in full – in an Australian medical journal. It took until 2009 for the Virginia group to catch up to it, after they had already published their first alert.
That was unfortunate, because the crucial detail in Van Nunen’s research wasn’t just that her cases were earlier than the first round of American ones. It was that they were caused by bites from a different tick: Ixodes holocyclus, called the paralysis tick. Alpha-gal allergy was not just an odd occurrence in one part of the USA. It had occurred in the opposite hemisphere, making it literally a global problem.
And so it has proved. Alpha-gal reactions linked to tick bites have now been found in the UK, France, Spain, Germany, Italy, Switzerland, Japan, South Korea, Sweden, Norway, Panama, Brazil, Côte d’Ivoire and South Africa. These cases trace back to at least six additional tick species. (An online map on which patients list themselves includes over a dozen more countries.)
Wherever ticks bite people – everywhere other than the Arctic and Antarctic – alpha-gal allergy has been recorded. In Belgium, patients reacted badly to a drug produced in rabbit cells. In the Italian Alps, men who went hunting in the forests were more at risk than women who stayed in their village. In Germany, the most reactive food was a traditional delicacy, pork kidneys. In Sweden, it was moose.
Van Nunen herself has now seen more than 1,200 patients. “The next busiest clinic, about 350,” she says. Those cases have all occurred in two decades, less than the span of a single human generation. As in America, the surge leaves Van Nunen mystified as to what the cause might be. She reasons that the rise cannot be due to something in her patients; neither genetic nor epigenetic change could occur so quickly.
“It has to be environmental,” she says.
Because Commins was part of Platt-Mills’s earliest research, he has been seeing alpha-gal patients for more than a decade now. He estimates he has treated more than 900 men and women; five new patients arrive every week. He has coached a significant number of them back to eating some mammal products and managing their exposures to the things they can’t handle, so their worst experience is hunting for an emergency Benadryl, not being rushed to the ER.
Not every patient can do this. Julie LeSueur, who is 45 and lives in Richmond, Virginia, has been monitored by Platts-Mills for four years. (He is one of several doctors she has seen for the condition, after years of severe stomach issues escalated to repeated attacks of anaphylaxis that put her in hospital. One physician, frustrated she wasn’t getting better, told her: “This is all in your head.”)
What started as an allergy to meat expanded into reactions to anything with an animal connection, including gelatine in medications and animal products in cosmetics, and then to sensitising her immune system to an array of other irritants, from nuts to mould. She buys vegan soap and shampoo, has prescriptions formulated by a compounding pharmacy, and mostly works from home to avoid unintended exposures. Reluctantly, she cut back a hobby that meant the world to her: fostering animals that have been rescued from abuse.
“I’m at home all the time now,” she tells me by phone. “I’m lucky to get off the couch.”
Commins and Platts-Mills named alpha-gal allergy a decade ago, and Van Nunen saw her first patient 20 years before that. A lab test for the allergy, the one that Tami McGraw received, has been on the market since 2010. (Platts-Mills and Tina Hatley, now Merritt, share the patent.) That makes it hard to understand why patients still struggle to be diagnosed and understand the limits of what they can eat or allow themselves to be exposed to. But alpha-gal allergy defies some of the bedrock tenets of immunology.
Food allergies are overwhelmingly caused by proteins, tend to surface in childhood and usually trigger symptoms quickly after a food is consumed. Alpha-gal is a sugar; alpha-gal patients tolerate meat for years before their reactions begin; and alpha-gal reactions take hours to occur. Plus, the range of reactions is far beyond what’s normal: not only skin reactions in mild cases and anaphylaxis in the most serious, but piercing stomach pain, abdominal cramps and diarrhoea as well.
But alpha-gal reactions are definitely an allergy, given patients’ results on the same skin and IgE tests that immunologists use to determine allergies to other foods. That leads both Van Nunen and Commins to wonder whether the syndrome will help to reshape allergy science, broadening the understanding of what constitutes an allergy response and leading to new concepts of how allergies are triggered.
Merritt, who estimates she has seen more than 500 patients with alpha-gal allergy, has it herself; she has had bad reactions to meat all her life, since being bitten by seed ticks at Girl Scout camp, and was re-sensitised by a lone star tick bite last year. She is sensitive enough to react not only to meat, but to other products derived from mammal tissues – and as she has discovered, they are threaded throughout modern life.
The unrecognised dangers aren’t only sweaters and soaps and face creams. Medical products with an animal origin include the clotting drug heparin, derived from pork intestines and cow lung; pancreatic enzymes and thyroid supplements; medicines that include magnesium stearate as an inert filler; vaccines grown in certain cell lines; and other vaccines, and intravenous fluids, that contain gelatine.
“We have enormous difficulty advising people about this,” Van Nunen says. “Sometimes you have to sit down for seven hours, write seven emails and have four telephone conversations to be able to say to a 23-year-old woman who’s about to travel: ‘Yes, you may have this brand of Japanese encephalitis vaccine because they do not use bovine material. The vaccine is made in [cells from] the African green monkey and I have looked up that monkey and it does not contain alpha-gal.’”
Some replacement heart valves are grown in pigs; they may cause alpha-gal sensitisation that could trigger an allergy attack later. And cardiac patients who have alpha-gal allergy seem to use up replacement heart valves more quickly than normal, putting them at risk of heart failure until they can get a replacement.
"It’s hard to know how many people may be sensitised to alpha-gal without knowing it"
There’s also a growing sense that alpha-gal may be an occupational hazard. Last year, researchers in Spain treated three farm workers who developed hives and swelling and had difficulty breathing after being splashed with amniotic fluid while they were helping calves to be born. All three of them – a 36-year-old woman, a 56-year-old woman and a 53-year-old man – already knew they had alpha-gal sensitivity, but had never imagined that skin contact would be risky.
Commins has treated hunters who developed reactions after being splashed with blood after field dressing deer; those cases raise the possibility that meat-processing workers could be at risk. In the two main Facebook groups where patients gather, it’s common to hear school cafeteria workers fret about reactions from breathing the fumes of meat cooking.
Last summer, researchers working with Commins reported that people with alpha-gal allergy may have greater allergic reactions to the stings of bees and wasps, potentially endangering landscapers and other outdoor workers.
It’s hard to know how many people may be sensitised to alpha-gal without knowing it. A project at the National Institutes of Health (NIH) that studies unexplained occurrences of anaphylaxis found last year that 9 per cent of the cases weren’t unexplained after all: they were alpha-gal patients whose sensitivity had never been diagnosed.
Platts-Mills points out that the prevalence of high levels of alpha-gal IgE in his earliest studies was up to 20 per cent in some communities, “but that was absolutely not the prevalence of allergic reactions to meat,” he says. “So there are clearly plenty of people out there who’ve got the antibody but don’t have this syndrome.”
What this all means is that there are almost certainly people for whom a meat-containing meal or medical intervention could trigger an alpha-gal reaction of unknown severity.
The patients with the undetected allergy had more arterial plaque than the ones without, and, most worrisome to the researchers, their plaques were of a type that is more likely to break away from the arterial wall and cause heart attacks and strokes. Though the research is early – done in one group of 118 patients, in a known hotspot for alpha-gal – Platts-Mills worries it presages a risk for heart disease that is larger than anyone expects.
When a new disease surfaces in the USA, it’s usually the CDC that investigates, pouring epidemiologists and data scientists into the field to track down connections and bring back samples for lab analysis. But investigation of alpha-gal is caught in a bureaucratic quirk of federal science. The CDC is responsible for infections spread by insects and arthropods – but alpha-gal syndrome is not an infection. That makes it the responsibility of NIH – which has abundant lab scientists, but no shoe-leather disease detectives.
NIH does seem to be taking an interest. In June 2018, it hosted an invitation-only one-day IgE-mediated Meat Allergy Workshop; in the past, such meetings have indicated the giant agency is considering launching a research programme. But just reading the workshop’s programme provides a hint of how new alpha-gal research is; participants called the problem by multiple different names, displaying that there isn’t even yet any agreed nomenclature for it. Similarly, the US-run universal search engine for journal articles, PubMed, indexes papers on alpha-gal under “allergy to galactose-alpha-1,3-galactose”, “mammalian meat allergy”, “delayed red meat allergy”, “galactose-α-1,3-galactose syndrome” and more.
In August, Commins gave a talk on alpha-gal allergy at the International Conference on Emerging Infectious Diseases, a conference held every two or so years and sponsored by the CDC that often surfaces the earliest signals of illnesses that are destined to become big problems.
The CDC’s director of foodborne illness was in the audience; so was its director of vector-borne diseases, the department that deals with ticks. Afterwards, they both zoomed up to ask him questions. “I kind of had the impression this was just a weird, small thing,” Dr Lyle Petersen, the vector-borne director, told him. “But this seems like kind of a big deal.”
