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 fiber, gelatin 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.
The allergy puzzle
In 1987, Dr Sheryl van Nunen was confronted with a puzzle. She was the head of the allergy department at a regional hospital in the suburbs of Sydney, Australia, and had a reputation among her colleagues for sorting out mysterious episodes of anaphylaxis. This time, a man had been sent to see her who kept waking up, in the middle of the night, in the grip of some profound reaction.
Van Nunen checked the man for the obvious irritants and, when those tests came up negative, took a thorough look at his medical history and did a skin test for everything he had eaten and touched in the hours before bedtime. The only potential allergen that returned a positive result was meat.
Then a few more such patients came her way. There were six additional ones across the 1990s; by 2003, she had seen at least 70, all with the same problem, all apparently affected by meat they had eaten a few hours before. Groping for an explanation, she lengthened the list of questions she asked, quizzing the patients about whether they or their families had ever reacted to anything else: detergents, fabrics, plants in their gardens, insects on the plants.
“And invariably, these people would say to me: ‘I haven’t been bitten by a bee or a wasp, but I’ve had lots of tick bites,” Van Nunen recalls.
When a new disease is discovered, there is usually a long, painful period of time, before it becomes the focus of scientific research. In this case, an odd set of coincidences brought alpha-gal allergy to the attention of researchers almost as soon as it occurred in patients.
The story begins with a cancer drug called cetuximab, which came onto the market in 2004. In clinics in North Carolina and Tennessee, 25 of 88 recipients were hypersensitive to the drug, with some so sick they needed emergency shots of epinephrine and hospitalization. At about the same time, a patient who was receiving a first dose of cetuximab in a cancer clinic in Bentonville, Arkansas, collapsed and died.
News of this death soon reached Dr Thomas Platts-Mills, an allergy researcher at the University of Virginia, who saw these reactions as an intriguing research opportunity.
Platts-Mills pulled together a team, and fairly quickly, they discovered the source of the problem. People were reacting to the drug because they had a pre-existing sensitivity, indicated by a high level of antibodies (called immunoglobulin E, or IgE for short) to a sugar that is present in the muscles of most mammals, though not in humans or other primates. The name of the sugar was galactose-alpha-1,3-galactose, known for short as alpha-gal.
Team members scrutinized the patients and their famlilies 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.
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 neighbors, 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.”
The lone star tick
The question then became: what in rural Tennessee could trigger a reaction like this?
The answer arose from a second coincidence. Dr Jacob Hosen, a researcher in Platts-Mills’s lab, stumbled across a map drawn by the Centers for Disease Control and Prevention (CDC) showing the prevalence of an infection called Rocky Mountain spotted fever. It exactly overlapped the hot spots where the cetuximab reactions had occurred.
Rocky Mountain spotted fever is transmitted by the bite of a tick: Amblyomma americanum, one of the most common ticks in south-eastern USA. It’s known as the lone star tick for a blotch of white on the back of the female’s body.
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?
Dr Scott Commins, another postgraduate fellow in Platts-Mills’s group, took it upon himself to phone every new patient to ask whether they’d ever suffered a tick bite. “I think 94.6 per cent of them answered affirmatively,” he says. “And the other few per cent would say, ‘You know, I’m outdoors all the time. I can’t remember an actual tick that was attached, but I know I’d get bites.’”
Meat from mammals inevitably contains alpha-gal – so in already sensitized individuals, eating meat might constitute a second exposure, in the same way infusing cetuximab had been.
If tick bites had sensitized 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 realized, 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.”
In the middle of the night, he woke up covered in hives.
A global problem
The lone star tick doesn’t receive much attention in the USA, but its 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.
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.
What does the future hold?
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.
There may be further peril awaiting them. In June, Platts-Mills and other researchers revealed that more than a quarter of patients who came to the University of Virginia’s medical center for cardiac catheterization, to clear out life-threatening blood-vessel blockages, were sensitized to alpha-gal without knowing it.
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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.
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.”
With an increasing number of academics and institutions paying attention, research into alpha-gal might be reaching a threshold, a moment at which isolated investigations might coalesce into answers. For the patients, who feel isolated too, that can’t come soon enough.
Copyright 2015 The Wellcome Trust. Some rights reserved.