To understand the latest developments in the fight against food allergies, it helps to turn the calendar back a century.
In 1908, London doctor Alfred T. Schofield published “A Case of Egg Poisoning” in the medical journal the Lancet, in which he described treating a 13-year-old boy afflicted with egg allergies. Schofield fed the boy pills that contained infinitesimal fractions of the food: 1/10,000th to start. He increased the dosage incrementally until, eight months later, the boy could manage to get down an entire egg in one sitting without any ill effect. “It would seem that with sufficient care and patience,” Schofield wrote, “tolerance may be established in the case of the most poisonous food.”
Today, Schofield’s method is known as oral immunotherapy (OIT), a way of desensitizing the immune system to a dangerous allergen. But despite a century’s head start, OIT has yet to find a major place in food-allergy treatment. Currently, only a few hundred patients are treated this way across Canada, mostly in clinical trials and a few allergists’ practices. It’s not covered by provincial health plans.
That could change soon: A California-based company plans to submit an orally administered immunotherapy capsule for peanut allergies for approval in Canada, the U.S. and Europe this year. It’s an advance that might seem long overdue, says Dr. Julia Upton, an assistant professor in the Department of Pediatrics and the Division of Allergy & Immunology at the University of Toronto and a staff physician at Toronto’s Hospital for Sick Children.
“But our understanding of food allergies and treatment has developed enormously in just the past few years.” With more and more serious allergies affecting the population, extra time, money and medical brainpower is being devoted to breathing new life into old ideas, like oral immunotherapy, as well as to pursuing new paths of study that may, eventually, yield something like a cure.
This renewed focus is creating a surge in promising new treatments and prevention possibilities and turning over long-held orthodoxies about why a food may be harmless to one person and lethal to another.
“There haven’t really been any major advances in treatment since epinephrine,” says Dr. Eyal Grunebaum, Upton’s colleague and head of Immunology & Allergy at SickKids. “It took time for the medical and research community to respond to the severity and prevalence of food allergies. But now, there’s so much… When I look at the pace of change, it’s grown — I can’t even say how-many-fold.”
There is a broad consensus that allergies are increasing in incidence and severity. A 2015 study by Canada’s Allergy, Genes and Environment Network (AllerGen) found that more than 2.5 million Canadians are affected by food allergies, with peanuts the biggest offender by far, followed by tree nuts, fish and shellfish. Peanut allergies affect more than 2 percent of children, compared with 0.7 percent of adults — evidence of a generational increase, especially since allergies tend to stick around in adulthood. Another study, led by McGill University researcher Moshe Ben-Shoshan in 2010, found food allergies highest among those under three years old.
Fatal reactions, however, are becoming more rare. A study of anaphylaxis deaths in Ontario, published in 2013 in the journal Allergy, Asthma & Clinical Immunology, found that 28 fatal reactions between 1986 and 1998 were caused by food, compared with 12 between 1999 and 2011. (Experts assume that decline can be extrapolated across the country, since it was so significant.) The study’s authors cite Ontario’s Sabrina’s Law as a possible contributing factor. Named after Sabrina Shannon, a 13-year-old who died in 2003 at a school in Pembroke, Ont., the bill was put into effect in 2006 and mandated that every Ontario school board establish a policy for acute allergic reactions, including anaphylaxis. It inspired other provincial laws across the country.
But anaphylactic shock still claims lives in Canada: Late last year, 33-year-old Justin Matthews of Edmonton suffered a fatal reaction to walnut shells that had been used to blast paint off the walls of a fire station. The tragedy was a stark reminder that avoidance is the only strategy that most food-allergy sufferers have, and it’s by no means foolproof.
Desensitization, the underlying principle behind a pharmaceutical product like the peanut capsule (known as AR101 and developed by Aimmune Technologies), has already been leveraged to treat other allergies. “It’s the same mechanism behind allergy shots for dust mites and pollen,” says Dr. Susan Waserman, a professor in the Division of Clinical Immunology & Allergy at McMaster University in Hamilton, Ont. “The reason it was slow to start for food is in part because of uneasiness around making patients eat something potentially dangerous.” She points to an immunotherapy study conducted in Colorado in 1997, during which a child died of anaphylactic shock.
“That kind of tragedy derailed study in the area for a long time.”
Upton at SickKids served as a sub-investigator for Aimmune’s AR101 clinical trials and helped supervise the Toronto trial site. She’s now part of another clinical trial, involving more than 100 children nationwide, on OIT for milk, lead by Dr. Bruce Mazer. She cautions that while promising, OIT has its downsides: Patients should expect months or even years of regular doctor’s visits when “updosing” to higher concentrations of the allergen to reach a “maintenance dose,” followed by daily dosing at home, possibly for a lifetime. In general, OIT clinical trials have about 20 percent of patients drop out, some citing side effects like gastrointestinal distress. And for most patients, tolerance will be limited: Severely allergic kids won’t suddenly be packing PB&J sandwiches into their school lunches.
Aimmune estimates it’s possible that the capsule could be on the market in 2019, but 2020 is more likely.
Across the ocean, another pharmatech company has made big strides in the same area. France’s DBV Technologies is developing two products, Viaskin Peanut and Viaskin Milk, based on “epicutaneous immunotherapy” — using the same principle as OIT but delivered via an allergy patch. So far, results are mixed: The company announced last October that, in trials, its peanut patch resulted in increased tolerance for 35 percent of patients, all children aged four to 11. This February, though, the company announced somewhat better results in the phase II trial for its milk patch: Tolerance in the four-to-11-year- old group was 57.9 percent (though the placebo group also saw a rise in tolerance of 30 percent). Once its work is farther along, the company intends to seek FDA approval for the treatment. (It would have to go through Health Canada to be available here.)
Neither the patch nor the pill is a cure — what Dr. David Fischer, president of the Canadian Society of Allergy and Clinical Immunology, calls the “holy grail” of allergy research. “But the risk of catastrophic accidental exposure could be reduced dramatically.” Kids who prove to be a good fit for either treatment may be able to go to birthday parties and play dates without having to fear being exposed to a smidgen of a peanut. Parents will be able to send their children off to school without fretting over what might be lurking in the cafeteria. For families used to the daily background anxiety of severe allergies, lifting that burden would be a huge relief.
But an honest-to-goodness cure is still just theoretical. One promising concept is being pursued at the University of Saskatchewan, where Dr. John Gordon, a professor in the Division of Respirology, is pursuing research on “humanized” mice, those whose immune systems have been rebuilt by white blood cells from peanut-allergic humans, essentially giving the mice an equivalent immune system. Dendritic cells, which Gordon describes as “sentinels,” are key to the research. “Their job is to intercept anything entering the body,” he says, “and they cover the surfaces where foreign bodies make contact: skin, lungs, gut. They take what enters, show it to the immune system and tell it how to react.” In allergic people, the dendritic cells instruct the immune system to attack otherwise harmless things — pollen, peanuts, milk — causing a reaction.
Gordon’s research involves modifying dendritic cells to undo that response and injecting them into the bloodstream of humanized mice to reprogram their immune systems. The technique successfully reduced anaphylaxis in the treated mice, and if further studies go well, human trials might not be far off. The best-case scenario, says Gordon, is a “cure” (he’s careful to use air quotes around the term, so as not to over- promise) for 25 to 40 percent of affected individuals within a decade or so, and more modest improvements for others.
What’s better than a cure? According to Dr. Edmond Chan, head of the Allergy Clinic at BC Children’s Hospital, it’s preventing allergies in the first place. Chan was the sole Canadian contributor to an expert panel sponsored by the U.S. National Institute of Allergy and Infectious Diseases in 2016. Based in part on a 2015 NIAID study of 640 children, the panel overturned the long- held belief that young children should be shielded from potential allergens. It introduced new guidelines that suggest that exposure to peanut allergens is beneficial.
“It was inspired by previous observations about peanut allergy in Israel versus the U.K.,” says Chan. “In Israel, there are almost no peanut allergies, and it’s believed that’s because almost every child is introduced to peanuts early and eats them often, in a peanut snack called Bamba. In the U.K., and here, we have this huge hesitancy around peanuts that Israel doesn’t have.”
The theory that early introduction of allergens may help prevent development of allergies is backed by the Canadian Healthy Infant Longitudinal Development (CHILD) Study, which began to track 3,500 pregnant women in 2008 and continued to track their children up to at least age five. That study looked at the interaction between children’s immune systems and their microbiomes (the collection of bacteria and other micro-organisms in the human body) by collecting samples from blood and dirty diapers. It too found that early exposure to allergens reduces sensitivity; for example, children in the study who weren’t exposed to cow’s milk in their first year of life were nearly four times as likely to develop sensitivities.
This official change in stance was released over a year ago, though Chan says it will take some time before parents, and even some allergists, are comfortable with the concept. (Family doctors should help guide new parents through this process.)
But those already suffering will no doubt flock to products like AR101 and Viaskin that may offer relief. Chan, who was a sub-investigator on Viaskin, cautions that, while he is optimistic about the potential of immunotherapy, he foresees challenges to its widespread use. “Even if it’s safe and effective, there are still mixed feelings in the allergy community as to whether [immunotherapy] should be done outside a research setting,” says Chan. “And there’s the question of how the health care system incorporates it. Which prescription plan will cover it? Which allergists will have the time to offer it? My waiting list is 13 months already; how do you tack on all these follow-up visits for updosing appointments? It’s promising, but there are big challenges.”
Nonetheless, “promising” is more than allergy sufferers and their families have heard for a long time. A century ago, Schofield probably wouldn’t have imagined that the most advanced treatments available in 2018 would essentially be refinements of his own work. It’s not likely to be another century before the next breakthrough.
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