Small Doses

Counter-clockwise from top: StockSolutions; Bellamy Brewster; Grzegorz Wozniak/EyeEm; Magone/Getty Images

They never identified the cause. Maybe the oil that the restaurant used held traces of milk or egg. Maybe when Stefan Lainovic, only 4, laid his ice pop down on the table, a dusting of other food clung to it. Suddenly he began to sneeze. He vomited. A rash spread across his body as his face swelled. He struggled to breathe and then passed out. Thanks to an injection of epinephrine (which constricts blood vessels, raising blood pressure) and the further care of ambulance and hospital staff, he survived, but the Lainovics were changed. “That was the day we understood just how bad this could get,” says his mother, Rebecca. “We needed to engage.” She recalls how alone she and her husband, Sacha, MBA ’81, felt over the next 16 years, as they supported allergy advocacy and research. “It’s a life-threatening disability,” she says, “but it was not viewed that way then.” In the 1990s and early 2000s, people treated the couple as if they were helicopter parents or attention seekers. Though they did everything possible to give Stefan a normal life, they were constantly on guard—checking ingredients, avoiding restaurants, packing every meal he ate away from home until he was 18—and always kept an EpiPen on hand. Not until 2012, when Stefan was halfway through college, did they hear about Kari Nadeau, a Stanford professor of medicine and of pediatrics who was conducting an allergen desensitization trial. Rebecca and Sacha flew to Stanford and met with her. “No doctor had ever said these words to us before, or since,” Rebecca says. “She said, ‘I think I can help your son.’ I still get emotional. I’ll never forget that day.” 

In the United States alone, an estimated 7.6 percent of children and 10.8 percent of adults have food allergies. That’s 5 million children and 26 million adults.

Nadeau’s trial required participants to ingest powdered allergens in tiny doses that increased as they gained immunity—with the goal of full tolerance or at least sufficient desensitization that accidentally eating the allergen wouldn’t make them seriously ill. The first trial to desensitize people to multiple food allergies at once, it addressed a growing epidemic. Worldwide and among all age groups, rates of food allergies have risen from less than 2 percent in the 1950s to nearly 8 percent today. In the United States alone, an estimated 7.6 percent of children and 10.8 percent of adults have food allergies. That’s 5 million children and 26 million adults—and, Nadeau says, about half of children are allergic to more than one food. The disease demands constant vigilance, even toward foods that are supposedly safe but have been processed in facilities with allergens. For some children, just being hit by cheese during a food fight could kill them. But, though once a life sentence, food allergies are increasingly treatable. “Some people are already getting cured,” Nadeau says. With Sloan Barnett—a journalist whose son overcame allergies in the trial—Nadeau recently co-authored The End of Food Allergy: The First Program to Prevent and Reverse a 21st Century Epidemic. “Really more like the beginning of the end,” Nadeau says, since the treatments she pioneered are not yet in widespread use and she continues developing better therapies that, by adding medication to neutralize allergic reactions, have accelerated desensitization and revolutionized the field of allergy medicine. 

Understanding the treatments in Nadeau’s trial requires a foray into the medical history. The End of Food Allergy offers just that, describing the search for remedies and the epidemic’s cause. The leading theory is the hygiene hypothesis: Too much sanitization has stripped homes of the dirt and germs that strengthen children’s immune systems. “If they don’t encounter foreign microbes, blood cells that would normally differentiate between threatening invaders and innocent guests never have a chance to become trained at their job,” Nadeau and Barnett write. “As a result, our immune systems remain weak, unable to ward off infections and confused about when to attack and when to stand down.” Excess hygiene (a misnomer, the authors point out, since scientists aren’t advocating against handwashing, a crucial practice for protecting against pathogens such as SARS-CoV-2) results from reliance on bleach and antibacterials. It may also increase rates of hay fever and eczema, health conditions even more present in households where there are fewer children tracking dirt and germs into the home. 

Eczema—specifically, the permeability of dry, cracked skin—turns out to be a key driver of food allergies. In our evolution, the parasites and bacteria that entered us through the skin demanded a rapid and severe immune response, whereas the gut was primed to view foreign materials as nutrients. “The gut lining is filled with immune cells that automatically are more tolerant,” Nadeau says. “They’re like the United Nations Peacekeepers, whereas on your skin, it’s more like the Marines.” And once the skin’s cells detect an intruder, the entire immune system is put on high alert for those antigens. Certain foods—milk, egg, peanuts—are so common in households that trace amounts of them in the air and on surfaces can penetrate the eczematic skin of newborns before they are old enough to ingest them and are henceforth treated by their bodies as invaders. “Introducing foods early through the mouth,” Nadeau and Barnett write, “can make all the difference.”

While no one theory may fully explain allergies, the impoverished microbiomes of Westernized societies offer additional clues. For instance, mice that are fed the gut bacteria of human babies allergic to milk develop the same allergy. “Changes in how we live—away from animals, away from dirt, with an excessive use of antibiotics and a diet lacking a variety of plants—are the culprit behind our diminished microbiome,” the authors write.

A childhood in a moldy New Jersey houseboat had Nadeau struggling to breathe at night long before she knew what allergies were. In high school, after a counselor told her women couldn’t be doctors, she confirmed with her pediatrician that this wasn’t true. Then, to find out if she had what it took, she joined an ambulance volunteer squad. “I thought, OK, this is good. I really like to take care of people,” she says. “I like the action, and I’m not afraid of blood.” Studies followed: biology at Haverford College, then an MD/PhD at Harvard Medical School, where she met her future husband, Paul Jackson, ’88, also in the program. In 2003, the couple moved west to complete residencies at Stanford. One of her patients was a boy who died from a milk allergy. “I thought it was such a tragedy that the parents had lost their child due to something that could have been prevented,” she says. Over the years that followed, as Nadeau and Jackson started a family and raised five children (including two sets of twins), allergies became her focus.

Food allergies turned out to be complex—the ways, for instance, that the skin could be allergic but not the digestive tract, or that a transplanted organ could confer allergies on the recipient, as happened in the case of the boy who died. When his liver was donated, it gave the recipient his milk allergy. As Nadeau investigated the cellular pathways causing the cascade into full anaphylactic shock—a drop in blood pressure; a weak, accelerating pulse; the narrowing of airways; nausea and vomiting—she turned her attention to treatments.

‘I had my own little lunch table sectioned away with red tape, six feet from all my friends . . . I always felt isolated and strange.’

Fortunately, the historical record is not without references to oral desensitization. Mithridates the Great, the tyrannical ruler of Pontus from 120 to 63 BCE, dosed himself with poisons to immunize himself against plotting rivals. “For hundreds of years, the concept of desensitization has been occurring in many populations,” Nadeau says. “In the rain forest, when parents saw their children brush up against a plant and a child had a rash, they would start feeding that child the same leaf.” But whereas doctors began using injections to desensitize people with respiratory allergies to pollen or animal dander in 1911, widespread medical treatment for food allergies lagged—even though a treatment had been published in the Lancet in 1908 by Alfred Schofield, a London doctor. His patient was a 13-year-old boy who had suffered allergic reactions to egg more than 150 times: hives, swollen lips, wheezing. If he touched raw egg, his skin blistered. But over six months, Schofield fed him pills. The first batch held one-ten-thousandth of a raw egg. The next, one-thousandth, and so on. Soon, the boy was comfortable eating ever-larger amounts of egg. 

Schofield’s work was largely forgotten, and the idea of single-allergen desensitization didn’t gain traction in the medical community until the 1980s. But since desensitization can take years and many people suffer from multiple allergies, Nadeau decided to run a trial that desensitized patients to as many as five allergens at once, giving them tiny doses of the offending food proteins, which had been purified in pharmaceutical-grade facilities and approved by the FDA. 

One of the participants, Kate Kepner, then 5, was allergic to sesame, peanut, walnut, pecan, egg and milk—ingredients so common in other kids’ lunches that she faced a daily risk of going into shock simply from crumbs left behind. She couldn’t visit friends without her mother. School was worse. “I had my own little lunch table sectioned away with red tape, six feet from all my friends, kind of like with COVID except everything was normal, so I always felt isolated and strange,” says Kepner, now 15. For her, the trial’s first reward came during its scariest moment: the food challenge, when participants had to eat small amounts of allergens to prove to the researchers that they were allergic. Upon learning that touching milk gave Kepner rashes, Nadeau explained that skin has a longer immune memory than the digestive tract. When she had Kepner drink milk through a straw to bypass the skin of the lips, there was no reaction. Throughout the trial, Kepner would consume progressively larger doses of peanut, walnut, pecan, sesame and egg—but not of milk. There was no need: Once she began consuming it regularly through a straw, her immune system adjusted, and her skin lost its allergy. “That was the first absolutely life-changing thing,” her mother, Melissa, recalls. “Kari was knowledgeable and brave enough to challenge her. No other doctor would touch this. They would say, ‘Look, if I put a drop on her skin, she gets hives all over. I’m not going to have this child drink it.’ ” The trial itself took three years. Every two weeks, Kepner and her mother traveled from San Francisco to Stanford, where Kate was hooked up to an IV in case she needed rapid epinephrine delivery. By the end, she was desensitized to all her allergens. Whereas the family once made constant calculations—scrutinizing the ingredients in a new food or determining the distance to the nearest hospital—she could now attend sleepaway camps, eat in restaurants and travel at ease.

For Stefan Lainovic, who participated in the same trial as Kepner, the results were similarly dramatic. He made up for missed time at Williams College, in Massachusetts, by taking classes at Stanford. With eggs, he can now “freestyle”—has full tolerance—whereas with milk, he is slightly sensitive to large quantities. Each day, he eats a small yogurt as a maintenance dose to keep his immune system familiar with his old nemesis. “After college,” his mother says, “he traveled all over the world—the most amazing two years of his life—and he was able to experience all kinds of international cuisine.” 

‘Being a food-allergy parent is the diametric opposite of having a psychologically healthy relationship to your child.’

While desensitization has changed lives, the trial had a second arm that transformed the field of allergy medicine. It used the asthma drug Xolair, a monoclonal antibody targeting the body’s own antibodies that trigger allergic reactions. Nadeau hypothesized that it might accelerate desensitization by preventing the immune system from becoming reactive. Participants in the Xolair arm of the trial received the medication in addition to doses of their allergens, allowing Nadeau to compare the two trial groups and assess the efficacy of Xolair. The process was documented by Melanie Thernstrom in a 2013 article in the New York Times Magazine that focused on Tessa Grosso, an 8-year-old in the Xolair group who was allergic to multiple foods and had nearly died twice from accidentally eating wheat. Tessa’s mother, Kim, recalls hearing of a peanut desensitization trial before meeting Nadeau. “It would have taken three years, and she had 20 different allergies,” she says. “She would have been 60 by the time she finished all of the foods.” With Xolair, Tessa was desensitized to her five worst allergens in four months. 

Not all children completed the trial. Some experienced abdominal pain and quit; others felt too much anxiety eating their allergens; a few moved away. But for those who did finish, Thernstrom saw their families change. “Being a food-allergy parent is the diametric opposite of having a psychologically healthy relationship to your child,” she says. Parents guarded anxious children, keeping them from cultivating freedom and a sense of security. “It took a couple of years for the trauma to wear off and the nature of that parent-child relationship to ease,” says Thernstrom, whose own son, Kieran, completed the non-Xolair arm of the trial in two years. “But I saw so many families flower.”

While the success rate of those taking only the allergens was 33 percent, the Xolair group’s was much higher: 83 percent, the most successful of any multiple-allergen trial to date. Though the treatment is not yet widely available, as it’s offered by only a few private clinics, Nadeau is working on a final-phase trial funded by the National Institutes of Health, Genentech and Novartis. She anticipates that Xolair will receive FDA approval for the treatment of food allergies within the next few years.

People have a distinct way of talking about Nadeau. Rebecca Lainovic describes her as “ethereal” and “the miracle of Kari.” Maria Garcia-Lloret, an assistant clinical professor in allergy and immunology at UCLA Medical Center, says Nadeau has “the angels”—a gift for speaking to others. “She was the first to do these multi-allergen oral therapies,” Garcia-Lloret says. “A lot of people thought she was crazy.” But many have believed in Nadeau. The Lainovics, the Kepners and other families have supported her research financially. In 2014, Sean Parker, Facebook’s first president, pledged $24 million to Stanford Medicine to establish the Sean N. Parker Center for Allergy Research. As its director, Nadeau leads a team of 60, and she partners with researchers throughout the United States. One of her many collaborators at Stanford, Stephen Galli, professor of pathology and of microbiology and immunology, calls her “one of the most innovative leaders of efforts to understand the origin and, importantly, the effective prevention or treatment of food allergies.”

Published this past September, The End of Food Allergy is more than the culmination of this work. It grew from Nadeau’s own experience with a health scare, her 2004 diagnosis with a rare form of leukemia that ostensibly gave her a few years to live. She flew to the disease’s leading specialist, who told her not to do chemotherapy—that her form of the disease was caused by a virus and would pass. It did, but she was left with a sense of unease: “This really drove home that many people don’t have the same access to make a definitive decision about what they should do next. That’s why I wrote the book.” Susie Hultquist, founder and CEO of Spokin, an app that helps people manage their food allergies, calls the book “a tool and a resource like no other.” She says, “It’s really hard to get access to the front-row seat to one of the leading minds in the food allergy community.”

Recently, Nadeau co-founded SpoonfulOne, a line of baby foods containing doses of 16 common allergens to prime the immune system. She is working with a team at Stanford to develop allergy diagnostics so that children don’t risk their lives to find out what they can eat. And she is launching a new desensitization trial that combines Xolair with dupilumab, a monoclonal antibody that the FDA recently approved to treat asthma, hay fever and eczema, and that targets cytokines—inflammatory molecules underlying allergy symptoms. Whereas Xolair stops “the match that lights the fire behind allergic reactions,” Nadeau says, dupilumab can prevent the painful symptoms that make people leave trials. “We need to make sure that if the fire is going to happen, then that fire is dampened,” she says. “We need to make sure that the treatment is safer and more tolerable, and that we can get up to a 100 percent cure rate. That’s my goal.” 


Deni Ellis Béchard is a senior writer at Stanford. Email him at dbechard@stanford.edu.