Don't Kill the Birthday Girl

by Sandra Beasley

  There’s even an experimental treatment specific to this theory, Helminth therapy, which posits that circulating small amounts of a parasitic worm ova (Trichuris suis, pig whipworm) through the body will desensitize those with food allergies. The effects of the residency of the worm itself are benign; the point is to give the immune system another target. Patients mix a vial of the ova with water or juice and drink it. Given that in recent years the breakfast industry has marketed every imaginable variety of orange juice—no pulp, extra pulp, calcium added, homestyle, pineapple blend—if this Helminth experiment proves fruitful, I’m looking forward to the “Now with an infusion of whipworm” campaign.

  Though it is intuitively appealing, the Hygiene Hypothesis falters under logical scrutiny. The theory might justify why food allergy has surged in developed countries more so than in undeveloped countries. But why would incidence spike in inner-city settings, not rural environments? New York City basements and alleys don’t lack for dirt.

  Another hypothesis aims an accusing finger at the uptake of folic acid by pregnant women, who are hoping to ward off other birth defects. There’s no purported mechanism of causation in place, but some find it a compelling concurrence that the 1980s saw both the rise of folate supplements and the rise of allergies in children.

  Alternately, some point toward the correlation between vitamin D deficiency and skyrocketing rates of asthma, dermatitis, and allergy. I find it a stretch that low vitamin D levels would foster asthma, and not the other way around. After experiencing a few attacks, the kid with the inhaler is rarely the one rushing out to play kickball in the sunshine. And yes, the mother of a kid with eczema is going to slather him in sunscreen.

  Within the world of allergists, the question of “why is this happening?” is moot in the short-term. The phenotypes of allergy sufferers are too diverse to draw meaningful conclusions based on contributing factors of lifestyle or ethnicity. Within the world of allergy research, the focus is on treating existing food allergies. That’s where the suffering is palpable, and that’s also where the money is. As Michael Pollan has argued, groups pursuing research often have to accept partial sponsorship for their clinics from those who profit from management, not prevention.

  Most doctors believe desensitization is the key to treatment. For many years, allergic rhinitis has been predominantly treated by allergen-based injections. But there is another way. Injections were actually preceded—as early as 1905, in Germany—by experiments in administering minute dosages of allergens via droplets under the tongue.

  Around 1910, New York pediatrician Oscar M. Schloss took on the case of a child, age two, with suspected egg allergy. His mother had noticed that when her son played with empty eggshells, hives broke out on his hands and arms. At the age of fourteen months, the boy had also exhibited extreme hives around the tongue and mouth after being given a soft-boiled egg to eat. That was the first egg the boy had ingested since a preliminary exposure at the age of ten days, when a bout of diarrhea had been treated with barley water and raw egg white. This was a common folk-cure of the time; barley water is still used today, minus the raw egg.

  Schloss tested for allergy by injecting a guinea pig with the boy’s blood, then feeding egg to the guinea pig. The guinea pig, which had previously tolerated egg, responded with symptoms of shock.

  Schloss decided to treat the boy by mixing water with the white of a raw egg, diluting it over and over, and then finally feeding it to him. No reaction. The next day, he administered the same “medicine,” diluting it a little less. No reaction. He did this the next day, and the next, each time making the solution stronger, until the boy could eat eggs in moderation. In 1912, he published the results of his treatment, suggesting that oral desensitization was a reliable option. But the enthusiasm for hypodermic treatment, as pioneered by Leonard Noon and John Freeman, had taken a firm hold on the market the year before, and would remain the dominant mode throughout the twentieth century.

  The notion of taking treatments by mouth has been resurrected today under the terms sublingual immunotherapy (SLIT) and oral immunotherapy (OIT). With SLIT, a solution is deposited and held for one to two minutes under the tongue. The optimal frequency and duration of treatment has yet to be determined. SLIT offers the advantage of requiring only the tiniest amount of allergen, which, because it is internalized without going through the gut-based process of digestion and absorption, combines efficacy with an exceptionally low risk of anaphylaxis.

  The SLIT method of treatment has been overshadowed by its younger brother, oral immunotherapy. In OIT, substantive milligrams of an allergen are ground up or otherwise reduced, combined with another food substance, and ingested daily in increasing amounts. Side effects, which are essentially minor reactions, tend to be limited to sneezing, nausea, hives, and vomiting—not bronchial distress—though there is a higher risk of anaphylaxis than with SLIT treatment. Doctors seem to prefer it as a technique, perhaps because it is mimetic of everyday eating, and they can envision a more natural transition from in-office to at-home treatment.

  Most OIT treatments are paced over a matter of months if not years. But there has been preliminary investigation into “rush oral immunotherapy” (ROIT), which accelerates exposure by doubling the dosage each time (unless there is anaphylactic reaction) and administering it multiple times over the course of two weeks or less.

  The second morning of the AAAAI conference, I was invited to attend a press forum on the latest developments in treatment for food allergies. I picked up a cup of sour (but free) coffee en route to grabbing my seat. We were being given audience with three top allergists, which could literally be referred to as the “A team”: Hugh A. Sampson, Robert A. Wood, and A. Wesley Burks. They were experts I had seen quoted in article after article, without ever knowing the faces behind the names. One by one, they were introduced.

  Dr. Hugh Sampson, of Mount Sinai School of Medicine in New York City: spectacled, straightforward, hair slicing a quadratic curve across his forehead.

  Dr. Robert Wood, of Johns Hopkins Children’s Center in Baltimore: A shock of Santa-worthy white hair and, again, delicate eyeglasses. The word disarming comes to mind. This is, after all, the man who wrote Food Allergies for Dummies.

  Dr. Wesley Burks: That thin nose. That expression, both mild and grave. Oh. Oh! Apparently I had met Dr. Burks, aka chief of the Pediatric Allergy and Immunology Division at Duke University, aka one of the world’s top five experts in food hypersensitivity, the day before. When I mistook him for some guy from FAAN.

  I hoped he did not remember me.

  The AAAAI organizers had assembled this panel to discuss, in part, the latest results from a number of OIT experiments (and, to a lesser extent, SLIT experiments) being conducted across the country. The lead story concerned a trial headed by Dr. Burks, coordinated between Duke University and the University of Arkansas for Medical Sciences, in which oral immunotherapy treatment appeared to increase the threshold levels (the amount of allergen that can be ingested sans reaction) among a group of peanut-allergic children.

  The children who had received OIT, versus placebo treatment, expanded their thresholds from 315 milligrams, a fraction of a peanut, to 5,000 milligrams—approximately fifteen peanuts. In another set of just-released experimental results, fifty-five egg-allergic children between the ages of five and eighteen had been randomized to receive OIT, using either egg whites or a placebo. In subsequent food challenges given forty-four weeks into OIT treatment, more than half of the forty who received OIT egg whites “passed” by ingesting egg without reaction; not one did from the control group. Taken together, these studies were a testament to the potentials of OIT.

  These are the kinds of experimental outcomes that, by the time they land in USA Today or the New York Times, are wrongfully portrayed as promising a cure for allergy. The news stories are often illustrated by a stock photo of a smiling child at the lunch table. Because the media doesn’t measure success in milligrams, they round up to the near
est breakthrough even if it is at the cost of accuracy. The questions become, Can they eat scrambled eggs for breakfast yet? What about a peanut butter sandwich?

  Reporters are not the only ones quick to hop to the lily pad of a cure. Doctors, facing constant queries from parents, are anxious for these trials to yield a practical course of treatment—one covered by health insurance.

  “Everyone in the medical community asks, ‘Can I take this back to my office now?’ ” Dr. Wood told us.

  But as the doctors at the heart of the research were quick to caution, we are not there yet. Not by a long shot. OIT has to be recalibrated every time the patient suffers breathing distress, and any number of things outside the doctor’s control can derail treatment, from viral infection to exercising too soon after exposure.

  One of the biggest gaps between what the media reports and what researchers deliberate over is the gap between desensitization and tolerance. There is accumulating evidence for the ability to induce desensitization, in which allergens do not cause reactions as part of a steady, ongoing exposure trial. But we are only just beginning to test the ability to maintain tolerance, in which the subject can digest an allergen safely in the absence of supervised treatment.

  In other words, as doctors ask among themselves, What happens when the oral immunotherapy stops? Will the child resensitize? Need there be an artificial supplement, a daily pill like a vitamin, that guarantees allergen exposure?

  In addition to the study that desensitized children to peanuts, Duke and the University of Arkansas staged a study that looked at establishing residual tolerance. Twelve children who completed between thirty-two and sixty-one months of OIT, to the point of being considered desensitized to the allergen, were retested with an oral food challenge four weeks after going off treatment. Nine of the twelve subjects passed.

  On one hand, that’s great that nine children could then add peanuts to their diets. On the other hand, that’s a 25 percent rate of relapse. For three families, all the progress earned with years of time-consuming and nerve-racking treatment unraveled in one month. Even for those who didn’t relapse after one month, what is to say that they won’t relapse after three months, or six?

  “None of us—and each of us sees food allergy patients—” Dr. Burks said, looking at his colleagues. “None of us would practice this now.”

  Scientists are also looking at the difference in reaction levels among allergic children to “baked” variations on food, in which the food’s protein has been heated or denatured. The key is epitope diversity. An IgE antibody reaction is triggered by the antibody’s recognition of a site on the allergen molecule—an epitope—that matches the IgE’s target pattern. Because this epitope is rendered in three dimensions, it may appear as designed, with the amino acids in sequence (the “sequential epitope”), or it may be altered, folded over itself so that nonadjacent acids are juxtaposed and seem as if they are in sequence (a “conformational epitope”).

  When a food is prepared—microwaved, sautéed, creamed, hydrolyzed, roasted, and so on—each process renders a conformational epitope. A child with limited epitope recognition who eats the food in one of these variant forms might fool her IgE antibodies into overlooking it. A child with diverse epitope recognition reacts regardless.

  Figuring out the role of epitopes has helped explain some of the quirkier mysteries of food allergies. Take allergies to shellfish, historically one of the most troubling and persistent of the “big eight.” It turns out that those allergic to shellfish typically have especially diverse epitope recognition: they are primed to recognize traces of shellfish in any form, whether raw or cooked or reduced to its broth.

  Or look at nuts. One of the reasons there is so much overlap within the sphere of nut allergies is that the epitope patterns are so similar. A person with walnut allergy might react to a macadamia protein not because she is allergic to macadamia but because her body mistakenly reads the epitope as being from walnut. Some scientists wonder if the rise of peanut allergies is related to the fact that most commercially available peanut butter has become hydrogenated, which changes its prevalent epitope shape. In stabilizing peanuts for the sake of storing them in a jar, we may have destabilized their consistent ability to be recognized as food by the body. The body attacks what it does not see as nourishment.

  On a pragmatic level, doctors are relieved to find a justification for many of the troubling contradictions they hear while taking case histories. “All of us have, in the past, had mothers come in and report that the child ‘tolerated a cupcake,’ ” Dr. Sampson said. “Doctors were uncomfortable with that—we weren’t thinking about it in terms of the structural molecular shift.” The mothers weren’t crazy. In some cases children reacted to raw milk only. Baked milk snuck past their immune systems.

  Sitting in the audience, I had to keep reminding myself that this was a press conference, not storytelling hour. I craved the chance to share my firsthand experience. Despite having a confirmed egg allergy, for years I ate tempura on occasions when well-meaning waitresses assured my parents there was no egg. They thought we were asking about fresh egg, I’m sure. They didn’t think about batters with dried, premixed ingredients. While some of the tempura batters might have been a Westernized quick-fry of flour, as I learned more about traditional Japanese cuisine, I became certain there was more than one occasion when I was exposed to egg. But the allergen was in such a thoroughly denatured form, its epitope such a weird variation on its natural shape, that I did not react.

  Once I wised up, I couldn’t enjoy tempura anymore. Yet by then I was into sushi, and I would order the occasional sushi roll with imitation crab or spicy tuna. Eventually I figured out that these, too, probably contained small amounts of egg. Why hadn’t I ever reacted? I had always been too embarrassed to ask Dr. Latkin, my allergist, expecting to be chided for even risking an allergy attack.

  I wish I had that kind of occasional tolerance when it came to dairy. Many do. A 2008 survey published in the Journal of Allergy and Clinical Immunology estimated that 75 percent of the children living with cow’s-milk allergy could tolerate extensively heated milk. As the panel pointed out, this is an extremely encouraging statistic for two reasons: One, it has potency as a predictor for those who may outgrow their allergy. Two, it means that if these children undergo OIT, there is a form of the allergen that can be administered with reasonable confidence that anaphylactic reaction will not occur.

  Dr. Sampson led the research team behind the 2008 baked-milk study. His hope is to develop a blood-assay test that can dentify the baked-milk-tolerant majority, who can then adopt an allergy management plan that—instead of preaching 100 percent avoidance—includes some common dairy-containing foods.

  But as he told the audience, his team is struggling with the fact that not all baked-milk products are alike. They had begun by challenging patients with muffins and waffles, with consistent success. Yet when they switched to using pizza (“because that’s what everyone wanted,” he said), 15 percent of those who could tolerate a muffin could not tolerate pizza. The problem was probably that the cheese offered an overly concentrated exposure to casein. The next goal was to see if puddings could be deemed safe—which would be a boon to parents everywhere trying to pack school lunches for an allergic child. But puddings, which combine a high dairy concentration with a low cooking temperature, have proven particularly difficult.

  As I listened to these doctors talk more about immunotherapy options, I realized that—beyond a little good fortune with baked egg—I was a clinical terror. So many of these preliminary success stories include a preface, early on, of potential subjects who had been excluded because they would be “poor candidates” for further treatment. Those candidates typically had especially elevated IgE levels (like me) or a tendency to react to a particularly diverse range of allergen epitopes (like me) or multiple allergies (like me).

  Will there be a division, a generation from now, between those with “treatable” and “chronic” fo
od allergies?

  One recent survey of six hundred charts from the Jaffe Food Allergy Institute showed that 78 percent of allergy patients between the ages of four and eighteen are avoiding an average of three to four allergens. Even if you discount those avoiding foods out of mere phobia, this suggests pediatricians are, by and large, treating patients with multiple allergies. What are the treatment options for those with more than one severe food allergy?

  “That’s where the Chinese medicine approach comes in,” said Dr. Sampson.

  Along with a colleague, Dr. Sampson has developed what is being called the Food Allergy Herbal Formula–2 (FAHF-2), currently under review by the FDA. This formula draws on centuries of practice by Chinese physicians, who have traditionally treated illness with herbs such as Qu Mai (Dianthus superbus), known for its pink flowers and its power to “move the blood.” FAHF-2 combines nine herbs and would be administered in tablet form; upon ingestion, the herbs appear to release compounds that bind with IgE to the point of preventing anaphylaxis. Because it is not allergen specific, the formula has the potential to quell reactions even in a patient with multiple allergies.

  Treatment with FAHF-2 is unlikely to prove tantamount to a cure. But it might decrease sensitivity in a patient, like me, with perpetually and particularly elevated IgE levels. I could accept my allergies in terms of continuing to limit my diet but be able to live without fear of anaphylaxis from accidental allergen contamination. Or I could have the option of safely pursuing additional OIT or SLIT.

  With the same purpose, some allergy patients have been experimentally treated with the anti-IgE monoclonal antibody omalizumab (known by its trade name, Xolair). Xolair is usually given to those with persistent and life-threatening asthma that has proven resistant even to high dosages of corticosteroids. But the cost of this drug, which was developed using recombinant DNA technology and appears to require a lifelong course of treatment, is exceptionally high—ten to thirty thousand dollars per year—not to mention that its long-term effects are unknown.