In the December 2015 issue of Annals of Allergy Asthma and immunology, I saw a letter written in response to an earlier article called “Epidemiological and Clinical Predictors of Biphasic Reactions in Children With Anaphylaxis”, which had somehow escaped my eagle eye. The original article said that about 15% of children experiencing anaphylaxis who went to the emergency department had biphasic reactions, that is delayed reactions that may occur up to 72 hours after the initial event, urging EDs to prolong observation to a minimum of six hours after even mild reactions. The letter writers said, “The authors [of the original piece] did not discuss the reactions after observed exposure to allergenic foods, such as those exposures during oral food challenges (OFCs) or oral immunotherapy (OIT) dosing.”
The authors continue, “We are concerned that adopting a recommendation for an extended period of observation may deter allergists from performing an OFC, an important and underused procedure.”
We have been following this issue on and off around here, recently with a piece by Dr. Scott Sicherer called “Who’s afraid of the food challenge?” and further back with Paul’s response to a survey showing fewer than half of allergists had learned to do OFCs during their training. In that survey, the reasons respondents gave time (3-4 hours), low reimbursement, and risk of adverse events as the top three reasons for not doing them.
With that threshold in mind, no wonder the authors of this new letter were concerned. If 3-4 hours are a burden, what will happen when 6 hours is on the table? When I looked at the names of the letter writers, I was delighted to see that one of them was our contributor and my friend, Anna Nowak-Wegrzyn of the Jaffe Food Allergy Institute at Mount Sinai along with doctors from Israel and Philadelphia, so I reached out to her. (The other authors are Yitzhak Katz, MD, of Assaf Harofeh Medical Center in Tel Aviv, Israel, and Jonathan M Spergel, MD, PhD, of Children’s Hospital of Philadelphia.) – Henry Ehrlich
AAC: Thanks, Anna, for taking your time to answer questions for our readers. First, why do biphasic reactions happen?
Dr. Nowak-Wegrzyn: During an acute, IgE-mediated allergic reaction, caused by food or other allergen, basophils and mast cells release previously formed chemicals, so called mediators, such as histamine and tryptase that are responsible for the early symptoms of anaphylaxis. In some patients, a second phase of anaphylactic reaction may occur and it is caused by the release of newly synthesized mediators such as leukotrienes or cytokines that are produced by the activated mast cells or basophils and usually are released within few (2-4) hours from the onset of the reaction.
AAC: How did this letter come to be written? Your co-authors are not people whom you meet around the water cooler. One is in another U.S. city and one in a distant country.
Dr. Nowak-Wegrzyn: Yitzhak Katz and Jonathan Spergel and I are colleagues and share special interest in food allergy. We have spoken before about the importance of oral food challenges for the diagnosis and management of food allergy and share the concern that food challenges are underutilized by the physicians caring for patients with food allergy.
AAC: You have administered food challenges—double-blind placebo-controlled and unblinded—and also done OIT in a research setting. What do these procedures involve that makes them less likely to result in a late-phase reaction than an emergency case?
Dr. Nowak-Wegrzyn: Food challenges are done in a very controlled and careful manner, the patient is usually fasting before the challenge and the food is eaten in gradually increasing amounts. Fasting means empty stomach and no interference from the other foods in the GI tract that may delay the absorption of the allergic food, causing delayed onset of symptoms caused by a larger dose of the allergic food. The patient is examined carefully to identify any signs of an allergic reaction before each dose of the challenge. These precautions allow the physicians to capture allergic reaction at an early stage at the lowest possible amount of the allergic food and treatment is initiated immediately without any delay. In contrast, none of these factors are controlled during a food allergic reaction at large and as such, these “spontaneous” reactions are usually associated with a higher amount of the ingested food allergen, delayed recognition of the symptoms and delayed administration of epinephrine, compared to a physician-supervised oral food challenge. More severe initial reactions seem to be associated with a higher likelihood of second-phase of anaphylaxis.
AAC: Could you talk about the severity and sequence of treatment? You say in the letter that they are typically brief and easy to treat.
Dr. Nowak-Wegrzyn: In my experience, true biphasic reactions are very uncommon in the setting of an oral food challenge, less than 2%. When we reviewed our data, we found that among 568 positive food challenges performed in the inpatient hospital and in the ambulatory unit, 62 reactions were treated with epinephrine, and there was 1 biphasic reaction (1.6%) This patient had a delay in onset of his initial anaphylactic symptoms, which did not occur until an hour after the OFC had already been discontinued because of milder symptoms. His anaphylactic symptoms responded to the initial dose of epinephrine but reoccurred after an hour and required administration of a second dose of epinephrine.
AAC: Because the study is retrospective, it’s possible some of the reported biphasic reactions were actually “prolonged” reactions. Could you describe the difference and tell us whether it’s important for patients to be able to distinguish?
Dr. Nowak-Wegrzyn: Biphasic means that initial symptoms go away, with or without treatment and then re-occur after few hours. Prolonged anaphylaxis describes a reaction in which initial symptoms do not resolve completely and then re-escalate within few hours.
AAC: Finally, you mention late phase or biphasic asthma reactions, which may last for several days, as opposed to the usually brief episode with food allergies. Why do the asthma attacks last so long by comparison?
Dr. Nowak-Wegrzyn: Asthma has a different immunologic mechanism, in which T lymphocytes play an important role, e.g. by producing inflammatory mediators and cytokines that affect other allergic cells. In a food-induced anaphylaxis, there is probably less involvement of T cells and less accumulation of the allergic cells, which in turn don’t contribute to the ongoing symptoms.
AAC: Thanks for your time and expertise.
Dr. Anna Nowak-Wegrzyn is one of the leading authorities on food allergies in the world. She is a clinician and clinical researcher in the Jaffe Food Allergy Institute at Mount Sinai Medical Center in New York City. Her research interests, funded by in part by the National Institutes of Health and Food Allergy Initiative, include: egg and milk allergy, food-induced anaphylaxis treatment and risk factors, diagnostic issues in food allergy, food protein-induced enterocolitis syndrome and pollen-food allergy syndrome (oral allergy). She formerly chaired the Adverse Reactions to Food Committee of the American Academy of Allergy, Asthma & Immunology and was President of the New York Asthma & Asthma Society.