A perspective on the pediatric death from oral food challenge reported from the Allergy Vigilance Network
Authors: Julia Upton, Montserrat Alvaro, Kari Nadeau
Journal: Allergy (2019)

The current edition of Allergy contains a report of 18 food allergy deaths from the French Anaphylaxis Vigilance Network (AVN) from 2002 to 2018.1 The AVN maintains a database of food allergy-related severe anaphylaxis formed of voluntary, structured reports of anonymous patients submitted by allergists. Therefore, no population estimates can be made, but important cases can be revealed. All deaths from food allergy are tragic events. Fatal anaphylactic deaths were associated with both nonclinical and clinical settings. Lack of food allergy diagnosis, nonavailability, or delayed use of adrenalin auto-injectors (AAIs), and lack of an individual healthcare plan at school were some of the factors cited as contributing factors to deaths associated with anaphylaxis in nonclinical settings such as schools, homes, and restaurants. The data make clear the importance of making AAIs more accessible and the need to educate individuals, school staff, parents, and caregivers on signs of severe allergic reaction and timely use of AAIs in cases of anaphylaxis. Fatal anaphylactic deaths were also associated with hospitals and doctors' offices. This report deserves further consideration because it describes the first known oral food challenge (OFC)-related death from Europe and the second OFC-related death reported overall. The first was in 2017 in which a 3-year-old boy died after a baked milk challenge in a Children's Hospital in America.2 In this current report, an 11-year-old boy died after an OFC was performed in a hospital setting to confirm peanut allergic reactivity prior to beginning oral immunotherapy (OIT). Severe bronchospasm and cardiovascular failure occurred after a cumulative reactive dose of 16 mg peanut protein. He died despite prompt epinephrine injection and infusion, resuscitation, and ICU admission. The need for accurate diagnoses of food allergy to achieve the best care of patients is indisputable. OFCs are the most accurate method for food allergy diagnosis. Ruling out food allergy, as well as a confirmed diagnosis of food allergy, improves quality of life and avoids unnecessary avoidances and potential nutritional deficiencies.3 Delayed introduction of foods, especially peanut, increases the risk of allergy to the delayed food. Potential treatments of food allergy, such as OIT, are expensive and time-consuming and need to be directed to those with confirmed food allergy.4 Multiple factors are considered when offering and interpreting OFCs. Patient selection (eg, age, history of asthma, allergy testing results), food, location (hospital or clinic), and OFC stopping criteria (eg, objective criteria or subjective) can be used to triage patients to home, office, medically intensive settings, or to defer OFCs.5 When OFCs are performed for confirmation of food allergy, the risk of reaction, eliciting dose, and severity of reaction may be very different than if the OFC is intended to rule out food allergy. Most children undergoing challenges to rule out allergy are at a low risk of reaction because of a lack of recent history of reactions, low allergy testing results, or a history suggestive of tolerance. In this scenario, severe reactions to OFC performed in a pediatric hospital clinic setting are very low. The rate of allergic reaction in a survey of five pediatric food allergy centers in the United States found only 14% had a positive challenge and just 2% experienced anaphylaxis.6 An international multi-center survey of hospital-based challenges of 1634 children found 32% failed the OFC and the dose required to elicit a reaction in 10% of patients, the ED10, was 20 mg (95% CI: 15,25).7 In comparison, the reaction rates are higher and eliciting doses lower in confirmatory challenges. In 1445 OFCs in Stanford-initiated OIT treatment protocols, 73% reacted to ≤500 mg food protein and the 347 peanut food challenges had an ED10 of only 1.52 mg (95% CI: 0.89, 2.15) protein.8 While these OFC failure rates were high, even in these highly selected patients in which food allergy was strongly suspected, 27% did not have an allergic reaction, further illustrating the need for this diagnostic procedure.8 Furthermore, in 74 patients with food allergy confirmed for a clinical trial, 39% were treated with epinephrine.9 These higher risk, lower threshold confirmatory OFCs are expected to become increasingly in demand as food allergy therapies continue to be adopted. Despite careful patient selection and planning, the OFC maintains a risk of anaphylaxis and therefore a very small risk of death, even in a hospital setting. Clear and informed consent from the patient and family of the risks and benefits of the procedure specific to their situation is paramount. The exact risk of death to an OFC cannot be provided because the overall number of OFCs which resulted in two reported deaths over decades is not known, although it is clearly very low. Thousands of confirmatory OFCs have been performed in pediatric trials without death. Furthermore, an EAACI task force, the Food Immunotherapy Practice Nation Differences Across Europe (FIND) project, surveying 146 centers in Europe has not reported any deaths from OFC (Alvaro, un-published data). Patient access to OFC is currently limited. More than 50% of allergists surveyed cited time limitations and the risk of adverse event as barriers to offering OFCs.10 Currently however, the OFC remains a powerful tool in food allergy diagnostics, with a long track record of safety in both clinics and clinical trials. The two reported deaths from OFC will further push the allergy community to seek the safest possible approaches to the accurate diagnosis of food allergy. There are ongoing research efforts to refine the OFC procedure, as was recently reviewed.2 For example, appropriate total food doses may reduce false-negative OFCs, a single-dose OFC approach of only 1.5 mg of peanut protein may allow the identification of very low threshold reactors with only a mild allergic reaction, higher fidelity monitoring may detect reactions earlier, and research for improved biomarkers to confirm or rule out allergy may reduce the need for OFC. Currently, the OFC remains the gold standard for food allergy diagnosis. National and international registries on food-associated anaphylaxis are key to provide a better understanding of the risk factors for anaphylaxis and assist with guidelines for implementing better preventative measures both in clinical and nonclinical settings.