Abstract
Purpose of Review
This review aims to provide an update of recent advances in the epidemiology, clinical features and diagnosis, and management of food-induced anaphylaxis (FIA).
Recent Findings
Food allergy prevalence and FIA rates continue to rise, but FIA fatalities are stable. Basophil and mast cell activation tests promise more accurate identification of food triggers. Oral, sublingual, and epicutaneous immunotherapy can desensitize a significant portion of subjects. Epinephrine use for FIA remains sub-optimal.
Summary
As the burden of food allergy continues to increase, it appears that the corresponding increase in research focused on this epidemic is beginning to bear fruit. The stable number of FIA fatalities in the face of an ongoing epidemic indicates lives have already been saved. The emergence of new diagnostic tests and interventional therapies may transform the management of FIA in the coming years.
Similar content being viewed by others
Introduction
IgE-mediated food allergy is a serious worldwide problem of increasing prevalence. The most feared outcome of food allergy is anaphylaxis: a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergen [1]. While fatalities due to food allergy are quite rare, the constant vigilance and lifestyle modifications necessary for those living with food allergy can have profound effects on quality of life (QoL) [2,3,4,5]. Significant unmet needs exist in our abilities to accurately diagnose and manage food-induced anaphylaxis (FIA), but progress has been made in recent years with new diagnostic methods and promising therapeutic options under investigation.
Epidemiology
Food allergy affects approximately 1 in 13 children and 2 to 3% of adults in the United States (US) [6, 7], while challenge-proven rates reach nearly 10% in Australian children [8]. Lifetime prevalence of anaphylaxis due to all causes is estimated to be between 1.6 and 5.1% in the US [9]. Food is the most common cause of anaphylaxis in children and young adults and about 40% of the US children with food allergy experience severe reactions [10]. An ED visit due to FIA occurs every 6 min on average in the US [11]. Nearly 10% of Australian adolescents with food allergy report symptoms consistent with anaphylaxis annually [12]. A recent prospective study in Denmark found that food was responsible for 61% of anaphylaxis in children and 17% in adults [13•]. In recent years, emergency department visits and hospitalizations due to FIA have increased, but only a single Australian study indicated a parallel rise in fatalities [14,15,16, 17••, 18, 19].
Fatal Reactions
Turner et al. [20••] reviewed recent reports on food anaphylaxis deaths and illustrated that in the general population the rate of fatal food anaphylaxis (0.03 to 0.3 deaths per million person years in the general population) [21•, 22] is comparable to that of death due to lightning. Even among those with known food allergy, the rate is about 1 per one million person years, which is orders of magnitude lower than death by accident, murder, or fire (Fig. 1). As such, a diagnosis of food allergy does not significantly affect overall mortality risk, although patients and caregivers still perceive the risk as significant [23]. Rates of fatal food anaphylaxis vary geographically from an estimate of 0.04 per million person years in the US [14] to 0.08 in Ontario, Canada [16], 0.09 in Australia [18], and 0.12 in the United Kingdom (UK) [17••], although reasons underlying this variation are unknown.
The most common food triggers of fatal anaphylaxis worldwide are peanut and tree nuts [20••], while milk is commonly implicated in young children [17••]. This pattern of food triggers has been replicated in most studies from Europe and the US. Regional variations of food triggers exist, with seafood the culprit in up to 50% of deaths in Australia [18]. While egg allergy is very common in young children, it is rarely implicated in deaths [20••].
Factors associated with fatal FIA have been identified through case series (Table 1) but, as discussed later in this text, severity of individual reactions cannot be accurately predicted. Sampson et al. noted delay in epinephrine administration beyond 30 min from reaction onset in fatal but not near-fatal FIA in their landmark 1992 report [24]. This association with delayed epinephrine use has been observed in numerous subsequent studies [16, 18, 25, 26]. Improved rates of epinephrine autoinjector (EAI) prescriptions have been documented [17••] and a corresponding increase in use of epinephrine could plausibly explain the discordance between rising FIA rates and stable fatality rates. However, fatalities do occur despite rapid administration of epinephrine [25, 28] and clinical trial evidence that epinephrine can prevent fatalities is absent [29] for ethical reasons. Rates of FIA and hospitalization are highest among infants and young children, yet fatalities are very rare at these ages, while adolescents and young adults in the second and third decade of life are overrepresented in series of FIA deaths [14, 17••, 18, 19]. Prior reactions to foods are commonly noted, but are not always severe [17••], possibly related to the age at the time of the reactions. Asthma has been noted in 70 to 75% of fatalities in recent series [17••, 18] and even greater proportions of earlier series [24,25,26, 30, 31]. Severe respiratory symptoms predominate in fatal FIA, with cardiovascular comprise occurring secondarily as a result of respiratory failure [32]. While intuitively this association should inspire more aggressive asthma treatment in patients with food allergy, asthma control has not been clearly proven to affect risk of death [20••]. Other fatality risk factors include use of alcohol or recreational drugs [18] and upright posture [27], while evidence is inconsistent for associations with African American [19] or UK-resident South Asian race [17••], multiple food allergies, and acute illness [33].
Non-Fatal Reactions
Patterns of food triggers for non-fatal anaphylaxis mirror those for fatal reactions, with peanuts and tree nuts predominating while milk is common in infants and younger children [13•, 15, 34,35,36]. Food was the most common specified trigger for anaphylaxis leading to PICU admission in North America from 2010 to 2015, with peanut (45%), tree nuts/seeds (19%), and milk (10%) as the main culprits [37]. Nut allergy was associated with triple the likelihood of anaphylaxis compared to other food allergies in Australian adolescents [12]. More severe reactions to milk and egg are associated with persistent allergy into adolescence instead of resolution by school age [38, 39]. Regional variations in patterns are noted, with peanut strikingly uncommon in Portugal [40] and walnut and pine nut common in South Korea [41]. Another Korean study listed seafood, meat, and grains including wheat as more common triggers than nuts [42]. There is evidence in Western countries that ethnicity may affect risk of anaphylaxis. Patients of Asian ethnicity are disproportionately affected [15, 35, 37]. While Hispanics have the lowest rates of FIA, their rates of ED and hospital visits for FIA are increasing rapidly [15, 34].
Clinical Presentation and Diagnosis
Anaphylaxis is a clinical diagnosis with rapid onset after allergen exposure of symptoms affecting the skin and mucous membranes (urticaria, angioedema, pruritus, flushing), respiratory tract (cough, shortness of breath, wheezing, stridor), gastrointestinal (GI) tract (abdominal pain or vomiting), and/or cardiovascular system (light-headedness or syncope) [1]. Diagnostic criteria include rapid onset of symptoms and either mucocutaneous involvement after possible allergen exposure plus respiratory compromise and hypotension; involvement of two or more systems rapidly after exposure to a likely allergen; or hypotension after exposure to a known allergen [1]. In FIA symptoms typically occur within minutes to a few hours of ingestion, with cutaneous symptoms (typically urticaria) most common and usually associated with respiratory (cough, wheeze, stridor) and/or GI symptoms (abdominal pain, vomiting) [34]. The diagnosis of anaphylaxis is often missed, in part because of wide variation in clinical symptoms and a plethora of potential underlying causes and triggers [43•].
FIA is much more likely to include respiratory symptoms than hypotension as prominent clinical features, and most deaths are due to respiratory arrest, with cardiovascular collapse occurring as a late result of respiratory collapse [17••, 31]. While this may be due to comorbid asthma, many food allergic patients without a diagnosis of asthma also have bronchial hyperreactivity that may predispose to severe reactions [44, 45]. Presentation may also vary by age, with infants experiencing hives and vomiting, young children presenting with wheezing and stridor, and adolescents reporting “difficulty breathing” or “trouble swallowing” [34].
Anaphylaxis is under-diagnosed, with as few as 13% of children and 6% of infants that meet criteria receiving the diagnosis at the time of ED discharge [34]. Infants and younger children are unable to describe symptoms and some potential indications of reaction overlap with normal behavior (e.g., crying, irritability, drooling). Adolescents often fail to recognize symptoms as anaphylaxis, with less than half of anaphylactic reactions being self-identified as such in a recent Australian study [12]. Lack of cutaneous symptoms has been identified as a factor leading to failure to recognize and promptly treat anaphylaxis, with resulting poor outcomes [25].
Two atypical forms of FIA should also be mentioned: food-dependent exercise-induced anaphylaxis (FDEIA) and delayed anaphylaxis to red meat due to allergy to galactose-apha-1,3-galactose (α-gal). In FDEIA, patients can tolerate both the culprit food (most commonly wheat) and exercise separately, but if the food is eaten within several hours of exercise, the result may be anaphylaxis [46]. In alpha-gal allergy, first described in 2009 [47], the allergen is not a protein but rather a sugar moiety present in all non-primate mammalian tissues and reactions may be idiosyncratic. The presentation typically involves delayed onset (3 to 6 h post-ingestion) of severe cutaneous symptoms [48] and sensitization has been linked to tick bites [49, 50]. A recent report indicates a prominence of abdominal symptoms and more rapid onset among rural South African patients [51].
Clinical Course
The clinical course of FIA varies, but usually includes rapid onset of symptoms and rapid resolution after treatment. In a recent cohort study of pediatric hospitalizations for FIA, symptoms resolved while in the ED 92% of patients and inpatient interventions were needed in only 16% of patients, most commonly albuterol administration in those with a history of asthma [52]. One can reasonably assume that most of these patients were admitted despite symptom resolution to monitor for biphasic reactions, which occur in about 4.6% of anaphylactic reactions overall and less frequently in FIA [53]. The disproportion between admissions and need for interventions likely reflects the lack of clear predictors for biphasic reactions [53, 54]. A recent analysis found that prior anaphylaxis, unknown inciting trigger, and delayed epinephrine increased risk of biphasic reactions [54]. Identification of further factors could help distinguish which patients need prolonged observation after resolution of symptoms and which can be safely discharged after shorter observation periods.
Tryptase in FIA
The diagnosis of anaphylaxis is clinical, and laboratory tests are not included in diagnostic criteria. Serum tryptase has been used to confirm mast cell activation in anaphylaxis triggered by venom [55] and drugs [56]. Such elevations have not been seen consistently in fatal or near-fatal FIA [24], although tryptase elevation was noted in 6 of 8 fatal food reactions in one early study [57]. A recent prospective study showed that tryptase levels increased from baseline and peaked at 2 h in positive peanut challenges in adults [58•]. Levels rose by a median of 78% among patients with anaphylaxis, but remained in the normal range (≤ 11.4 ng/mL) for 10 of the 14 anaphylactic reactions and all non-anaphylactic positive reactions. The increases seen were significantly larger than inter-day variation in baseline levels. Severe anaphylaxis occurred in all four cases where tryptase rose above normal. These findings may not be generalizable to children or infants, especially considering that baseline levels are elevated in infants, more so in those with atopy [59, 60]. Other investigators have observed smaller peaks in tryptase during food-induced reactions as opposed to allergens delivered rapidly and directly into the systemic circulation (anesthetics, intravenous drugs, venoms) [61]. It remains unclear whether the smaller rise in tryptase during FIA is due to slow allergen absorption, differences in patterns of mast cell activation and secretion (e.g., mucosal GI tract mast cells secreting tryptase into GI lumen), or lower tryptase content in mucosal mast cells [62]. Basophils contain much less tryptase than mast cells [63], so it has also been proposed that basophil activation may play a more prominent role in food-induced reactions [24].
Identification of Food Triggers
The clinical determination of food allergy as the cause of anaphylaxis is generally suggested by the history and confirmed with documentation of sensitization to the suspected food trigger with skin-prick testing and/or serum food-specific IgE measurement [64]. Predictive cutoff values for skin-prick test wheal size [65,66,67] and serum food-specific IgE [68,69,70,71,72] have been established for many foods. Skin testing can be performed safely even in patients with prior episodes of FIA. Broad panels of food-specific IgE testing are not recommended due to poor specificity leading to overdiagnosis [73]. The basophil activation test (BAT) and component-resolved diagnostics have shown promise in predicting the likelihood of reactivity to foods, especially when traditional tests are inconclusive [74, 75]. However, the BAT is limited by the requirement for fresh blood and the fact that 10 to 15% of patients have uninterpretable results due to basophils unresponsive to IgE-mediated stimuli. Santos et al. recently described a novel mast cell activation test (MAT) using LAD2 mast cells and patient plasma, which allows for use of stored samples [76]. The MAT was not as sensitive as the BAT, but did allow for conclusive results in subjects with nonresponsive basophils. A separate report by Bahri et al. found that MAT, using human blood-derived mast cells (hMCs) cultured from peripheral blood precursors, outperformed conventional tests and BAT, with patterns of MAT reactivity correlating with reaction phenotypes upon peanut oral food challenge (OFC) [77•]. Another emerging diagnostic tool is a recently developed nanoallergen platform, which has been used to identify immunogenic epitopes on the major peanut allergen Ara h2 and may further improve diagnostic precision [78••].
While history and testing often suffice to establish a diagnosis of FIA and confirm the food trigger, OFC (specifically double-blind placebo-controlled food challenge or DBPCFC) is the gold standard for diagnosis of food allergy and may be performed safely in the office of experienced allergists [64]. OFC is often done when history and initial tests are inconclusive or to assess for the development of tolerance. Detailed instructions for the safe performance of OFCs have been published by a workgroup report of the AAAAI [79] and will be updated in the near future. With the recent recommendation for early peanut introduction [80] based on the results of the landmark LEAP study [81], the need for OFCs in infants has greatly increased and practical guidance has been published [82]. For standardized OFCs performed in research settings, the PRACTALL guidelines offer strict parameters for OFC protocols [83]. OFCs are associated with improved food allergy specific health-related quality of life and reduced parental burden [84]. However, OFCs are not risk-free. There has been a single death reported as a result of an OFC, which occurred in a 3-year-old boy after baked milk OFC [85•], and other reactions have been severe enough to require hospitalization and intensive care support [86, 87]. While OFC remains the gold standard for confirming a diagnosis of food allergy, the high specificity in vitro tests such as the BAT and MAT may allow more accurate diagnosis with fewer OFCs and therefore less risk in the future.
Predicting Reaction Severity
Much effort has been expended in the attempt to identify factors that predict severe food-induced reactions and better risk-stratify patients. Such factors may be specific to the trigger (higher risk with peanut, tree nuts, shellfish, milk, and wheat; lower risk with egg and soy) or the patient (higher risk with past anaphylactic reactions, increased age, asthma, allergic rhinitis) [86, 88•, 89]. Reaction outcomes are also influenced by treatment decisions such as timing of epinephrine administration.
Allergen-specific skin-prick test wheal size and serum IgE can suggest the likelihood of reaction upon ingestion [64], and component-resolved diagnostics may further improve diagnostic accuracy [75, 90, 91]. However, such markers do not reliably predict reaction severity. Analysis of 583 entry DBPCFCs for highly sensitized subjects in a phase 3 peanut OIT study showed no association between markers of peanut sensitivity (peanut SPT mean wheal diameter, peanut-specific IgE, or Ara h2-specific IgE) and severity of reaction [92]. Another recent study found that although several factors were independent predictors of severity (age, SPT, eliciting dose (ED), allergen-specific IgE, reaction time, and severity of accidental reaction), even in combination, they explained less than 25% of the variance, leaving reaction severity largely unpredictable [93]. BAT has correlated with reaction severity in some studies [90, 94] but not others [95, 96]. The MAT as performed by Santos et al. also showed some predictive value regarding severity of OFC reactions, with excellent sensitivity and NPV but poor PPV [76].
Given the inability of individual markers to predict reaction severity, more comprehensive predictive models have been studied. Sugiura et al. developed promising models to stratify risk for egg, wheat, and milk OFCs with predictive scores that incorporate factors such as age, allergen-specific or component-specific IgE levels, total IgE < 1000, and complete allergen avoidance [97,98,99]. Chinthrajah et al. proposed a clinical severity scoring system for peanut allergy with scores ranging from 1 to 6 based on threshold of sensitivity combined with a severity clinical indicator meant to indicate a reaction severe enough that most clinicians would treat with epinephrine [100]. Machine learning procedures then determined that the BAT (ratio of CD63+ basophils after stimulation with peanut vs. anti-IgE) was most predictive of severe reactions, and developed an algorithm incorporating threshold BAT values and clinical factors (history of exercise-induced asthma and FEV1/FVC ratio below 80%). Validation of all these models in further studies will be needed before widespread application. It is important to note that severity as predicted by each of these models is actually a composite measure of both reaction severity and reaction threshold. While intuitively a severe reaction that occurs at a low dose indicates more severe allergy than if the same reaction occurs at a much higher dose, the evidence for correlation between threshold dose and reaction severity is lacking [93, 101, 102].
Management of FIA
Acute Management
Successful management of anaphylaxis requires rapid recognition followed by prompt removal of any suspected triggers, rapid assessment of circulation, airway, breathing, skin, and weight [103]. Patients should be placed in a supine position unless doing so worsens respiratory status, as upright posture has been associated with poor outcomes [27]. Epinephrine is the first-line treatment for anaphylaxis and should be administered intramuscularly without delay in the mid-outer thigh at a dose of 0.01 mg/kg utilizing the 1:1000 formulation (max dose of 0.5 mg) or an epinephrine autoinjector (EAI) [104,105,106]. EAIs have long been available in 0.15 and 0.3 mg doses. The need for a 0.1 mg EAI has been recognized [107], and the first such product is now available for use in infants. In a canine anaphylaxis model, epinephrine had no therapeutic effect when administered after shock fully developed [108]. Such studies cannot be done in humans for ethical reasons, but anaphylactic deaths are clearly associated with delay in epinephrine administration [24, 31].
There are no absolute contraindications to epinephrine use in anaphylaxis but adverse events range from accidental self-injection (often from use of live epinephrine instead of training device and rarely significant) [109] to cardiac events including stress (Takotsubo) cardiomyopathy [110] and myocardial infarction (usually in the setting of underlying coronary artery disease) [111]. It may be difficult to differentiate such events attributable to epinephrine from allergic vasospastic angina (Kounis syndrome), a rare complication of anaphylaxis that results from inflammatory cytokines released by mast cells [112]. Cardiac events and epinephrine overdose in general occur more commonly with IV than IM administration [113]. Shaker et al. published a recent review of epinephrine adverse events and also used computer simulation and Markov modeling to predict epinephrine-associated death in 0.07% of recipients [114]. The model is limited by the accuracy or lack thereof of the FDA reports of epinephrine AEs on which it is based. The authors also noted that with an assumed 10-fold increased risk of fatal anaphylaxis from epinephrine non-use, simulated anaphylaxis fatalities would increase from 226 to 1090 annually, clearly illustrating that the risks of non-use outweigh the risks associated with epinephrine. Their literature review led them to recommend use of IV epinephrine only in cases refractory to IM epinephrine (due to increased risk of adverse cardiac events), vigilance to ensure proper dosing with the IV (1:10,000) versus IM (1:1000) formulations of epinephrine, awareness of the potential cardiac risk in patients presenting with cardiac manifestations, and advising families to be sure they use their training device when practicing epinephrine administration.
High-flow oxygen (8–10 L/min via face mask) and intravenous fluid resuscitation (10 to 20 mL/kg 0.9% saline over 5–10 min) should be administered when indicated [103]. Continuous monitoring of vitals including pulse oximetry is indicated and if necessary appropriate cardiopulmonary resuscitation should be initiated. Adjunctive medications such as antihistamines and glucocorticoids should not be used prior to or instead of epinephrine [103]. Because of the risk of biphasic or protracted anaphylaxis, prolonged observation is recommended [1, 103].
A recent case report documented near-fatal anaphylaxis to milk in a 15-year-old that seemed to improve only after placement of a nasogastric tube and gastric drainage despite prompt, aggressive treatment with multiple doses of intramuscular epinephrine followed by continuous intravenous infusion, intubation and respiratory support and IV fluid resuscitation [115]. While gastric drainage is not part of the recommended management of anaphylaxis, cessation of exposure to the inciting trigger (e.g., stop the infusion of an intravenous drug) is recommended. If ingested food remains in the stomach and absorption is ongoing, then gastric drainage may halt ongoing allergen exposure. Many allergists view emesis in patients with FIA as a positive occurrence often followed by subsequent improvement, presumably for the same reason. While a single case report is not sufficient evidence to change practice, perhaps such maneuvers should be considered in severe reactions with poor response to standard treatment.
Long-Term Management
Outside the acute setting, management of FIA focuses on prevention of future reactions and proper treatment of reactions that occur despite prevention efforts. Written anaphylaxis or food allergy action plans should be provided. Patients should be referred to an allergist for confirmation of the trigger and education on allergen avoidance and management of reactions [103]. Overall rates of allergist referral and EAI prescription fulfillment are low after anaphylaxis, with only 29% of patients following up with an allergist within 1 year and only 46% filling an EAI prescription, but these rates are higher for FIA (39.8% for allergist follow-up and 69.4% filling EAI prescription) [116]. From 2005 to 2014 EAI, dispensation rates increased by 38% for adults after FIA, while rates for children did not increase but have always been high (84%). Patients and/or caregivers should be trained in use of EAIs, and clinicians should be aware that periodic repeat training is necessary as misuse is common [117] and knowledge of proper use may be lost with time [118]. Proper education on food avoidance is necessary as reactions may occur due to misreading of labels, cross-contamination, cross-reactivity (e.g., pistachio ingestion in patient with cashew allergy), and even intentional exposure. Many schools have implemented peanut-free policies, but there is no evidence to date that these effectively reduce risk and QoL is not improved by such policies [119].
With increased research on interventional therapies for food allergy, there is hope that long-term management in the future will include treatment to induce desensitization and lower the risk of future reactions. Oral, epicutaneous, and sublingual immunotherapy have all shown promise in achieving desensitization to foods, and any significant increase in reactivity threshold induced is likely to be clinically relevant. A recent analysis estimated that an increase in peanut threshold of reactivity from ≤ 100 to 300 mg would reduce the risk of reaction to contaminated cookies, ice cream, doughnuts/snack cakes, and snack chip mixes by over 95% [120••]. There is also evidence that desensitization decreases the severity of subsequent reactions upon exit DBPCFC [121]. There is some evidence that oral immunotherapy (OIT) may improve food-specific QoL [122, 123]. However, this evidence may be exaggerated by lack of confirmatory DBPCFC prior to initiation of OIT. It remains to be seen if findings will be similar in patients with challenge-proven allergy undergoing OIT. OIT may also be cost-effective, but may actually increase the total number of anaphylactic reactions to foods [124]. It is conceivable that the predictability of reactions occurring after OIT dosing may lead to less patient and caregiver stress than anaphylaxis after unpredictable accidental ingestion, which often occurs despite constant vigilance on the part of patients and caregivers [125]. No deaths have been attributed to OIT to date, but one school-age boy in Japan suffered respiratory arrest during milk OIT resulting in ventilator dependence (Personal correspondence, Motohiro Ebisawa, MD, Ph.D). Products for both peanut OIT and epicutaneous immunotherapy are currently undergoing phase 3 clinical trials with hopes of commercial availability in the future. In the meantime, these promising interventional therapies should remain reserved for research settings.
Shaker and Greenhawt recently analyzed two strategies utilized at times for peanut allergy: avoidance of products with precautionary allergen labeling and EAI administration for peanut allergen ingestion even when symptoms were not present [126]. Their analysis found that neither strategy was cost-effective, but that low-dose (1.5 mg) peanut threshold challenge was cost-effective to facilitate consumption of products with PAL, which may then lead to improved QoL.
Epinephrine Use and Underuse
Despite guideline recommendations and the well-documented association between delay in epinephrine use and poor outcomes, epinephrine remains underutilized for FIA in all settings worldwide [13•, 127,128,129,130,131]. While allergists have been critical of underuse of epinephrine by first responders and emergency departments [132, 133], we also fail to administer epinephrine in many cases of anaphylaxis. Noone et al. noted the use of epinephrine in 39% (29 of 74) of positive DBPCFCs performed as screening for food allergy therapy trials [134]. While their study did not focus on anaphylaxis, the two reactions deemed severe (2.7% of total reactions) and 75% of those deemed moderate (34% of total reactions) received epinephrine. It is interesting to note that virtually all patients in this study (97%) reported GI symptoms, typically subjective abdominal discomfort. In van der Valk et al.’s recent retrospective study of open and DBPC OFCs performed in children at three tertiary care centers in the Netherlands [135], epinephrine was given to only 39% of children (32 of 83) who met the EAACI criteria for anaphylaxis [106]. This study included OFCs done in clinical settings and research settings, with the use of epinephrine significantly higher (71%) in the clinical group than the research group (16%). This difference was driven by a parallel disparity in epinephrine use between patients with skin plus GI symptoms (22% treated with epinephrine, much more common in the research group) as opposed to skin plus respiratory symptoms (70% treated with epinephrine, much more common in the clinical group). This implies that allergists’ use of epinephrine in FIA may be influenced by the clearly documented risk associated with respiratory symptoms and the previously discussed view of GI symptoms as potentially positive, especially emesis.
Epinephrine is also underutilized for reactions during OIT, and this is important to note as epinephrine use has been used as a surrogate for OIT-induced anaphylaxis rates [136,137,138,139]. The largest OIT safety analysis to date estimated that epinephrine was warranted but not given for 9% of OIT AEs [88•], illustrating both the underuse of epinephrine and the resulting limitations of its use as a surrogate for anaphylaxis during OIT.
However, allergists do not always underutilize epinephrine. Analysis of entry DBPCFCs for a phase 3 peanut OIT study revealed that of 583 North American participants, only 28 (5%) were deemed to meet NIAID-FAAN criteria for anaphylaxis, but 240 (41%) were treated with epinephrine [92]. Only 3% of the reactions were graded as severe. In the European challenges of the same study, only 15% were treated with epinephrine despite overall similarity of reaction severity, indicating a possible geographic variation in epinephrine use [140].
Better understanding of why epinephrine is underused may allow better understanding of how best to increase appropriate administration of epinephrine. Documented reasons for parental non-use of EAIs include failure to recognize anaphylaxis, unavailability of the EAI, fear of EAI use, waiting for more symptoms, and/or uncertainty whether EAI use was needed [141]. Supervised parent/child epinephrine EAI administration during OFC reactions increased parental confidence in multiple domains relating to EAI use for anaphylaxis [142], but it remains unproven whether or not this will translate to higher rates of EAI use in practice. Online educational programs have shown promise in improving knowledge in parents and caregivers of children with food allergy [143], but this may or may not improve epinephrine use. Social media is another potentially powerful tool for influencing food allergy management, but it is likely underutilized [144]. An analysis of the cost-effectiveness of bystander epinephrine in community anaphylaxis estimated the cost of preventing one venom-associated death using bystander epinephrine to be $71,519 [126]. Given that anaphylaxis fatality rates are comparable for venom and foods [20], this may be a cost-effective approach to prevent food allergy deaths as well. Unassigned stock epinephrine was used in 68% of 31 cases in the first 2 years after implementation of a stock epinephrine program in a large school district in Texas, often for adolescents with known food allergy but no assigned epinephrine [145]. Most likely, a multi-pronged approach including education of patients and caregivers, first responders, ED providers, and allergists will need to be combined with improved availability of epinephrine (including use of bystander or stock epinephrine) to maximize appropriate and timely epinephrine use.
Conclusion
Food-induced anaphylaxis continues to be a significant public health problem, and many related needs remain unmet. It remains difficult to predict which patients will suffer the most severe reactions, epinephrine remains underutilized, and the only approved management strategy is strict avoidance and preparation to treat reactions when they occur. Future needs in the area of FIA diagnosis and management are listed in Table 2.
However, there are numerous reasons for optimism. Despite increasing rates of food allergy and ED visits and hospitalizations for FIA, fatalities due to food allergy are not increasing. As early peanut introduction becomes more widely implemented, we may begin to see decreasing rates of peanut allergy in the future. The diagnostic toolbox for identifying allergic triggers and predicting reaction severity continues to expand with component-resolved diagnostics, basophil and mast cell activation tests, and multifactorial algorithms. Progress has been made in making stock or bystander epinephrine more readily available to treat FIA that occurs in schools and other public places. Potentially even more impactful are emerging interventional therapies including oral, sublingual, and epicutaneous immunotherapy as well as biologic therapy targeting Th2 inflammation. With continued improvements in our understanding of food allergies and anaphylaxis we should expect that the progress made so far to continue and improve life for those affected by food-induced anaphylaxis.
References
Papers of Particular Interest, Published Recently, Have Been Highlighted as: • Of Importance, •• Of Major Importance
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report––second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391–7. https://doi.org/10.1016/j.jaci.2005.12.1303.
Greenhawt M. Food allergy quality of life and living with food allergy. Curr Opin Allergy Clin Immunol. 2016;16(3):284–90. https://doi.org/10.1097/ACI.0000000000000271.
Cummings AJ, Knibb RC, King RM, Lucas JS. The psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families: a review. Allergy. 2010;65(8):933–45. https://doi.org/10.1111/j.1398-9995.2010.02342.x.
Lau GY, Patel N, Umasunthar T, Gore C, Warner JO, Hanna H, et al. Anxiety and stress in mothers of food-allergic children. Pediatr Allergy Immunol. 2014;25(3):236–42. https://doi.org/10.1111/pai.12233.
Sicherer SH, Noone SA, Munoz-Furlong A. The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol. 2001;87(6):461–4. https://doi.org/10.1016/S1081-1206(10)62258-2.
Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2007;120(3):638–46. https://doi.org/10.1016/j.jaci.2007.05.026.
Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549–55. https://doi.org/10.1542/peds.2009-1210.
Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Lowe AJ, Matheson MC, et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol. 2011;127(3):668–76 e1-2. https://doi.org/10.1016/j.jaci.2011.01.039.
Wood RA, Camargo CA Jr, Lieberman P, Sampson HA, Schwartz LB, Zitt M, et al. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol. 2014;133(2):461–7. https://doi.org/10.1016/j.jaci.2013.08.016.
Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9–17. https://doi.org/10.1542/peds.2011-0204.
Clark S, Espinola J, Rudders SA, Banerji A, Camargo CA Jr. Frequency of US emergency department visits for food-related acute allergic reactions. J Allergy Clin Immunol. 2011;127(3):682–3. https://doi.org/10.1016/j.jaci.2010.10.040.
McWilliam VL, Koplin JJ, Field MJ, Sasaki M, Dharmage SC, Tang MLK, et al. Self-reported adverse food reactions and anaphylaxis in the SchoolNuts study: a population-based study of adolescents. J Allergy Clin Immunol. 2018;141(3):982–90. https://doi.org/10.1016/j.jaci.2017.09.012.
• Ruiz Oropeza A, Lassen A, Halken S, Bindslev-Jensen C, Mortz CG. Anaphylaxis in an emergency care setting: a one year prospective study in children and adults. Scand J Trauma Resusc Emerg Med. 2017;25(1):111. https://doi.org/10.1186/s13049-017-0402-0. COMMENT: Rare prospective analysis of anaphylaxis epidemiology reported higher rates than other European studies, illustrated low rates of epinephrine use as well.
Ma L, Danoff TM, Borish L. Case fatality and population mortality associated with anaphylaxis in the United States. J Allergy Clin Immunol. 2014;133(4):1075–83. https://doi.org/10.1016/j.jaci.2013.10.029.
Dyer AA, Lau CH, Smith TL, Smith BM, Gupta RS. Pediatric emergency department visits and hospitalizations due to food-induced anaphylaxis in Illinois. Ann Allergy Asthma Immunol. 2015;115(1):56–62. https://doi.org/10.1016/j.anai.2015.05.006.
Xu YS, Kastner M, Harada L, Xu A, Salter J, Waserman S. Anaphylaxis-related deaths in Ontario: a retrospective review of cases from 1986 to 2011. Allergy Asthma Clin Immunol. 2014;10(1):38. https://doi.org/10.1186/1710-1492-10-38.
•• Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T, et al. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992–2012. J Allergy Clin Immunol. 2015;135(4):956–63 e1. https://doi.org/10.1016/j.jaci.2014.10.021. COMMENT: Comprehensive epidemiologic study of food-induced anaphylaxis and deaths in the UK over 20-year period.
Mullins RJ, Wainstein BK, Barnes EH, Liew WK, Campbell DE. Increases in anaphylaxis fatalities in Australia from 1997 to 2013. Clin Exp Allergy. 2016;46(8):1099–110. https://doi.org/10.1111/cea.12748.
Jerschow E, Lin RY, Scaperotti MM, McGinn AP. Fatal anaphylaxis in the United States, 1999–2010: temporal patterns and demographic associations. J Allergy Clin Immunol. 2014;134(6):1318–28 e7. https://doi.org/10.1016/j.jaci.2014.08.018.
•• Turner PJ, Jerschow E, Umasunthar T, Lin R, Campbell DE, Boyle RJ. Fatal anaphylaxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5(5):1169–78. https://doi.org/10.1016/j.jaip.2017.06.031. COMMENT: Excellent review of all recent data on fatal anaphylaxis, including comparison to likelihood of death by other causes.
• Umasunthar T, Leonardi-Bee J, Turner PJ, Hodes M, Gore C, Warner JO, et al. Incidence of food anaphylaxis in people with food allergy: a systematic review and meta-analysis. Clin Exp Allergy. 2015;45(11):1621–36. https://doi.org/10.1111/cea.12477. COMMENT: Systematic review and meta-analysis of FIA.
Umasunthar T, Leonardi-Bee J, Hodes M, Turner PJ, Gore C, Habibi P, et al. Incidence of fatal food anaphylaxis in people with food allergy: a systematic review and meta-analysis. Clin Exp Allergy. 2013;43(12):1333–41. https://doi.org/10.1111/cea.12211.
Hu W, Grbich C, Kemp A. When doctors disagree: a qualitative study of doctors’ and parents’ views on the risks of childhood food allergy. Health Expect. 2008;11(3):208–19. https://doi.org/10.1111/j.1369-7625.2008.00506.x.
Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992;327(6):380–4. https://doi.org/10.1056/NEJM199208063270603.
Pumphrey RS, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999–2006. J Allergy Clin Immunol. 2007;119(4):1018–9. https://doi.org/10.1016/j.jaci.2007.01.021.
Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001–2006. J Allergy Clin Immunol. 2007;119(4):1016–8. https://doi.org/10.1016/j.jaci.2006.12.622.
Pumphrey RS. Fatal posture in anaphylactic shock. J Allergy Clin Immunol. 2003;112(2):451–2.
Grabenhenrich LB, Dolle S, Moneret-Vautrin A, Kohli A, Lange L, Spindler T, et al. Anaphylaxis in children and adolescents: the European Anaphylaxis Registry. J Allergy Clin Immunol. 2016;137(4):1128–37 e1. https://doi.org/10.1016/j.jaci.2015.11.015.
Sheikh A, Shehata YA, Brown SG, Simons FE. Adrenaline for the treatment of anaphylaxis: cochrane systematic review. Allergy. 2009;64(2):204–12. https://doi.org/10.1111/j.1398-9995.2008.01926.x.
Bock SA, Muñoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol. 2001;107(1):191–3. https://doi.org/10.1067/mai.2001.112031.
Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000;30(8):1144–50.
Turner PJ, Campbell DE. Epidemiology of severe anaphylaxis: can we use population-based data to understand anaphylaxis? Curr Opin Allergy Clin Immunol. 2016;16(5):441–50. https://doi.org/10.1097/ACI.0000000000000305.
Turner PJ, Baumert JL, Beyer K, Boyle RJ, Chan CH, Clark AT, et al. Can we identify patients at risk of life-threatening allergic reactions to food? Allergy. 2016;71(9):1241–55. https://doi.org/10.1111/all.12924.
Rudders SA, Banerji A, Clark S, Camargo CA Jr. Age-related differences in the clinical presentation of food-induced anaphylaxis. J Pediatr. 2011;158(2):326–8. https://doi.org/10.1016/j.jpeds.2010.10.017.
Speakman S, Kool B, Sinclair J, Fitzharris P. Paediatric food-induced anaphylaxis hospital presentations in New Zealand. J Paediatr Child Health. 2018;54(3):254–9. https://doi.org/10.1111/jpc.13705.
Kool B, Chandra D, Fitzharris P. Adult food-induced anaphylaxis hospital presentations in New Zealand. Postgrad Med J. 2016;92:640–4. https://doi.org/10.1136/postgradmedj-2015-133530.
Ramsey NB, Guffey D, Coleman NE, Davis CM. Characteristics, morbidity, and mortality of anaphylaxis-associated admissions to North American PICUs, 2010–2015. J Allergy Clin Immunol. 2018;141(Supplement 2):AB148–8.
Wood RA, Sicherer SH, Vickery BP, Jones SM, Liu AH, Fleischer DM, et al. The natural history of milk allergy in an observational cohort. J Allergy Clin Immunol. 2013;131(3):805–12. https://doi.org/10.1016/j.jaci.2012.10.060.
Savage J, Sicherer S, Wood R. The natural history of food allergy. J Allergy Clin Immunol Pract. 2016;4(2):196–203; quiz 4. https://doi.org/10.1016/j.jaip.2015.11.024.
Fernandes RA, Regateiro F, Pereira C, Faria E, Pita J, Todo-Bom A, et al. Anaphylaxis in a food allergy outpatient department: one-year review. Eur Ann Allergy Clin Immunol. 2018;50(2):81–8. https://doi.org/10.23822/EurAnnACI.1764-1489.45.
Jeong K, Lee SY, Ahn K, Kim J, Lee HR, Suh DI, et al. A multicenter study on anaphylaxis caused by peanut, tree nuts, and seeds in children and adolescents. Allergy. 2017;72(3):507–10. https://doi.org/10.1111/all.13096.
Kim SY, Kim MH, Cho YJ. Different clinical features of anaphylaxis according to cause and risk factors for severe reactions. Allergol Int. 2018;67(1):96–102. https://doi.org/10.1016/j.alit.2017.05.005.
• Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol. 2017;140(2):321–33. https://doi.org/10.1016/j.jaci.2017.06.012. COMMENT: Excellent review of clinical presentation, diagnosis, etiologies, and management of all types of anaphylaxis.
Krogulska A, Dynowski J, Wasowska-Krolikowska K. Bronchial reactivity in schoolchildren allergic to food. Ann Allergy Asthma Immunol. 2010;105(1):31–8. https://doi.org/10.1016/j.anai.2010.05.015.
Kivity S, Fireman E, Sade K. Bronchial hyperactivity, sputum analysis and skin prick test to inhalant allergens in patients with symptomatic food hypersensitivity. Isr Med Assoc J. 2005;7(12):781–4.
Asaumi T, Ebisawa M. How to manage food dependent exercise induced anaphylaxis (FDEIA). Curr Opin Allergy Clin Immunol. 2018;18(3):243–7. https://doi.org/10.1097/ACI.0000000000000442.
Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2009;123(2):426–33. https://doi.org/10.1016/j.jaci.2008.10.052.
Commins SP, James HR, Stevens W, Pochan SL, Land MH, King C, et al. Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2014;134(1):108–15. https://doi.org/10.1016/j.jaci.2014.01.024.
Commins SP, Platts-Mills TA. Tick bites and red meat allergy. Curr Opin Allergy Clin Immunol. 2013;13(4):354–9. https://doi.org/10.1097/ACI.0b013e3283624560.
Commins SP, James HR, Kelly LA, Pochan SL, Workman LJ, Perzanowski MS, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2011;127(5):1286–93 e6. https://doi.org/10.1016/j.jaci.2011.02.019.
Mabelane T, Botha M, Thomas HF, Levin M. Alpha gal allergy in rural black African subjects associated with a high prevalence of abdominal manifestations and a more rapid onset of symptoms. J Allergy Clin Immunol. 2018;141(Supplement 2):AB200.
Rudders SA, Clark S, Camargo CA Jr. Inpatient interventions are infrequent during pediatric hospitalizations for food-induced anaphylaxis. J Allergy Clin Immunol Pract. 2017;5(5):1421–4 e2. https://doi.org/10.1016/j.jaip.2017.04.036.
Lee S, Bellolio MF, Hess EP, Erwin P, Murad MH, Campbell RL. Time of onset and predictors of biphasic anaphylactic reactions: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2015;3(3):408–16 e1-2. https://doi.org/10.1016/j.jaip.2014.12.010.
Lee S, Peterson A, Lohse CM, Hess EP, Campbell RL. Further evaluation of factors that may predict biphasic reactions in emergency department anaphylaxis patients. J Allergy Clin Immunol Pract. 2017;5(5):1295–301. https://doi.org/10.1016/j.jaip.2017.07.020.
van der Linden PW, Hack CE, Poortman J, Vivie-Kipp YC, Struyvenberg A, van der Zwan JK. Insect-sting challenge in 138 patients: relation between clinical severity of anaphylaxis and mast cell activation. J Allergy Clin Immunol. 1992;90(1):110–8.
Mertes PM, Alla F, Trechot P, Auroy Y, Jougla E, Groupe d’Etudes des reactions Anaphylactoides P. Anaphylaxis during anesthesia in France: an 8-year national survey. J Allergy Clin Immunol 2011;128(2):366–373. doi:https://doi.org/10.1016/j.jaci.2011.03.003.
Yunginger JW, Nelson DR, Squillace DL, Jones RT, Holley KE, Hyma BA, et al. Laboratory investigation of deaths due to anaphylaxis. J Forensic Sci. 1991;36(3):857–65.
• Dua S, Dowey J, Foley L, Islam S, King Y, Ewan P, et al. Diagnostic value of tryptase in food allergic reactions: a prospective study of 160 adult peanut challenges. J Allergy Clin Immunol Pract. 2018; https://doi.org/10.1016/j.jaip.2018.01.006. COMMENT: Prospective evidence that tryptase elevation does occur in food-induced anaphylaxis in adults
Komarow HD, Hu Z, Brittain E, Uzzaman A, Gaskins D, Metcalfe DD. Serum tryptase levels in atopic and nonatopic children. J Allergy Clin Immunol. 2009;124(4):845–8. https://doi.org/10.1016/j.jaci.2009.06.040.
Belhocine W, Ibrahim Z, Grandne V, Buffat C, Robert P, Gras D, et al. Total serum tryptase levels are higher in young infants. Pediatr Allergy Immunol. 2011;22(6):600–7. https://doi.org/10.1111/j.1399-3038.2011.01166.x.
Sala-Cunill A, Cardona V, Labrador-Horrillo M, Luengo O, Esteso O, Garriga T, et al. Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients. Int Arch Allergy Immunol. 2013;160(2):192–9. https://doi.org/10.1159/000339749.
Schwartz LB, Irani AM, Roller K, Castells MC, Schechter NM. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol. 1987;138(8):2611–5.
Castells MC, Irani AM, Schwartz LB. Evaluation of human peripheral blood leukocytes for mast cell tryptase. J Immunol. 1987;138(7):2184–9.
Sampson HA, Aceves S, Bock SA, James J, Jones S, Lang D, et al. Food allergy: a practice parameter update-2014. J Allergy Clin Immunol. 2014;134(5):1016–25 e43. https://doi.org/10.1016/j.jaci.2014.05.013.
Sporik R, Hill DJ, Hosking CS. Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin Exp Allergy. 2000;30(11):1540–6.
Knight AK, Shreffler WG, Sampson HA, Sicherer SH, Noone S, Mofidi S, et al. Skin prick test to egg white provides additional diagnostic utility to serum egg white-specific IgE antibody concentration in children. J Allergy Clin Immunol. 2006;117(4):842–7. https://doi.org/10.1016/j.jaci.2005.12.1304.
Roberts G, Lack G. Diagnosing peanut allergy with skin prick and specific IgE testing. J Allergy Clin Immunol. 2005;115(6):1291–6. https://doi.org/10.1016/j.jaci.2005.02.038.
Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105(3):582–6. https://doi.org/10.1067/mai.2000.104941.
Boyano-Martinez T, Garcia-Ara C, Diaz-Pena JM, Martin-Esteban M. Prediction of tolerance on the basis of quantification of egg white-specific IgE antibodies in children with egg allergy. J Allergy Clin Immunol. 2002;110(2):304–9.
Perry TT, Matsui EC, Kay Conover-Walker M, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. 2004;114(1):144–9. https://doi.org/10.1016/j.jaci.2004.04.009.
Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. 2001;107(5):891–6. https://doi.org/10.1067/mai.2001.114708.
Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, Martin-Munoz F, Reche-Frutos M, Martin-Esteban M. Specific IgE levels in the diagnosis of immediate hypersensitivity to cows’ milk protein in the infant. J Allergy Clin Immunol. 2001;107(1):185–90.
Bird JA, Crain M, Varshney P. Food allergen panel testing often results in misdiagnosis of food allergy. J Pediatr. 2015;166(1):97–100. https://doi.org/10.1016/j.jpeds.2014.07.062.
Santos AF, Douiri A, Becares N, Wu SY, Stephens A, Radulovic S, et al. Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children. J Allergy Clin Immunol. 2014;134(3):645–52. https://doi.org/10.1016/j.jaci.2014.04.039.
Nicolaou N, Poorafshar M, Murray C, Simpson A, Winell H, Kerry G, Härlin A, Woodcock A, Ahlstedt S, Custovic A Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics. J Allergy Clin Immunol 2010;125(1):191–7 e1–13. https://doi.org/10.1016/j.jaci.2009.10.008, 197.e13.
Santos AF, Couto-Francisco N, Becares N, Kwok M, Bahnson HT, Lack G. A novel human mast cell activation test for peanut allergy. J Allergy Clin Immunol 2018. https://doi.org/10.1016/j.jaci.2018.03.011.
• Bahri R, Custovic A, Korosec P, Tsoumani M, Barron M, Wu J, et al. Mast cell activation test in the diagnosis of allergic disease and anaphylaxis. J Allergy Clin Immunol. 2018; https://doi.org/10.1016/j.jaci.2018.01.043. COMMENT: Along with Santos et al, first reports of mast cell activation assay for use in diagnosis of food allergy.
•• Deak PE, Vrabel MR, Kiziltepe T, Bilgicer B. Determination of crucial immunogenic epitopes in major peanut allergy protein, Ara h2, via novel nanoallergen platform. Sci Rep. 2017;7(1):3981. https://doi.org/10.1038/s41598-017-04268-6. COMMENT: New diagnostic tool that identifies allergens at the epitope level.
Nowak-Wegrzyn A, Assa’ad AH, Bahna SL, bock SA, Sicherer SH, Teuber SS et al. Work Group report: oral food challenge testing. J Allergy Clin Immunol 2009;123(6 Suppl):S365–S383. https://doi.org/10.1016/j.jaci.2009.03.042.
Togias A, Cooper SF, Acebal ML, Assa’ad A, Baker JR, Jr., Beck LA et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol 2017;139(1):29–44. https://doi.org/10.1016/j.jaci.2016.10.010.
Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803–13. https://doi.org/10.1056/NEJMoa1414850.
Bird JA, Groetch M, Allen KJ, Bock SA, Leonard S, Nowak-Wegrzyn AH, et al. Conducting an oral food challenge to peanut in an infant. J Allergy Clin Immunol Pract. 2016;5:301–311.e1. https://doi.org/10.1016/j.jaip.2016.07.019.
Sampson HA, Gerth van Wijk R, Bindslev-Jensen C, Sicherer S, Teuber SS, Burks AW, et al. Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol. 2012;130(6):1260–74. https://doi.org/10.1016/j.jaci.2012.10.017.
Kansen HM, Le TM, Meijer Y, Flokstra-de Blok BMJ, Welsing PMJ, van der Ent CK, et al. The impact of oral food challenges for food allergy on quality of life: a systematic review. Pediatr Allergy Immunol. 2018; https://doi.org/10.1111/pai.12905.
• College of Allergy AIAAoA. Statement by the American College of Allergy AIAAoA, Asthma & Immunology; and the Canadian Society of Allergy and Clinical Immunology. Allergists respond to death of 3 year-old boy during oral food challenge. 2017. COMMENT: Statement regarding the only reported death due to FIA after OFC.
Cianferoni A, Khullar K, Saltzman R, Fiedler J, Garrett JP, Naimi DR, et al. Oral food challenge to wheat: a near-fatal anaphylaxis and review of 93 food challenges in children. World Allergy Organ J. 2013;6(1):14–0. https://doi.org/10.1186/1939-4551-6-14.
Perry TT, Matsui EC, Conover-Walker MK, Wood RA. Risk of oral food challenges. J Allergy Clin Immunol. 2004;114(5):1164–8. https://doi.org/10.1016/j.jaci.2004.07.063.
• Virkud YV, Burks AW, Steele PH, Edwards LJ, Berglund JP, Jones SM, et al. Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy. J Allergy Clin Immunol. 2017;139(3):882–8 e5. https://doi.org/10.1016/j.jaci.2016.07.030. COMMENT: Largest study to date on adverse effects associated with OIT, identified new risk factors including allergic rhinitis.
Yanagida N, Sato S, Asaumi T, Ogura K, Ebisawa M. Risk factors for severe reactions during double-blind placebo-controlled food challenges. Int Arch Allergy Immunol. 2017;172(3):173–82. https://doi.org/10.1159/000458724.
Song Y, Wang J, Leung N, Wang LX, Lisann L, Sicherer SH, et al. Correlations between basophil activation, allergen-specific IgE with outcome and severity of oral food challenges. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology. 2015;114(4):319–26. https://doi.org/10.1016/j.anai.2015.01.006.
Shreffler WG, Beyer K, Chu TH, Burks AW, Sampson HA. Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes. J Allergy Clin Immunol. 2004;113(4):776–82. https://doi.org/10.1016/j.jaci.2003.12.588.
Vickery BP, Beyer K, Burks AW, Casale T, Hourihane J, Jones S, et al. Outcome of 583 entry double-blind placebo-controlled peanut challenges during screening for the palisade phase 3 oral immunotherapy trial. J Allergy Clin Immunol. 2017;139(2, Supplement):AB381.
Pettersson ME, Koppelman GH, Flokstra-de Blok BMJ, Kollen BJ, Dubois AEJ. Prediction of the severity of allergic reactions to foods. Allergy. 2018; https://doi.org/10.1111/all.13423.
Santos AF, Du Toit G, Douiri A, Radulovic S, Stephens A, Turcanu V, et al. Distinct parameters of the basophil activation test reflect the severity and threshold of allergic reactions to peanut. J Allergy Clin Immunol. 2015;135(1):179–86. https://doi.org/10.1016/j.jaci.2014.09.001.
Ocmant A, Mulier S, Hanssens L, Goldman M, Casimir G, Mascart F, et al. Basophil activation tests for the diagnosis of food allergy in children. Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology. 2009;39(8):1234–45. https://doi.org/10.1111/j.1365-2222.2009.03292.x.
Reier-Nilsen T, Michelsen MM, Lodrup Carlsen KC, Carlsen KH, Mowinckel P, Nygaard UC, et al. Predicting reactivity threshold in children with anaphylaxis to peanut. Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology. 2018;48(4):415–23. https://doi.org/10.1111/cea.13078.
Sugiura S, Sasaki K, Matsui T, Nakagawa T, Kando N, Ito K. Development of a prediction model for a severe reaction in cow’s milk challenges. Allergol Int. 2017;66(3):493–4. https://doi.org/10.1016/j.alit.2016.11.005.
Sugiura S, Matsui T, Nakagawa T, Sasaki K, Nakata J, Kando N, et al. Development of a prediction model of severe reaction in boiled egg challenges. Allergol Int. 2016;65(3):293–9. https://doi.org/10.1016/j.alit.2016.01.005.
Sugiura S, Matsui T, Furuta T, Sasaki K, Kando N, Ito K. Development of a prediction model for severe wheat allergy. Pediatr Allergy Immunol. 2018;29(1):93–6. https://doi.org/10.1111/pai.12806.
Chinthrajah RS, Purington N, Andorf S, Rosa JS, Mukai K, Hamilton R, et al. Development of a tool predicting severity of allergic reaction during peanut challenge. Ann Allergy Asthma Immunol. 2018; https://doi.org/10.1016/j.anai.2018.04.020.
Blumchen K, Beder A, Beschorner J, Ahrens F, Gruebl A, Hamelmann E, et al. Modified oral food challenge used with sensitization biomarkers provides more real-life clinical thresholds for peanut allergy. J Allergy Clin Immunol. 2014;134(2):390–8. https://doi.org/10.1016/j.jaci.2014.03.035.
Dubois AEJ, Turner PJ, Hourihane J, Ballmer-Weber B, Beyer K, Chan CH, et al. How does dose impact on the severity of food-induced allergic reactions, and can this improve risk assessment for allergenic foods?: report from an ILSI Europe Food Allergy Task Force Expert Group and Workshop. Allergy. 2018; https://doi.org/10.1111/all.13405.
Simons FE, Ardusso LR, Bilo MB, El-Gamal YM, Ledford DK, Ring J, et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011;4(2):13–37. https://doi.org/10.1097/WOX.0b013e318211496c.
Kemp SF, Lockey RF, Simons FE, World Allergy Organization ad hoc Committee on Epinephrine in A. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization. Allergy 2008;63(8):1061–1070. doi:https://doi.org/10.1111/j.1398-9995.2008.01733.x.
Lieberman P, Nicklas RA, Randolph C, Oppenheimer J, Bernstein D, Bernstein J, et al. Anaphylaxis––a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115(5):341–84. https://doi.org/10.1016/j.anai.2015.07.019.
Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fernandez Rivas M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026–45. https://doi.org/10.1111/all.12437.
Simons FE, Anaphylaxis SHA. Unique aspects of clinical diagnosis and management in infants (birth to age 2 years). J Allergy Clin Immunol. 2015;135(5):1125–31. https://doi.org/10.1016/j.jaci.2014.09.014.
Bautista E, Simons FE, Simons KJ, Becker AB, Duke K, Tillett M, et al. Epinephrine fails to hasten hemodynamic recovery in fully developed canine anaphylactic shock. Int Arch Allergy Immunol. 2002;128(2):151–64. https://doi.org/10.1159/000059406.
Cardona V, Ferre-Ybarz L, Guilarte M, Moreno-Perez N, Gomez-Galan C, Alcoceba-Borras E, et al. Safety of adrenaline use in anaphylaxis: a multicentre register. Int Arch Allergy Immunol. 2017;173(3):171–7. https://doi.org/10.1159/000477566.
Nazir S, Lohani S, Tachamo N, Ghimire S, Poudel DR, Donato A. Takotsubo cardiomyopathy associated with epinephrine use: a systematic review and meta-analysis. Int J Cardiol. 2017;229:67–70. https://doi.org/10.1016/j.ijcard.2016.11.266.
Jayamali WD, Herath H, Kulathunga A. Myocardial infarction during anaphylaxis in a young healthy male with normal coronary arteries––is epinephrine the culprit? BMC Cardiovasc Disord. 2017;17(1):237. https://doi.org/10.1186/s12872-017-0670-7.
Memon S, Chhabra L, Masrur S, Parker MW. Allergic acute coronary syndrome (Kounis syndrome). Proc (Bayl Univ Med Cent). 2015;28(3):358–62.
Campbell RL, Bellolio MF, Knutson BD, Bellamkonda VR, Fedko MG, Nestler DM, et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract. 2015;3(1):76–80. https://doi.org/10.1016/j.jaip.2014.06.007.
Shaker M, Toy D, Lindholm C, Low J, Reigh E, Greenhawt M. Summary and simulation of reported adverse events from epinephrine autoinjectors and a review of the literature. J Allergy Clin Immunol Pract. 2018; https://doi.org/10.1016/j.jaip.2018.04.006.
Lazar I, Cavari Y, Levitas A, Mandolla AB, Broides A. Gastric drainage in the treatment of near-fatal food-induced anaphylaxis. Pediatr Emerg Care. 2017:1. https://doi.org/10.1097/PEC.0000000000001293.
Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Bellamkonda VR, Nestler DM, et al. Temporal trends in epinephrine dispensing and allergy/immunology follow-up among emergency department anaphylaxis patients in the United States, 2005–2014. J Allergy Clin Immunol Pract. 2017;5(5):1272–9 e1. https://doi.org/10.1016/j.jaip.2017.06.009.
Brown J, Tuthill D, Alfaham M, Spear E. A randomized maternal evaluation of epinephrine autoinjection devices. Pediatr Allergy Immunol 2013;24(2):173–177. https://doi.org/10.1111/pai.12048.
Arga M, Bakirtas A, Catal F, Derinoz O, Harmanci K, Razi CH, et al. Training of trainers on epinephrine autoinjector use. Pediatr Allergy Immunol. 2011;22(6):590–3. https://doi.org/10.1111/j.1399-3038.2011.01143.x.
Patel DR, Upton JEM, Wang J, Harada L, Guffey D, Minard CG, et al. Quality of life for parents of children with food allergy in peanut-restricted versus peanut-free schools in the United States and Canada. J Allergy Clin Immunol Pract. 2018;6(2):671–3 e7. https://doi.org/10.1016/j.jaip.2017.08.013.
•• Baumert JL, Taylor SL, Koppelman SJ. Quantitative assessment of the safety benefits associated with increasing clinical peanut thresholds through immunotherapy. J Allergy Clin Immunol Pract. 2018;6(2):457–65 e4. https://doi.org/10.1016/j.jaip.2017.05.006. COMMENT: Quantifies the real-life benefits of the desensitization provided by immunotherapy methods currently being investigated.
Bird JA, Spergel JM, Jones SM, Rachid R, Assa'ad AH, Wang J, et al. Efficacy and safety of AR101 in oral immunotherapy for peanut allergy: results of ARC001, a randomized, double-blind, placebo-controlled phase 2 clinical trial. J Allergy Clin Immunol Pract. 2018;6(2):476–85 e3. https://doi.org/10.1016/j.jaip.2017.09.016.
Factor JM, Mendelson L, Lee J, Nouman G, Lester MR. Effect of oral immunotherapy to peanut on food-specific quality of life. Ann Allergy Asthma Immunol. 2012;109(5):348–52 e2. https://doi.org/10.1016/j.anai.2012.08.015.
Epstein-Rigbi N, Goldberg MR, Levy MB, Nachshon L, Elizur A. Changes in quality of life of food-allergic children from initiation of oral immunotherapy, through up-dosing, upon reaching maintenance and after 6 months of follow-up. J Allergy Clin Immunol. 2018;141(Supplement 2):AB240.
Shaker MS. An economic analysis of a peanut oral immunotherapy study in children. J Allergy Clin Immunol Pract. 2017;5:1707–16. https://doi.org/10.1016/j.jaip.2017.04.016.
De Schryver S, Clarke A, La Vieille S, Eisman H, Morris J, Lim R, et al. Food-induced anaphylaxis to a known food allergen in children often occurs despite adult supervision. Pediatr Allergy Immunol. 2017;28(7):715–7. https://doi.org/10.1111/pai.12770.
Shaker MS, Corbin D, Shaker M, Shaker S. Cost-effectiveness of bystander epinephrine in community anaphylaxis. J Allergy Clin Immunol. 2018;141(Supplement 2):AB65.
Sole D, Ivancevich JC, Borges MS, Coelho MA, Rosario NA, Ardusso LR, et al. Anaphylaxis in Latin America: a report of the online Latin American survey on anaphylaxis (OLASA). Clinics (Sao Paulo). 2011;66(6):943–7.
Alvarez-Perea A, Tomas-Perez M, Martinez-Lezcano P, Marco G, Perez D, Zubeldia JM, et al. Anaphylaxis in adolescent/adult patients treated in the emergency department: differences between initial impressions and the definitive diagnosis. J Investig Allergol Clin Immunol. 2015;25(4):288–94.
Beyer K, Eckermann O, Hompes S, Grabenhenrich L, Worm M. Anaphylaxis in an emergency setting––elicitors, therapy and incidence of severe allergic reactions. Allergy. 2012;67(11):1451–6. https://doi.org/10.1111/all.12012.
Worm M, Eckermann O, Dolle S, Aberer W, Beyer K, Hawranek T, et al. Triggers and treatment of anaphylaxis: an analysis of 4,000 cases from Germany. Austria and Switzerland Dtsch Arztebl Int. 2014;111(21):367–75. https://doi.org/10.3238/arztebl.2014.0367.
Hitti EA, Zaitoun F, Harmouche E, Saliba M, Mufarrij A. Acute allergic reactions in the emergency department: characteristics and management practices. Eur J Emerg Med. 2015;22(4):253–9. https://doi.org/10.1097/MEJ.0000000000000155.
Robinson M, Greenhawt M, Stukus DR. Factors associated with epinephrine administration for anaphylaxis in children before arrival to the emergency department. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology. 2017;119(2):164–9. https://doi.org/10.1016/j.anai.2017.06.001.
Lee AY, Enarson P, Clarke AE, La Vieille S, Eisman H, Chan ES, et al. Anaphylaxis across two Canadian pediatric centers: evaluating management disparities. J Asthma Allergy. 2017;10:1–7. https://doi.org/10.2147/JAA.S123053.
Noone S, Ross J, Sampson HA, Wang J. Epinephrine use in positive oral food challenges performed as a screening test for food allergy therapy trials. J Allergy Clin Immunol Pract. 2015;3(3):424–8. https://doi.org/10.1016/j.jaip.2014.10.008.
van der Valk JPM, Berends I, Gerth van Wijk R, Arends NJT, van Maaren MS, de Groot H, et al. Small percentage of anaphylactic reactions treated with epinephrine during food challenges in Dutch children. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology. 2018;120(3):300–3. https://doi.org/10.1016/j.anai.2017.08.018.
Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, et al. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011;127(3):654–60. https://doi.org/10.1016/j.jaci.2010.12.1111.
Clark AT, Islam S, King Y, Deighton J, Anagnostou K, Ewan PW. Successful oral tolerance induction in severe peanut allergy. Allergy. 2009;64(8):1218–20. https://doi.org/10.1111/j.1398-9995.2009.01982.x.
Anagnostou K, Islam S, King Y, Foley L, Pasea L, Bond S, et al. Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial. Lancet. 2014;383(9925):1297–304. https://doi.org/10.1016/s0140-6736(13)62301-6.
Yu GP, Weldon B, Neale-May S, Nadeau KC. The safety of peanut oral immunotherapy in peanut-allergic subjects in a single-center trial. Int Arch Allergy Immunol. 2012;159(2):179–82. https://doi.org/10.1159/000336391.
Zigmont E, Zawadzki R, Beyer K, Burks AW, Casale T, Hourihane J, et al. International comparisons of patient characteristics in a phase 3 study of AR101 for peanut allergy. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology. 2017;119(5, Supplement S):S81.
Fleischer DM, Perry TT, Atkins D, Wood RA, Burks AW, Jones SM, et al. Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study. Pediatrics. 2012;130(1):e25–32. https://doi.org/10.1542/peds.2011-1762.
Soller L, Teoh T, Baerg I, Gonzalez T, Wong T, Hildebrand KJ, et al. Supervised epinephrine autoinjector administration in a cohort of children with anaphylaxis during oral food challenges (OFCs). J Allergy Clin Immunol. 2018;141(Supplement 2):AB252.
Ruiz-Baques A, Contreras-Porta J, Marques-Mejias M, Cardenas Rebollo JM, Capel Torres F, Arino Pla MN, et al. Evaluation of an online educational program for parents and caregivers of children with food allergies. J Investig Allergol Clin Immunol. 2018;28(1):37–41. https://doi.org/10.18176/jiaci.0214.
Alvarez-Perea A, Cabrera-Freitag P, Fuentes-Aparicio V, Infante S, Zapatero L, Zubeldia JM. Social media as a tool for the management of food allergy in children. J Investig Allergol Clin Immunol. 2018;0 https://doi.org/10.18176/jiaci.0235.
Neupert K, Kunnel S, Freeman S, Pont S, Varshney P. Epinephrine use in Austin Independent School District (AISD) schools after implementation of unassigned epinephrine. J Allergy Clin Immunol. 2018;141(Supplement 2):AB146.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Dr. Parrish reports personal fees and non-financial support from Pharmacy Times Continuing Education, non-financial support from DBV Technologies, and non-financial support from Aimmune Therapeutics, outside the submitted work. Dr. Kim declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Anaphylaxis and Drug Allergy
Rights and permissions
About this article
Cite this article
Parrish, C.P., Kim, H. Food-Induced Anaphylaxis: an Update. Curr Allergy Asthma Rep 18, 41 (2018). https://doi.org/10.1007/s11882-018-0795-5
Published:
DOI: https://doi.org/10.1007/s11882-018-0795-5