Risk factors for severe reactions in food allergy: Rapid evidence review with meta‐analysis

Abstract This rapid review summarizes the most up to date evidence about the risk factors for severe food‐induced allergic reactions. We searched three bibliographic databases for studies published between January 2010 and August 2021. We included 88 studies and synthesized the evidence narratively, undertaking meta‐analysis where appropriate. Significant uncertainties remain with respect to the prediction of severe reactions, both anaphylaxis and/or severe anaphylaxis refractory to treatment. Prior anaphylaxis, an asthma diagnosis, IgE sensitization or basophil activation tests are not good predictors. Some molecular allergology markers may be helpful. Hospital presentations for anaphylaxis are highest in young children, yet this age group appears at lower risk of severe outcomes. Risk of severe outcomes is greatest in adolescence and young adulthood, but the contribution of risk taking behaviour in contributing to severe outcomes is unclear. Evidence for an impact of cofactors on severity is lacking, although food‐dependent exercise‐induced anaphylaxis may be an exception. Some medications such as beta‐blockers or ACE inhibitors may increase severity, but appear less important than age as a factor in life‐threatening reactions. The relationship between dose of exposure and severity is unclear. Delays in symptom recognition and anaphylaxis treatment have been associated with more severe outcomes. An absence of prior anaphylaxis does not exclude its future risk.


| INTRODUC TI ON
Estimating the risk of severe reactions is one of the most significant knowledge gaps in managing people with food allergy. Near-fatal and fatal anaphylaxis to food are rare: the estimated incidence of fatal food-anaphylaxis is 1.81 (95% CI 0. 94-3.45) per million personyears. 1 Near-fatal anaphylaxis to food (requiring intensive care support) is around 10 times more common, but still rare. 2 However, such severe reactions are unpredictable. 3 Most people who die from fatal food-anaphylaxis only have a history of previous mild reactions. 3 Our inability to identify those at greater risk of severe reactions means that people with food allergy are often managed as being at equal risk of fatal reactions. This can cause unnecessary anxiety, excessive dietary restriction and reduced health-related quality of life. Ideally, clinicians would be able to risk-stratify people with food allergy, to provide cost-effective, targeted support to those at greatest risk. Various models incorporating potential risk factors have been proposed-both for any anaphylaxis, and anaphylaxis refractory to treatment (hereafter described as refractory anaphylaxis) 4,5 ; however, the underlying evidence is disparate. Some useful narrative reviews have begun to draw the evidence together, 3 but we identified no systematic reviews exploring this topic. In this rapid review, we summarize what is known about the risk factors for more severe reactions in people with food allergy.

| ME THODS
We systematically searched three bibliographic databases for studies relating to IgE-mediated food allergy or Food protein induced enterocolitis syndrome (FPIES), published between 1 January, 2010, and 31 August, 2021. We searched from 2010 because other reviews covered earlier literature. 3 We extracted data in duplicate, assessed the risk of bias and undertook meta-analysis where appropriate. The online supplement describes the methods in more detail and eligible studies (Tables S1-S5). We included 88 studies (4 systematic reviews, 9 randomized controlled trials and 75 observational studies) and synthesized the evidence according to the categories in Table 1, with an emphasis on modifiable risk factors which could be used to reduce risk.

| Key finding
Thirteen studies evaluated whether a history of prior anaphylaxis predicted future risk of any anaphylaxis. Prior anaphylaxis was not a good predictor, perhaps because severity depends on a range of factors including level of allergen exposure and the presence/absence of co-factors. For fatal food-anaphylaxis, most cases are not associated with a history of prior severe reactions.

| Evidence
There was no evidence that prior anaphylaxis predicted the risk of fatal or near-fatal reaction. 3,6 In the largest reported series of fatal anaphylaxis, over half of food-related fatalities were in individuals with only prior mild reactions. 7 In a unique but small study where food challenges were not terminated at onset of objective symptoms, 21/27 (78%) peanut-allergic children had anaphylaxis when given a sufficient dose of allergen. Thus, the absence of prior anaphylaxis (at least in peanut-allergic children) may reflect insufficient allergen exposure rather than an inherently lower risk of anaphylaxis. 5,8,9 However, many patients with prior anaphylaxis to a food only experience milder symptoms subsequently, whether due to accidental allergen exposure 6,[10][11][12] or at formal food challenges. [13][14][15][16][17][18][19][20] 2.2 | Impact of other allergic diseases

| Key finding
Thirty-four studies (including a systematic review) evaluated the impact of concomitant atopic disease on severity. While diagnosis of asthma was not a risk factor for more severe reactions (Figure 1), it is unclear whether poor asthma control is. In some individuals, active allergic disease of any type may exacerbate severity, but there are no data to suggest an increased risk of fatal or near-fatal outcomes.
although food-dependent exercise-induced anaphylaxis may be an exception. Some medications such as beta-blockers or ACE inhibitors may increase severity, but appear less important than age as a factor in life-threatening reactions. The relationship between dose of exposure and severity is unclear. Delays in symptom recognition and anaphylaxis treatment have been associated with more severe outcomes. An absence of prior anaphylaxis does not exclude its future risk. Note: For the purposes of this table, 'high certainty' means the evidence gives confidence in the conclusion that a variable is or is not a risk factor. Low certainty means that there was some evidence that a variable may be a risk factor, but we were not certain of this conclusion or the size of the impact.

| Evidence
Case series of fatal/near-fatal food-anaphylaxis indicate that asthma is a common co-morbidity. [21][22][23][24] Asthma has therefore been assumed to be a risk factor-something not unreasonable given that the main mechanism of severe outcomes in food allergy involve respiratory compromise. 3 However, asthma is common, present in over 50% of food-allergic individuals. 13,25-28 As a result, and because fatal reactions are rare, 1 the value of asthma as a predictor for severe reactions is low. The vast majority (>99.9%) of food-allergic individuals with asthma will never experience a truly life-threatening reaction. 3 We identified 32 primary research studies and one systematic review evaluating the relationship between asthma and severity (Table S6). 10,[13][14][15][16][17][18] Evidence for asthma as a risk factor was contradictory, even within the same dataset when severity is assessed using different criteria. 41,42 To address this heterogeneity, we performed a meta-analysis using a random effects model. We found no consistent evidence that asthma is associated with increased severity of food-induced reactions (i.e. any anaphylaxis) following accidental allergen exposure, or the need for ICU admission and/or intubation and mechanical ventilation ( Figure 1 and Table 2). Similarly, there was no association between asthma diagnosis and occurrence of any anaphylaxis at food challenge, although challenges are not usually performed in patients with poorly-controlled asthma. Only in retrospective observational studies, where the risk of bias is greater (Tables S4andS6), was there a weak association between asthma and severity.
Most studies, however, do not distinguish between a diagnosis of asthma and the degree of asthma control/underlying airway inflammation. Although evidence is lacking, asthma control may be more relevant than an asthma diagnosis per se. In the UK Fatal Anaphylaxis Registry, over 50% of cases had no evidence of asthma exacerbation in the weeks preceding the fatal event. 7 A retrospective study reported that peanut/tree nut-allergic patients with prior hospital admission for asthma were more likely to experience bronchospasm at historical reactions (OR 6.8, 95% CI 4.1-11.3), but was not included in this analysis due to publication prior to 2008. 53 This study is unfortunately affected by methodological inconsistencies and high risk of bias, but remains the only report identified which has attempted a more discriminatory approach to asthma control. It was included in a 2021 meta-analysis which-in contrast to our meta-analysisdid find a weak association between asthma and severity (OR 1.89,  Table 2 95% CI 1. 26-2.83). 52 This might be due to the inclusion of studies at medium-high risk of bias in the 2021 meta-analysis, and also that only two of the 13 studies included were specific to food.
Eleven papers evaluated the impact of a diagnosis of eczema and/or allergic rhinitis on severity of food-induced reactions. Most reported no association with eczema 10,[15][16][17]29,37,51,54 or allergic rhinitis. 10,15,16,29,33,54 In a prospective multicentre study of anaphylaxis presenting to Emergency Departments in Canada, severe reactions to fruit were more likely to occur in the springtime (OR 1.12, 95% CI 1.03-1.23, adjusted for age, sex, asthma and pre-hospital treatment). 55 There was a weak association between eczema and severity (adjusted OR 1.17, 95% CI 1.03-1.34). In contrast, a prospective study of food-allergic adults in The Netherlands found no impact of active rhinitis on reaction severity. 45 In the United Kingdom, hospital admissions for food-induced anaphylaxis (but not fatal foodanaphylaxis) appear to be more common in the pollen season. 3,56 However, this has not been observed for paediatric admissions to intensive care due to anaphylaxis in North America. 44 This may be because the baseline risk of fatal and near-fatal reactions is so small 1,2 that any impact of concomitant active atopic disease is negligible.

| Key findings
Twenty-five studies examined IgE-sensitization and/or basophil activation tests. Current evidence is that these do not adequately predict severity, although many studies report a correlation. For some foods, molecular allergology may be useful in predicting higher or lower risk of anaphylaxis, particularly when combined with other potential predictors. For tree nuts, IgE against 2S albumins has been reported to be associated with increased rate of any anaphylaxis. 49,51,57 For peanut, IgE-monosensitization to Ara h 8 is associated with a lower risk and usually implies pollen food allergy syndrome (PFAS). 58 LTP-sensitization in the absence of co-sensitization to pollens may imply higher risk in some regions. 59,60

| IgE-sensitization
While high-level IgE sensitization (skin prick test (SPT) wheal and/ or specific IgE to food allergens) are usually associated with clinical reactivity, they do not, in general, predict reaction severity or the occurrence of anaphylaxis at food challenge. 3 Many studies report a correlation between IgE-sensitization and anaphylaxis (Table 3); however, the overlap in SPT/IgE between those with and without anaphylaxis is so extensive that there is insufficient discrimination to predict risk. [14][15][16][17][18]20,27,28,35,39,40,49,51,57,58,[61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] This is clearly demonstrated in well-curated datasets such as the LEAP study cohort ( Figure 2): even IgE to Ara h 2 was not predictive of anaphylaxis at challenge, a finding confirmed elsewhere. 77 Some authors have overestimated the predictive utility of these tests by including non-allergic individuals as 'non-severe' reactors in their analyses. 65,69,[72][73][74]78 While this approach is reasonable in the context of predicting any clinical reaction in people without a confirmed diagnosis, for severity, clinicians more commonly want to assess risk in patients with known allergy. The inclusion of non-reactors significantly overestimates the specificity and thus, the likelihood ratio of the test (see example in Table 4).
The best evidence for IgE-sensitization being suggestive of a higher risk of severe reaction is for Pru p 3 (peach), 66,79 and the 2S albumins in tree nut allergy, 49,51,57 although this may be regiondependent. Some studies report an association between sensitization to specific IgE components and severity; however, often the term 'severity' is used to describe any systemic reaction (as opposed to local oral symptoms)-even if that systemic reaction does not meet established clinical criteria for anaphylaxis. Thus, some studies TA B L E 2 Meta-analysis of studies reporting impact of asthma on severity of food-induced allergic reactions (Forest plots shown in Figure 1) which report an association between severity and Ara h 2 for peanut, 80 Jug r 1/Jug r 4 for walnut, 70 or Cor a 9/Cor a 14 for hazelnut 63,64 are actually describing a higher risk of any systemic reaction, without differentiating between anaphylaxis and systemic (but nonanaphylaxis) reactions such as generalized urticaria. This may explain why the diagnostic cut-offs in some of these studies are similar to those reported to be 95% predictive of any clinical reaction.
Birch-pollen sensitization is associated with less severe reactions in people allergic to peanut 58 or hazelnut, 57 probably because this is indicative of Bet v 1-mediated PFAS, rather than primary sensitization to a food allergen. 81

| Variations in host cellular responses
Some studies report that the basophil activation test (BAT) predicts severity (Table 4), 35,40,70,74 but as with IgE-sensitization, reported analyses sometimes overestimate predictive utility by including nonreactive individuals. 70 Nonetheless, in a re-analysis of data from the LEAP study cohort (excluding non-allergic individuals), BAT was still the best predictor of life-threatening reactions (such as persistent hypotension and/or hypoxia with decreased level of consciousness) at peanut challenge, although IgE to peanut was not statistically inferior. However, in predicting any anaphylaxis (rather than lifethreatening anaphylaxis), BAT was inferior to IgE to peanut, Ara h 2 and even SPT (Table 4 and Figure S4). [70][71][72] Combining multiple parameters into a predictive model may provide better accuracy. Incorporating component-resolved diagnostics (but not IgE to whole allergen) into a model improved prediction of more severe symptoms and anaphylaxis for peanut, 48 hazelnut 49 and walnut. 41 Including BAT may further increase predictive utility, 70 because BAT reflects a more functional readout of the ability of IgE to trigger cellular degranulation-in much the same way that the mast cell activation test has also been shown to correlate with severity. 85 However, till date, this has only been evaluated in predicting lifethreatening reactions in a cohort where only 12 children had severe reactions. 70 The extent and frequency of IgE binding (including for specific epitopes) have been reported to correlate with symptom severity at food challenge in some studies, [86][87][88][89][90] but including IgE avidity and diversity in a prediction model for any symptoms in peanutallergic individuals did not improve diagnostic utility compared to peanut components. 87 These data imply that a more complex integration of different allergen-antibody-effector cell interactions might confer better severity prediction, but larger and combined datasets reflecting different populations are needed to evaluate whether such models can be helpful in risk-stratifying patients.

| Mastocytosis and elevated baseline mast cell tryptase
There is little evidence that the association of clonal mast cell disorders with severe hymenoptera allergy also applies to food allergy. 91 Raised mast cell tryptase (MCT) due to hereditary alpha tryptasaemia (HαT) affects around 5% of the population, and is associated with severity in hymenoptera allergy. 92

| Key findings
Thirty-three studies investigated aspects of allergen presentation.

| Evidence
Anaphylaxis to food is, in general, of lower severity than that due to non-food triggers, 12

| Dose
The relationship between dose/level of exposure and severity is complex and unclear. 5 For accidental reactions in the community setting, it can be very difficult to accurately determine the degree of allergen exposure associated with an event, particularly those associated with fatal outcomes. 5 Most individuals experience mild symptoms at food challenge prior to developing more significant (and less mild) symptoms to a dose sufficient to meet challenge stopping criteria 83 -after all, the basic premise of food challenges is the assumption that incremental dosing effectively dose-limits severity (see Figure 3). In a small study of 27 children reacting to peanut at food challenge, 21 had anaphylaxis but only three as initial presenting symptoms; 13 children presented with initial non-anaphylaxis symptoms but then developed anaphylaxis with further peanut ingestion. 8 This pattern has been reproduced elsewhere: that individuals often show a dose-response between symptoms and level of allergen exposure, at least for the occurrence of any anaphylaxis, but this may not be apparent in larger datasets. 9 In an analysis of 734 double-blind, placebo-controlled food challenges from The Netherlands, dose predicted only 4.4% of the variance in reaction severity 15 -in other words, dose was not an important factor. Within a population, there will be a mixture of different allergic phenotypes, with some individuals showing a dose-response but others not. 9 Most datasets show that severe reactions can occur at all levels of allergen exposure (which further obscures the dose-severity relationship in larger datasets), 29 although significant symptoms are very uncommon to sub-milligram levels of protein. 113,114 Finally, in the challenge setting, potential severity may be dose-limited; so, these data may F I G U R E 2 Raw data (skin prick test (SPT), IgE to peanut and Ara h 2) from children with peanut-induced allergic reactions in the LEAP study cohort. [72][73][74] There is extensive overlap between (A) those with anaphylaxis and (B) those with severe reactions (Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 reaction) and non-severe group despite statistical significance between groups not be applicable to accidental reactions in the community. 9 This is important, as controlling exposure is a key modifiable factor for food businesses aiming to provide safe food for people with food allergy.
For any given individual patient, therefore, the absence of prior anaphylaxis may be due to insufficient allergen exposure causing previous reactions, (rather than the patient being at an inherently lower risk). 3,5,6,8,9,12 Therefore, a history (or not) of anaphylaxis is a poor predictor of future anaphylaxis. 6 At least one fatal reaction to baked milk has been reported at inhospital food challenge. 120 It has been suggested that the lack of tolerance to baked milk may be a marker of more severe allergy to cow's milk, 121 although this has not been evaluated prospectively.
The fat content of the food matrix can impact on the dose threshold triggering symptoms, and the severity of those symptoms, at least for peanut 122,123 and hazelnut, 123 although not for egg. 124 Food processing has a significant impact on the bioavailability of egg and peanut allergens in vitro, [125][126][127] but the data are currently lacking to evaluate the clinical relevance of these findings.

| Key findings
Risk-taking is a clear concern in managing people with food allergy, but there is insufficient evidence that risk-taking is a major factor in TA B L E 4 Impact of including non-reactor patients on test sensitivity/specificity/likelihood ratio (LR) when evaluating the diagnostic utility of different biomarkers to predict the occurrence of anaphylaxis or severe reactions to peanut at food challenge, using data from the LEAP study cohort. [72][73][74] Bold text represent re-analysis using data from allergic individuals only, in contrast to analyses which included non-allergic participants as non-severe reactors. Receiver-operating characteristic (ROC) curves used to derive area under ROC curve (AUC) are shown in Figure S4 Parameter Diagnostic cut-off AUC

F I G U R E 3
Evolution of symptoms and clinical reactivity at food challenge. Many individuals will experience initially subjective symptoms, with objective symptoms appearing with further doses (A). Anaphylaxis will only develop if the food challenge continues. Others will experience anaphylaxis as their first objective symptom: either at a dose of allergen exposure with no preceding subjective symptoms (B), or with prior subjective symptoms (C), without evidence of a clear dose-response for symptoms. Note that anaphylaxis can occur at all levels of exposure (both at low levels of allergen exposure, represented by the solid bars, and higher doses indicated by dotted lines). Reproduced under the terms of the Creative Commons Attribution License from reference 9 2.5.2 | Impact of age Epidemiological data suggests an age-related increase in severe food-anaphylaxis in adolescents and young adults. 1,32-37,43,106-10 8 Often, this is assumed to be due to risk-taking behaviours such as deliberately eating risky food or refusing to carry rescue medication. 128,129 However, an analysis of national fatal anaphylaxis data from the UK reported that this age-related increase in near-fatal and fatal food-anaphylaxis persists well into the fourth decade of life. 2,34 The authors suggested that there may be an 'age-specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades'. 34 Adolescents use a variety of different strategies to manage risk, and most teenagers manage their food allergies well. 129,130 Risk-taking can be a deliberate act by adolescents to increase their independence, 3 but can be mitigated by 'transitioning' children to self-care (from around age 11 years). Specific educational interventions targeting teenagers and young adults are unlikely to be harmful, but there is an absence of evidence as to whether such strategies reduce the risk of severe outcomes. 130

| Exercise
Exercise is the most well-described cofactor in food-anaphylaxis, reported in 10-20% of cases. 47,131,132 It is also a common cofactor in adverse events due to oral immunotherapy. 47 developing allergic symptoms to more typical levels of wheat exposure in the context of exercise. 135 The authors suggest that many individuals with WDEIA are wheat-allergic even at rest, but tolerate normal levels of wheat ingestion in the absence of exercise due to a very high reaction threshold. However, in the presence of exercise, there is a significant drop in reaction threshold resulting in symptoms to more typical levels of wheat exposure, resulting in reactions.
The authors also observed a greater tendency towards any anaphylaxis with exercise, which might imply a relationship between dose and resulting reaction severity. 135 A randomized controlled study in 73 peanut-allergic adults reported that exercise can reduce an individual's reaction threshold. 13 However, this was based on dose-distribution modelling which may have over-estimated the effect. Analysis of the raw data shows that the average change was more modest. 136

| Key finding
Based on 6 studies, it is likely that β-blockers and/or angiotensinconverting enzyme (ACE) inhibitors can increase reaction severity, although any impact seems to be less than other factors such as age, exposure to a non-food trigger or mast cell disease.

| Evidence
The impact of medication on severity is difficult to disentangle, because the underlying reason for prescription (e.g. cardiovascular disease, age) is likely to be a confounder. 3,37 Few studies have attempted to adjust for this. In a large retrospective study of emergency presentations for anaphylaxis, ACE inhibitor prescription was associated with increased odds of severe reaction after adjusting for cardiovascular disease and age. There was no increased risk for antidepressants, β-blockers, alpha-adrenergic blockers or angiotensin II receptor antagonists. 33 An association between β-blockers or ACE inhibitors and severity has also been reported in prospective 48 and retrospective 41,131 case series. Acetylsalicylic acid (aspirin) and other non-steroidal, anti-inflammatory drugs (NSAIDs) have also been reported to increase severity in some analyses, 48,137 but not in others. 10 Cofactors such as NSAIDs and exercise may influence severity through an impact on allergen absorption. 3 The gastrointestinal epithelial barrier can be impaired in food allergy, although consistent evidence is lacking. 139 Intestinal permeability is not predictive of food allergy, 140 but may have a key role in WDEIA. 141 Measuring food proteins in serum following ingestion is difficult. 139 Nonetheless, greater absorption kinetics for peanut has been reported peanutallergic subjects compared with non-allergic controls: significantly lower amounts of peanut (30mg protein) were required to detect Ara h 6 in serum samples in peanut-allergic individuals, and for any given peanut dose ingested, higher Ara h 6 was found in sera from peanut-allergic participants versus controls. 139 Whether this phenomena reflects antibody-mediated facilitated absorption is unclear.
Allergen absorption kinetics may be a key determinant of severity in a murine model of peanut anaphylaxis 142 ; thus, further in-human studies are warranted.

| Non-modifiable host factors
Many studies report an association between age and risk of foodanaphylaxis of any severity, 20,28,33,37,44,104,110,114 but not all. 14,27,100 Anaphylaxis is most commonly reported in preschool children age 0-4 years, although severe or fatal outcomes in this age group are rare. 34,108 The age group at greatest (although still very low) risk of near-fatal and fatal anaphylaxis to food is in adolescents and adults up to age 40 years. 2,34,108 Males may be at slightly higher risk of severe anaphylaxis, both pre-and post-puberty. 143 At least one fatal series has reported male sex to be a risk factor. 106

| Management of allergic reaction
Delays in symptom recognition and treatment of anaphylaxis have been associated with more severe outcomes in anaphylaxis, including need for intensive care and length of hospital stay. 3,42,48,100,[145][146][147] Whether delays in adrenaline treatment also increase the risk of biphasic anaphylaxis is less clear. [145][146][147][148] There is no evidence that treating non-anaphylaxis reactions with adrenaline helps prevent progression to anaphylaxis. 147,149 Observational data from food challenges in peanut-allergic adults have shed new light on homeostatic mechanisms which can compensate for anaphylaxis and prevent severe outcomes. 150,151 One hypothesis is that individuals at greater risk of severe reactions may be less able to compensate for an allergic insult (e.g. through endogenous catecholamine production) ( Figure 4), 42,150 but this needs further evaluation.

| SE VERIT Y CONSIDER ATIONS: FOOD PROTEIN INDUCED ENTEROCOLITIS SYNDROME
We identified only 2 papers eligible for inclusion about FPIES. One noted that poor weight gain was more common where the trigger was cow's milk or banana. Why banana might be a risk factor is unclear. 152 Another study of 222 FPIES food challenges had only four severe reactions, which precludes any meaningful analysis. 153

| CON CLUS IONS
It is vital that food-allergic individuals receive reliable and accurate information to help them self-manage their condition. Our comprehensive review suggests that there is much left to learn about risk factors for anaphylaxis and life-threatening reactions ( Table 1).
Absence of prior anaphylaxis does not exclude future risk of anaphylaxis, and history alone is not a good predictor because severity depends on multiple factors including dose of exposure and the presence or absence of cofactors (e.g. exercise, concurrent viral infections and some medications).
Importantly, our review challenges widely-held (but evidencepoor) conventions that asthma or degree of IgE-sensitization are useful predictors. Our meta-analysis shows that a diagnosis of asthma in itself is unlikely to be a significant risk factor if asthma control is satisfactory.
Higher levels of IgE-sensitization are associated with a history of anaphylaxis, but in practice, biomarkers of IgE-sensitization are not helpful in predicting severity. Clinicians may incorrectly interpret low levels of IgE-sensitization as implying a lower risk of anaphylaxis and provide incorrect information to their patients as a result, while those with high IgE-sensitization are wrongly counselled that they are at high risk of severe reactions. Similarly, most individuals with food allergy experience oral symptoms to low doses: thus, the occurrence of oral symptoms alone to low allergen exposure must not be assumed to imply PFAS, and therefore, a lower risk of anaphylaxis.
Individuals with food allergy must understand that they can experience anaphylaxis in the future, even if they appear to be at low risk. All patients with food allergy need to be able to recognize and appropriately self-manage anaphylaxis. It is necessary to weigh up the whole clinical scenario carefully when evaluating risk. A history of previous anaphylaxis would place an individual in a risk group where access to self-injectable adrenaline is indicated. Healthcare professionals might consider that other factors, such as being an adolescent or young adult, also move an individual into a higher risk category.
Those with food allergy need to be informed that future reactions may be of differing severities. They need to be counselled as to the potential for some cofactors to increase reaction severity, and if they have coexisting asthma, it is prudent to optimize asthma control.
Our inability to accurately risk-stratify food-allergic individuals is an important knowledge gap. As a consequence, many patients are prescribed self-injectable adrenaline yet most do not use it, even when indicated. Being able to predict those most at risk would help to target interventions towards those at greatest risk. Large longitudinal population-based studies are needed to identify specific factors which predict future risk. This will help achieve a better understanding of the underlying mechanisms of severe allergic reactions, from initiation to end-organ involvement.

F I G U R E 4
Factors which influence the severity of anaphylaxis. Elicitors and cofactors may act synergistically making anaphylaxis more likely. The natural ability of the body to compensate for anaphylaxis in combination with therapeutic measures will moderate the severity of reaction. CMPA, cow's milk protein allergy; LTP, lipid transfer protein the receipt of honoraria or consultation fees by the following com-