University of Groningen
The Severity of Anaphylactic and Systemic Allergic Reactions
Pettersson, Maria Eleonore
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CHAPTER 9
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This thesis provides an overview of a number of biochemical, genetic and clinical factors influencing the severity of systemic allergic and anaphylactic reactions. Special attention was given to the relationship between the eliciting dose and the severity of reaction in food allergy. In this chapter, we provide a summary and general discussion of the main results of our research, with future perspectives.
SuMMaRY of paRt i: thE SEVERitY of SYStEMic anaphYlactic anD AllERgIC REACTIONS IN pEdIATRIC fOOd AllERgy
chapter 2 - is 30 minutes between doses long enough in oral food challenges?
The objective of the study in chapter 2 was to investigate whether an interval of 30 min-utes between doses in the DBPCFC is long enough for patients reporting time intervals of ≥30 minutes between ingestion of the culprit food and the subsequent reaction. These patients could receive a subsequent dose before having reacted to the previous dose and thus react to accumulated doses, which might be more severe than reactions to individual doses.
Patients were divided into two groups based on their reaction time, with comparison of the eliciting dose (ED), cumulative dose (CD) and the severity of the challenge reaction. This analysis showed that patients reporting time intervals of ≥30 minutes between inges-tion and reacinges-tion had higher EDs and CDs in the DBPCFC, than those reporting shorter time intervals between ingestion and reaction (<30 min). However, these patients did not have more severe reactions. This suggests that these patients do indeed accumulate doses in oral food challenges with 30 minute intervals between dose increments.
In conclusion, although some patients may accumulate and react to more than one dose during the DBPCFC, a dosing interval of 30 minutes is long enough to allow for this test to be conducted safely in these patients.
chapter 3 - prediction of the severity of allergic reactions to foods
The aim of this study was to identify independent predictors for the severity of diagnostic and accidental food allergic reactions. An additional objective was to quantify the impact of these factors and to investigate whether more severe reactions tended to occur at higher doses. The analysis was performed by using two different scoring systems for the reaction severity.
116 CHAPTER 9 The results of this study showed that the severity of reactions during DBPCFCs and ac-cidental reactions to foods are determined by numerous factors. However, the severity of food allergic reactions remains largely unpredictable.
The results also showed that the use of different severity scoring systems may give differ-ent or even contradictory results depending on the distribution of the data in a particular population. Although the severity of DBPCFC reactions are associated with a lower elicit-ing dose, the small size of this effect suggests that the impact of dose limitation as a public health measure is unlikely to reduce severe reactions more than milder ones. Finally, clinicians should not use the eliciting dose obtained from a graded food challenge to as-sess the need for stringent avoidance of allergenic foods or prescription of self-injectable epinephrine.
chapter 4 - Greater severity of peanut challenge reactions using a high fat versus low fat matrix vehicle
In chapter 4, we examined possible matrix effects of a high fat and low fat content food matrix during DBPCFCs with peanut, by comparing the severity of reactions and eliciting doses.
The results of this study showed that children challenged with peanut in the high fat ma-trix had more severe reactions during the DBPCFC, compared to children challenged with peanut in the low fat matrix. However, there was no significant difference in eliciting dose. In conclusion, this supports the role of the food matrix as a factor which may increase the severity of reactions. This result could have implications for the safety of oral food challenges and peanut immunotherapy.
chapter 5 - clinical reactivity to individual tree nuts and peanut differs among the sensitized pediatric population
The aim of the study in chapter 5 was to investigate whether there are any differences in the frequency and severity of accidental and DBPCFC reactions between tree nuts and peanut in children.
This showed that true clinical reactivity to hazelnut and almond was less frequent com-pared to peanut. Moreover, sensitization was more frequently asymptomatic for hazelnut and almond when compared to peanut. However, true clinical reactivity for cashew and walnut was more frequent than for peanut. No difference in the severity of the DBPCFC reaction between the different types of nuts was found. However, accidental reactions to cashew were more severe than those for peanut.
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In conclusion, the frequency of true clinical reactivity differs between patients sensitized to peanut and tree nuts. The DBPCFC is especially important for the confirmation of ha-zelnut and almond allergy due to common asymptomatic sensitization. Finally, cashew nut allergy should be prioritized for the development of measures to prevent severe ac-cidental reactions.
chapter 6 - apolipoprotein B: a possible new biomarker for anaphylaxis
The objective of this study was to examine the serum level of apolipoprotein B-100 as a potential biomarker for the occurrence and severity of anaphylactic reactions to foods. A more severe accidental reaction was associated with a lower serum level of apolipopro-tein B. The level of apolipoproapolipopro-tein B was not associated with the food challenge outcome or the severity of the DBPCFC reaction.
This suggests that the level of apolipoprotein B might be a biomarker for the severity of anaphylactic reactions, probably through its association with the less stable platelet-activating factor acetyl hydrolase. The serum level of apolipoprotein B only explains a relatively small part of the reaction severity, however serum samples collected closer in time to the reaction or from other types of anaphylactic reactions may be more informa-tive.
chapter 7 - association of Stat6 gene variants with food allergy diagnosed by double-blind placebo-controlled food challenges
The study in chapter 7 describes the role of two STAT6 gene variants in food allergic chil-dren diagnosed by double-blind placebo-controlled food challenges. This was performed by investigating the association of two selected single nucleotide polymorphisms (SNPs) in the STAT6 gene, rs324015 and rs1059513, with the level of sIgE, eliciting dose and the severity of the reaction during the DBPCFC.
The results showed that there is an association between a greater eliciting dose and the A alleles of rs1059513 in children allergic to peanut and cow’s milk. There was also an as-sociation with the A allele of rs324015 in peanut allergic children. This suggest that these A alleles are associated with a less dose sensitive phenotype, and that allergic subjects carrying these alleles are probably at lower risk for the occurrence of accidental allergic reactions. However, these A alleles were also associated with more severe DBPCFC reac-tions. This suggests that the severity of reaction and dose sensitivity should be considered as independent entities in food allergy, with separate genetic control.
In conclusion, STAT6 genetic polymorphisms are involved in the pathophysiology of food allergy and their role seems to be independent of the culprit food.
118 CHAPTER 9 SuMMaRY of paRt ii: thE SEVERitY of SYStEMic anaphYlactic anD allERGic REactionS in aDultS with YEllow jackEt VEnoM allERGY chapter 8 - Mastocytosis and age, but not baseline tryptase, specific igE or total igE, independently determine the severity of systemic reactions to yellow jacket stings.
The purpose of this study was to determine independent clinical risk factors for systemic reaction severity to yellow jacket stings in untreated patients, with and without indolent systemic mastocytosis (ISM). An additional aim was to quantify the impact of these factors. The results showed that ISM and older age were independent predictors for the severity grade, but not baseline serum tryptase (bsT) level , specific IgE, total IgE or a history of serious cardiovascular event. This prediction model explained 23.0% of the variance of the severity grade. Thus, ISM and older age should be considered in the risk assessment of severe yellow jacket sting reactions. BsT does not predict the reaction severity indepen-dently of the diagnosis of ISM. However it is useful for diagnosing and screening for ISM. In conclusion, the severity of reactions to yellow jacket stings remains for the greatest part unpredictable.
GEnERal DiScuSSion
the relationship between dose and severity of reactions
The relationship between the dose and the severity of reaction is complex. The concept of threshold dose illustrates this complex relationship. The threshold dose has been defined as the lowest dose which elicits an allergic reaction in an individual patient. (1) Ingestion of a dose below this amount will not elicit an allergic response. This phenomenon is shown during oral food challenges, since not all allergic patients react to the first dose. How-ever, this concept has been further extrapolated to the notion that a larger dose above a subject’s individual threshold will cause a more severe reaction, even though there is no direct evidence for this. (2) In this section we will look more closely into the relationship between the severity of reaction and dose.
The threshold dose is a theoretical concept and therefore it cannot be determined clini-cally. An estimation of the threshold dose in clinical practice is the eliciting dose as deter-mined during diagnostic graded oral food challenges. The eliciting dose is thus probably slightly higher than the theoretical threshold dose, but it can identify highly dose sensitive patients as well as patients who react to large doses during the DBPCFC. (1)
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the eliciting dose and severity of reaction during DBpcfc reactions
There are several difficulties with examining the relationship between the eliciting dose and severity of reaction during oral food challenges. One of these difficulties is the stepwise administration of doses. Patients reporting longer time intervals between ingestion of the culprit food and the allergic reaction, compared to the time interval between doses, could receive a subsequent dose before having reacted to the previous dose and thus react to accumulated doses. This was examined in the study in chapter 2, which showed that these patients indeed had higher EDs and CDs, however they did not have more severe reac-tions. Thus, even though these patients received a higher dose in the DBPCFC, they did not have more severe reactions. Moreover, the stepwise administration of doses during oral food challenges have previously been shown to induce a short-lived desensitization effect in some patients, and could thus result in a transient oral tolerance to the tested food. (3) However, this effect was no longer present when the total cumulative dose ingested during the food challenge was given as one dose the next day.
Another challenge in examining the relationship between the severity of reaction and dose is the influence of the food matrix. Not only could the food matrix influence the digestion and the amount of allergen absorbed, but it could also have an impact on the immunological response to the specific allergen. (4) In chapter 4 this matrix effect was examined for peanut by using a high fat and a low fat food matrix during the DBPCFC. However, a previous study from our center showed no such effect for DBPCFC with hen’s egg. (5) Thus, matrix effects may differ for different types of food.
The severity of reaction during DBPCFCs are generally milder than accidental reactions. (chapter 3) This is probably due to that oral food challenges take place in a controlled environment and augmentation factors must be minimized and the patient stable before commencement of the test. However, relatively severe reactions do occur during oral food challenges, in spite of the previously mentioned reasons, and even though an incremental dosing scheme is being used.
accidental reactions, dose sensitivity and ingested dose
The relationship between the ingested dose and the severity of the accidental reaction is also difficult to study. Clinicians must rely on the ingested dose reported by patients, which is inexact and may be affected by recall bias. In addition, to be able to determine the difference between the ingested dose and the level of dose sensitivity, the eliciting dose for that patient must be known. Thus, in a research setting, using the eliciting dose is more reliable than estimations of the ingested dose. (2) The eliciting dose did not predict the severity of the accidental reaction.(chapter 3) This suggests that dose sensitivity does not have a large impact on the severity of accidental reactions.
120 CHAPTER 9 A recent study of single dose oral food challenges, which is more similar to accidental exposures than incremental oral food challenges, showed surprisingly mild reactions during the single low-dose oral food challenges. (6) In another study, where the oral food challenge procedure was allowed to continue with additional doses after an initial mild reaction, 62% of patients had allergic reactions which progressed to anaphylaxis with increasing doses. However, the eliciting dose did not predict anaphylaxis. (7) Thus, the concept that a larger dose above a subject’s individual threshold will cause a more severe reaction for all patients, seems to be too simplistic.
a theory for explaining the relationship between the severity of reaction and dose
The weak relationship between the eliciting dose and the severity of the DBPCFC reaction,(chapter 3) could theoretically be explained by differences in the slope and/or shift of dose-response curves in individual patients. These curves could possibly shift and reshape by the influence of augmentation factors, development of tolerance and other factors associated with the severity of reaction and eliciting dose. An example of factors previously shown to influence the threshold dose during oral peanut immunotherapy is lack of sleep, exercise and acute infections. (8) Furthermore, factors previously shown to be associated with a lower eliciting dose in children are increasing age, higher specific IgE level, and the absence of atopic dermatitis. (9) These factors were also shown to be predictive of the severity of accidental and/or DBPCFC reactions in chapter 3. Below we will explore the relationship between an increasing dose and the severity of reaction in four individual, hypothetical subjects.
In Figure 1 and Figure 2 the dose-response relationship for 4 subjects are shown, when ad-ditional doses are given after the initial response. Severity of reaction is graded as: mild= 1, moderate= 2, and severe= 3. In Figure 1, subject 1 reacts to the second dose and a severe reaction is provoked after dose 5 has been ingested. In subject 2, a reaction is seen after the 4th dose, however after all doses have been given the maximum reaction severity is a moderate reaction. Thus a severe reaction could not be triggered in this subject. In Figure 2, subject 3 reacts to the 2nd dose given and the severity of reaction gradually in-creases with each additional dose given, until the final dose, where the maximal response is reached. For subject 4 however, the initial reaction is instantly the most possible severe reaction at dose 7. Thus for subject 3, having a lower dose sensitivity compared to subject 4, but an equal maximum response, there is a clear dose-response relationship since the slope is less steep than the curve of subject 4.
SUMMARY AND GENERAL DISCUSSION 121
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Figure 1. Dose-response relationship in subject 1 & 2 when additional doses are given after the initial response.
In Figure 2, subject 3 reacts to the 2nd dose given and the severity of
reaction gradually increases with each additional dose given, until the final dose, where the maximal response is reached. For subject 4 however, the initial reaction is instantly the most possible severe reaction at dose 7. Thus for subject 3, having a lower dose sensitivity compared to subject 4, but an equal maximum response, there is a clear dose-response relationship since the slope is less steep than the curve of subject 4.
0 1 2 3
Dose 1Dose 2Dose 3Dose 4Dose 5Dose 6Dose 7Dose 8
Se ve rit y of re ac tio n (0 -3 ) Subject 1 Subject 2
Figure 1. Dose-response relationship in subject 1 & 2 when additional doses are given after the
initial response.
Figure 2. Dose-response relationship in subject 3 & 4 when additional doses are given after the initial response.
These figures illustrate that it is not possible to trigger a severe reaction all subjects, (subject 2) when additional doses are given. (7) It also shows that for some subjects the initial response is the most severe possible outcome (subject 4), while for others there is a clear dose-response relationship (subject 1-3). Previous studies have shown that the severity of reaction is associated with the basophil reactivity and that the eliciting dose is associated with the basophil sensitivity in the basophil activation test. (10, 11)
A possible explanation for why it is not possible to trigger a severe reaction in certain subjects when additional doses are given could be that these subjects have a reduced amount of reactive basophils. As a result, a severe reaction cannot be elicited because of a ceiling effect of the basophil activation and/or another immunological process. In addition, it is possible that the slope of the curve, could represent a function of the basophil activity and basophil sensitivity. Knowing the slope of the dose-response curve in individual patients, could be important for risk management. Thus it might be possible in the future to identify patients who show a
dose-0 1 2 3
Dose
1 Dose2 Dose3 Dose4 Dose5 Dose6 Dose7 Dose8
Se ve rit y of re ac tio n (0 -3 ) Subject 3 Subject 4
Figure 2. Dose-response relationship in subject 3 & 4 when additional doses are given after the
initial response.
These figures illustrate that it is not possible to trigger a severe reaction all subjects, (sub-ject 2) when additional doses are given. (7) It also shows that for some sub(sub-jects the initial response is the most severe possible outcome (subject 4), while for others there is a clear
122 CHAPTER 9 dose-response relationship (subject 1-3). Previous studies have shown that the severity of reaction is associated with the basophil reactivity and that the eliciting dose is associated with the basophil sensitivity in the basophil activation test. (10, 11)
A possible explanation for why it is not possible to trigger a severe reaction in certain sub-jects when additional doses are given could be that these subsub-jects have a reduced amount of reactive basophils. As a result, a severe reaction cannot be elicited because of a ceiling effect of the basophil activation and/or another immunological process. In addition, it is possible that the slope of the curve, could represent a function of the basophil activity and basophil sensitivity. Knowing the slope of the dose-response curve in individual patients, could be important for risk management. Thus it might be possible in the future to identify patients who show a dose-response relationship by basophil activation assays. In addition, it might also be possible to identify patients who will not develop a severe reaction, such as subject 2, with this test.
Genetics in food allergy, the severity of reaction and eliciting dose
In chapter 7 we examined the role of two STAT6 gene variants in food allergic children diagnosed by DBPCFCs. Interestingly, the results showed an association between the A alleles of rs1059513 in children allergic to peanut and cow’s milk. There was also an as-sociation with the A allele of rs324015 in peanut allergic children. This suggests that these A alleles are associated with a less dose sensitive phenotype, and that allergic subjects carrying these A alleles are thus probably at lower risk for the occurrence food allergic reactions. (chapter 7) Furthermore, in a previous study, a higher eliciting dose was associ-ated with an earlier resolution of milk, peanut and tree nut allergy. (12) Thus, our results are in line with another study which describes an association between the A genotype in rs324015 and a younger age of developing tolerance in cow’s milk allergy. (13)
However, both A alleles were also shown to be the risk allele for having food allergy and more severe DBPCFC reactions. (chapter 7) This result confirms recent insights into the in-dependence of clinical reaction severity and dose sensitivity in food allergy. (2, 7, 14) Here we add to these observations and show that clinical reaction severity and dose sensitivity may be under genetic control by a pleiotropic effect of STAT6. (chapter 7)
conclusion on the relationship between the eliciting dose and severity of reaction
Even though there seems to be a weak relationship between the eliciting dose and the severity of DBPCFC reactions, this association is not clinically useful. (chapter 3) Moreover, the results of this thesis shows clearly that the eliciting dose and the severity of reaction should be considered as separate factors in food allergy.(chapter 2-5 and 7)
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apolipoprotein B as a possible biomarker for the severity of anaphylactic reactions
Apolipoprotein B had a significant association with the severity of the accidental reaction in children suspected of food allergy. (chapter 6) However, apolipoprotein B was not a significant predictor for the severity of the yellow jacket venom sting reaction in an adult population. (chapter 8) This could be explained by the high rate of cardiovascular disease in the adult population as compared to the pediatric one. Apolipoprotein B does not only seem to be related to anaphylactic reactions (chapter 6), but it also has a strong con-nection to cardiovascular disease. (15) In our pediatric population this relationship was inverse, thus a higher level of apolipoprotein B was associated with less severe accidental reactions. However, an increasing level of apolipoprotein B is associated with several cardiovascular diseases and low levels may even be protective. (15) This could explain why apolipoprotein B was not a significant predictor for the reaction severity in yellow jacket venom allergy in adults.
current challenges and future perspectives in predicting the severity of anaphylactic and systemic allergic reactions
There are several challenges when aiming to predict the severity of anaphylactic and systemic allergic reactions. The multifactorial nature makes it difficult to predict and to identify all independent factors. (Chapter 3, 8) In addition, it has previously been shown that there is noteworthy inter-investigator variability in the interpretation of food allergic clinical symptoms. (16) The implementation of a widely accepted definition and clinical guidelines for diagnosing severe reactions could help to improve this issue. These will need to be applicable to diagnostic allergic reactions and to accidental reactions. The use of different scoring systems for severe reactions can lead to unexpected differ-ences in the results. An example of this was shown in chapter 3, where the direction of the association between the eliciting dose and severity of the DBPCFC reaction depended on the scoring system used. Therefore, the development of a unified scoring system for severe reactions would make the definition of severe reactions more clear and make the results of research easier to interpret and compare in systematic reviews.
In conclusion, the severity of anaphylactic and systemic allergic reactions is multifactorial and difficult to predict. Thus, the majority of factors determining the severity of anaphy-lactic and systemic allergic reaction remain unknown. New factors need to be identified to allow for accurate prediction of these severe reactions.
124 CHAPTER 9 REfERENCES
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