University of Groningen
The Severity of Anaphylactic and Systemic Allergic Reactions
Pettersson, Maria Eleonore
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Publication date: 2018
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Pettersson, M. E. (2018). The Severity of Anaphylactic and Systemic Allergic Reactions. University of Groningen.
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CHAPTER 2
I
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mINUTEsbETwEENDOsEsLONGENOUGhINORALfOODChALLENGEs?
M. Eleonore Pettersson Bertine MJ. Flokstra- de Blok Sicco van der Heide
Jeanet Kukler Anthony EJ. Dubois
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ABSTRACT
It is currently unknown whether the interval between doses in the double-blind, placebo-controlled food challenge (DBPCFC) is long enough to avoid accumulation of doses and the occurrence of potentially more severe reactions. The objective of this study was to investigate if patients who report longer time intervals (≥30 minutes) between ingestion of the allergen and the subsequent reaction, react to higher doses and have more severe reactions in the DBPCFC than patients with more rapid reactions (<30 minutes). The re-sults of this study showed that patients reporting longer time intervals between ingestion and reaction had a higher dose in the DBPCFC than those reporting more rapid reactions. (Eliciting dose: U=2531.5, P=0.004 Cumulative dose: U=2561.5, P=0.005) However, they did not experience more severe reactions (U=3149.0, P=0.214). An interval of 30 minutes between doses is thus long enough to allow for the DBPCFC to be performed safely in all patients, including those who may react to accumulated doses.
2 intRoDuction
To the Editor,
In clinical practice, the double-blind, placebo-controlled food challenge (DBPCFC) is consid-ered the gold standard for diagnosing food allergy (1). This test is performed with gradual increases in the dose of the culprit food at regular time intervals to reduce the adverse events. When performing the DBPCFC, an interval of 30 minutes is often used between the doses(1,2). However, it is currently unknown whether this interval is long enough to avoid reactions to accumulated doses, which might be more severe than reactions to individual doses.
The objective of this study was to investigate if an accumulation of doses in the DBPCFC occurs in patients who report longer time intervals (≥30 min) between ingestion of the culprit food and the subsequent reaction, as these patients could receive a subsequent dose before having reacted to the previous dose. This was done by dividing patients into two groups based on reaction time and comparing the eliciting dose (ED) and the cumula-tive dose (CD) as well as the severity of the challenge reaction, corrected for confounders for these outcomes. As patients with longer reaction times by history (≥30 min) might be expected to accumulate doses during challenge testing, they could have higher EDs and CDs as well as more severe reactions than those with shorter reaction times (<30 min). METhOdS
A database analysis of positive DBPCFCs (2002–2011), performed at University Medical Center Groningen was carried out. Children were challenged as a part of routine care for sus-pected food allergy. Unstable comorbidity or unwillingness to undergo the test were the only reasons to forego challenge testing, which was the case in <2% of the individuals. No children were excluded because of a history of previous anaphylaxis. Challenges were excluded from the present analysis when multiple food challenges to the same food were performed; in which case only the first challenge to each food was included (90 cases excluded). Patients were also excluded when there was no medical history for the tested food (103 cases) or if there was incomplete data for the relevant variables (92 cases). The exclusion of patients with only subjective symptoms in the DBPCFC (28 cases) had no influence on the outcome. Results from the five most commonly challenged foods were used for the analysis: milk, egg, peanut, hazelnut, and cashew nut. The DBPCFCs were performed according to previ-ously published procedures and protocols (2, 3). In brief, a food matrix was used to mask the suspected allergenic food. Administration of placebo and allergenic food using an
28 CHAPTER 2
incremental, ‘semi-logarithmic’ scale occurred on separate days, at least a week apart, in random order. Double blinding was maintained until 48 h after the second test day. A food challenge was considered positive when objective symptoms occurred on the allergenic food-test day but not on the placebo day (2–5).
A scoring system was used to determine the severity of the allergic reaction during the oral challenge test6. The patients’ symptoms were allocated to different categories and
received a corresponding score. The categories used and their score were the following: skin (1), upper airways (3), lower airways (3), gastrointestinal (2) and cardiovascular/ neurological symptoms (3). The scores of each category were summed and expressed as a severity index. The severity index ranges from 0–12 and is divided into groups. Scores from 0–2 are considered mild reactions. A score of 3–6 is regarded as a moderate reaction. The third group with scores of 7–12 is classified as severe reactions.
The statistical analysis of the data was performed using the statistics software package SPSS Statistics 17.0 for Windows. Reaction severity, ED, and CD were compared in patients with long (≥30 min) and short (<30 min) reaction times by history using the Mann–Whit-ney U-test. Possible confounders to the analysis were pre-selected through Spearman’s correlation test and multiple linear regression analysis by adopting a liberal p-value cut off (>0.2). Confounders reported in other studies were also included as well as biologi-cally plausible confounders and general demographics (age, sex). Subsequently, multiple linear regression analysis was used to assess any confounding by evaluating whether the coefficient of the association between reaction time and the outcomes changed by >10% by adding a possible confounder to the basic model. Factors tested and excluded as con-founders in the analysis were sex, age, type of allergenic food, history of asthma, history of atopic dermatitis, history of rhinoconjunctivitis, specific IgE level, and severity of the reaction following accidental ingestion by history.
RESultS
Two hundred and thirty-two cases were used for the final analysis. The age of the children ranged from 0.7 to 17.8 years, with a median of 5.8 years. Of the children, 56.9% were male and 43.1% were female. The DBPCFC were performed with peanut (34.1%), milk (27.2%), cashew nut (17.2%), egg (11.6%), and hazelnut (9.9%). For further demographics see Table 1. Patients reporting longer time intervals between ingestion and reaction (≥30 min) had a higher ED and CD in the DBPCFC than those reporting shorter time intervals between ingestion and reaction (<30 min) (Table 2). However, these patients did not have more severe reactions during the DBPCFC.
2
Table 1. Demographics of the two groups.
Group 1: time interval ≥30 minutes
n= 37
Group 2: time interval <30 minutes
n= 195
Range Mean Standard deviation
Range Mean Standard deviation
Age (months) 8.0 – 192.0 67.9 48.7 9.0-214.0 85.2 55.2
Specific IgE (kU/L) 0.3-101.0 19,5 28.6 0.3-101.0 27.3 34.7 Frequency Percent Frequency Percent
Sex Male Female 23.0 14.0 62.2% 37.8% 109.0 86.0 55.9% 44.1% Type of food Cashew nut Hazelnut Egg Milk Peanut 4.0 2.0 4.0 16.0 11.0 10.8% 5.4% 10.8% 43.2% 29.7% 36.0 21.0 23.0 47.0 68.0 18.5% 10.8% 11.8% 24.1% 34.9%
History of Atopic dermatitis
Positive Negative 34.0 3.0 91.9% 8.1% 170.0 25.0 87.2% 12.8% History of Asthma Positive Negative 19.0 18.0 51.4% 48.6% 107.0 88.0 54.9% 45.1% History of rhinoconjunctivitis Positive Negative 8.0 29.0 21.6% 78.4% 85.0 110.0 43.6% 56.4%
Table 2. Mann Whitney U test analysis of the differences in the dose and severity of reaction for
the two groups.
Group 1: time interval ≥30 minutes
n= 37
Group 2: time interval <30 minutes
n= 195
Median IQR Median IQR P-value
Eliciting dose 1.60 0.27-10.00 0.48 0.05-2.00 0.004 Cumulative dose 2.15 0.37-12.53 0.64 0.07-2.70 0.005 Severity of reaction in DBPCFC 3.00 1.00-5.00 3.00 2.00-6.00 0.214
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concluSion
This study has for the first time shown that patients reporting longer time intervals be-tween ingestion and allergic reaction by history (≥30 min) have higher EDs and CDs in DBPCFC compared with those with shorter time intervals (<30 min), which suggests that these patients do indeed accumulate doses in challenge procedures utilizing 30 minute intervals between dose increments. However, this did not result in more severe reactions during the DBPCFC in these patients. These results were not influenced by the possible confounding variables mentioned earlier. Thus, although some patients may accumulate and react to more than one dose of allergenic food, a dosing interval of 30 minutes is long enough to allow this test to be conducted safely in these patients.
2 REfERENCES
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