University of Groningen
The Severity of Anaphylactic and Systemic Allergic Reactions
Pettersson, Maria Eleonore
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CHAPTER 8
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AsTOCyTOsIsANDAGE,
bUTNOTbAsELINETRyPTAsE,
sPECIfICI
GE
ORTOTALI
GE,
INDEPENDENTLyDETERmINEThEsEvERITyOfsysTEmICREACTIONsTO yELLOwjACkETsTINGs
.
M. Eleonore Pettersson* Byrthe JPR. Vos* Boudewijn J. Kollen, Suzanne Arends
Joanne NG. Oude Elberink Anthony EJ. Dubois
*These authors contributed equally to this work
ABSTRACT
Background: Although entities such as mastocytosis, elevated basal tryptase values and
cardiovascular disease are considered to increase the risk of severe reactions to hyme-noptera stings, it is largely unknown to what extent these factors independently predict reaction severity and thus how much clinicians may rely on them to risk stratify venom allergic patients.
Objective: To determine independent clinical risk factors for systemic reaction severity to
yellow jacket stings in untreated patients, with and without indolent systemic mastocyto-sis (ISM).
Methods: All patients visiting our center between 2009 and 2015 because of a systemic
reaction to a yellow jacket sting and subsequently receiving a diagnosis of yellow jacket venom allergy were included. All patients were screened for mastocytosis. Systemic reac-tions were classified according to Mueller. The statistical analysis was performed using linear regression.
Results: Independent predictors for the severity grade were ISM (β= 0.415, P<0.001) and
older age (β= 0.219, P<0.001), but not baseline serum tryptase (bsT) (β=0.177, P=0.054), cardiovascular event (β=0.111, P=0.054), cardiovascular risk score (β=0.017, P=0.881), level of total IgE (β=-0.042, P=0.473) or level of sIgE (β=0.044, P=0.541). This prediction model explained 23.0% of the variance of the severity grade (N=253, P<0.001).
Conclusions: ISM and age should be considered in the risk assessment of severe reactions
to yellow jacket stings. BsT cannot predict the reaction severity independently of the diagnosis of ISM, but it is useful in diagnosis and screening for ISM. However, the severity of reactions to yellow jacket stings remains for the greatest part unpredictable.
clinical implications
Although several factors increase the risk of severe reactions to yellow jacket stings, these can only predict the severity of a reaction to a small extent. Thus, clinicians should not strongly rely on these factors to risk stratify venom allergic patients.
8 intRoDuction
Several patient characteristics have previously been shown to be associated with severe systemic sting reactions. Systemic reactions can present at any age although they occur less often, and are mostly mild in children. In contrast, individuals above 65 years of age are at risk for more severe reactions.(1, 2) Remarkably, there is no association between the risk of, or severity of systemic reactions and having an atopic constitution or having experienced anaphylaxis from other causes. Moreover, high levels of total IgE (>250 kU/L) do not seem to increase risk and might even be protective.(3-5)
Although it is plausible that patients with pre-existing respiratory and cardiovascular disease are prone to have more severe reactions, reports are contradictory.(6, 7) This also applies to beta-blocker and ACE-inhibitor use, which theoretically could lead to more severe and protracted anaphylaxis due to beta-adrenergic blockade and imbalances in the renin-angiotensin system. However, this effect has not consistently been found clinically.(7-10) There is a strong relationship between reaction severity to insect venoms and elevated baseline serum tryptase (bsT) levels. BsT is thought to reflect the mast cell burden (mast cell number and activity) as tryptase is predominantly produced by mast cells.(11) Approximately 10% of the Hymenoptera venom allergic population has an elevated bsT level, consisting of enzymatically inactive α- and β-protryptase that is spontaneously secreted by mast cells without stimulation. (10, 12) Even a small increase in this level seems to be associated with more frequent and severe systemic reactions, although this result was not adjusted for mastocytosis.(10) Patients with indolent systemic mastocytosis (ISM) suffer from a clonal proliferation of abnormal mast cells and represent a particular risk group for frequent and severe anaphy-lactic reactions, which probably relates to excessive mediator release following triggering of mast cells.(13)
It has previously been shown that platelet-activating factor (PAF), is closely correlated to the severity of anaphylactic reactions.(14, 15) PAF triggers hypotension, bronchoconstric-tion and vascular permeability.(16, 17) The catalyzabronchoconstric-tion of the degradabronchoconstric-tion of PAF is initi-ated by PAF acetylhydrolase (PAF-AH), and a lower level of of PAF-AH has been shown to increase the risk of life-threatening anaphylaxis.(18) PAF-AH circulates in complexes with low- and high-density lipoproteins in human plasma, and the main protein component of low-density lipoprotein particles is apolipoprotein B-100 (ApoB). A strong correlation between the activity of PAF-AH and the concentration of the more stable ApoB has previ-ously been shown.(19) Thus, this suggests an association between the severity of allergic reactions and the plasma concentration of ApoB.
Although entities such as mastocytosis and elevated basal tryptase are known to increase the risk of severe reactions to hymenoptera stings, it is largely unknown to what extent these factors predict reaction severity and thus how much clinicians may rely on them to risk stratify venom allergic patients. Moreover, it is currently not clear if tryptase and ISM are predictors of the reaction severity independently of each other. Thus, the purpose of this study was to determine independent clinical risk factors for the severity of systemic reactions to yellow jacket stings in untreated patients, with and without ISM.
METhOdS Subjects
Study design and population. All patients visiting the department of Allergology in our
ter-tiary care clinic between 2009 and 2015 because of a systemic reaction to a yellow jacket sting, and who after clinical evaluation received a diagnosis of yellow jacket venom (YJV) allergy, were included in the analysis. The diagnosis of YJV allergy followed international guidelines and was based on the patient’s history and YJV-specific (s)IgE ≥0.35 KUA/L or a
positive intracutaneous skin test (mean wheal diameter ≥5 mm at a concentration of ≤1 µg/mL).(20) Systemic reactions were classified according to Mueller, (21) with separation of grade IV reactions into severe (a) and very severe (b), as previously described.(22) The severity grade was determined by the severity of the systemic sting reaction immediately preceding the biochemical and immunological serum sampling, from now on referred to as the index sting. The local medical ethics committee deemed that official medical ethical approval was not required.
Exclusion criteria. Patients who visited our clinic after more than 3 years since the last sting
reaction were excluded, because the determinants (e.g. sIgE and bsT) in serum and urine may not be representative of the moment of the sting.(23, 24) Included patients were not treated with venom immunotherapy (VIT) before the index sting.
Clinical and biochemical data collection. All information was gathered from medical charts
regarding the severity of systemic reactions and demographic data, including cardiovascu-lar risk factors (hypertension, hypercholesterolemia, left ventricucardiovascu-lar hypertrophy, diabetes mellitus) and cardiovascular events (myocardial infarction (MI) or stroke) and antihyper-tensive medication use at the time of the index sting. All serum and urine samples were taken at the first patient visit. The time interval between the index sting and sample col-lection was at least two weeks, circumventing a potential interference of the index allergic reaction on the bsT level.
8 Cardiovascular risk score. A modified version of the scoring system from Pocock et al.(25)
was used to determine the cardiovascular risk profile of patients. This scoring system indi-cates the risk of death due to cardiovascular disease and gives weighed scores to sex, age, hypertension, hypercholesterolemia, a history of MI or stroke, left ventricular hypertrophy, and diabetes. Each factor received a corresponding weighed score while antihypertensive treatment reduced the score (Table 1). All of the individual scores for each factor were summed, and the total score ranged from 0-50.
Table 1. Cardiovascular risk score. Female
Risk factor Addition to risk score Risk score
Age (years) 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 0 +5 +9 +14 +18 +23 +27 +32 No Yes Systolic blood pressure >140 mm Hg 0 +3 Total cholesterol >6.5 mmol/l 0 +1 History of myocardial infarction 0 +8 History of stroke 0 +8 Left ventricular hypertrophy 0 +3 Diabetes 0 +9 Total risk score*
Male
Risk factor Addition to risk score Risk score
Male gender +12 Age (years) 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 0 +4 +7 +11 +14 +18 +22 +25 No Yes Systolic blood pressure >140 mm Hg 0 +3 Total cholesterol >6.5 mmol/l 0 +4 History of myocardial infarction 0 +8 History of stroke 0 +8 Left ventricular hypertrophy 0 +3 Diabetes 0 +2
Total risk score*
*If antihypertensive drugs are taken, the risk score is reduced by 2 points. Table modified from Pocock et al.9 Values
Diagnostic procedures
Serum analytes. YJV-sIgE and total IgE was measured using the ImmunoCAP system
(Ther-mo Fisher Scientific Inc., Phadia AB, Uppsala, Sweden). ApoB levels were determined in the same stored samples by means of immunonephelometry on the BNII System (Siemens Healthcare GmbH, Erlangen, Germany). BsT levels were determined with the B12 assay
using ImmunoCAP Tryptase reagents and the Phadia 250 analysis device (Thermo Fisher Scientific Inc., Phadia AB, Uppsala, Sweden). The inter-assay analytical coefficient of varia-tion in our laboratory is 5.8%. BsT concentravaria-tions >10 µg/L were checked and corrected for heterophilic antibodies.
Urine analytes. Urine samples for MH and MIMA determination were collected in
contain-ers with a small amount of chlorhexidine. Values consistent with mastocytosis were re-evaluated, collecting new samples after an overnight fast and discarding the first morning voiding. Subjects were asked to refrain from histamine-rich foods and drinks for 24 hours before urine collection. Levels of MH and MIMA were determined by an isotope-dilution mass fragmentographic method.(26, 27) The inter-assay analytical coefficient of variation in our laboratory is 6.8% for MH and 4.2% for MIMA.
Mastocytosis screening. The diagnosis of ISM was established according to the World
Health Organization (WHO) criteria.(28) All patients were screened for mastocytosis by serum bsT measurement, clinical history and skin inspection for clinical lesions compatible with urticaria pigmentosa (UP). All patients with UP underwent bone marrow examina-tions, irrespective of the bsT concentration. Patients without UP underwent bone marrow examinations when the bsT concentration was >10 µg/L. Bone marrow examinations were also performed when the bsT concentration was <10 µg/L and if the urinary meth-ylhistamine (MH) concentration was ≥176 and/or a methylimidazole acetic acid (MIMA) concentration of ≥2.0.(29) Patients with clinical suspicion of ISM that did not undergo bone marrow examinations for exclusion or confirmation of this diagnosis were classified as possible mastocytosis, because systemic mastocytosis cannot be ruled out.(29)
Bone marrow examinations. Bone marrow examinations were performed as previously
described.(30) Briefly, bone marrow biopsies were taken from the iliac crest and examined for the presence of multifocal clusters or cohesive aggregates/infiltrates of >15 mast cells and for spindle-shaped, immature mast cells and for mast cells with atypical morphology by tryptase and CD117 staining. Mast cell immunophenotyping was performed by analyz-ing CD45-positive/bright CD117-positive mast cells for expression of CD2 and CD25 by flow cytometry. The presence of the KIT D816V mutation was examined in RNA of bone marrow aspirates.
8 Statistical methods
Statistical analysis was performed with IBM Statistics 22.0 (SPSS, Armonk, NY). P values <0.05 were considered statistically significant. The variables included in the analysis were pre-selected according to previously published data in addition to variables hypothesized to be of influence on the outcome by the authors.
Predictor analysis for reaction severity was performed by using multivariate linear regres-sion with a conditional stepwise backward selection procedure (P<0.05). Only variables which had a P value of ≤0.20 in univariate analysis were included. Only statistically signifi-cant factors were included in the model. The variables time interval between index sting and serum sampling, level of MH, MIMA, bsT, YJV-sIgE and total IgE were logarithmically transformed. Back-transformed values were reported. All assumptions for conducting this statistical analysis were met.
RESultS
characteristics of the whole patient cohort
Between 2009 and 2015, 294 patients visited our clinic because of a YJV allergy of which 42 (14.3%) were ultimately diagnosed with ISM. After applying the pre-defined selection criteria, 270 patients were included in the analysis. The diagnosis of ISM was excluded in 211 patients. Two patients without clinical suspicion of ISM, in whom MH and MIMA determinations had not been done and with bsT levels of 3.2 and 4.1 µg/L were included in this non-mastocytosis group, since none of the patients without clinical suspicion of ISM and a bsT <5.0 µg/L had an elevated MH or MIMA. An overview of the patient selection procedure according to the diagnosis or exclusion of ISM is provided in Figure 1.
In the total study population, the mean patient age was 51.9 ±13.8 years and the majority of patients were male (52.6%). More than half of the patients had a severe or very severe reaction to the index sting (58.5%). Of all patients with a very severe reaction, 41.1% had a confirmed diagnosis of ISM. Some patients had known concomitant cardiovascular risk factors such as hypertension (21.9%), hypercholesterolemia (5.9%), left ventricular hypertrophy (1.1%), diabetes (7.4%) or had experienced cardiovascular events (7.0%). Some were taking antihypertensive medication at the time of the index sting for instance ACE-inhibitors (10.7%), beta-blockers (12.2%), or any antihypertensive drug (25.2%). The median time between the index sting and sampling of serum and urine was 4.8 months (2.3-8.5). The median YJV-sIgE was 4.3 kUA/L (1.2-12.7), median total IgE 61.0 kUA/L (29.3-136.0), median bsT 5.6 µg/L (4.2-8.2), and the mean ApoB g/L 1.10 ±0.31. Further patient
characteristics according to the severity grade are shown in Table 2. The results of the univariate analysis is shown in Table 3.
Figure 1. Flowchart of the patient selection procedure according to the status of indolent systemic
mastocytosis.
Abbreviations: ISM, indolent systemic mastocytosis; MH, methylhistamine; MIMA, Methylimidazole acetic acid; SR, severity grade; UP, Urticaria pigmentosa; YJV, yellow jacket venom.*MH and MIMA missing in two cases.
8 Table 2. Clinic al and biochemic al charact eris
tics of subjects with a his
tor y of s ys temic reactions t o yello w jack et s tings ac cording t o se verity grade. SR grade I SR grade II SR grade III SR grade IV a SR grade IVb N umber 17 41 54 68 90 Age at sting (y ears) 50.9 ±12.7 49.1 ±15.0 45.6 ±11.8 53.6 ±13.4 56.0 ±13.5 M ale, n (%) 8 (47.1) 20 (48.8) 29 (53.7) 35 (51.5) 50 (55.6) ISM, n (%) 0 (0) 0 (0) 0 (0) 5 (7.4) 37 (41.1) N on-ISM, n (%) 14 (6.6) 36 (17.1) 52 (24.6) 57 (27.0) 52 (24.6) H yper tension, n (%) 6 (35.3) 6 (14.6) 9 (16.7) 17 (25.0) 21 (23.3) H yper cholester olemia, n (%) 0 (0) 3 (7.3) 2 (3.7) 4 (5.9) 7 (7.8) M yocar dial infar ction or str oke, n (%) 0 (0) 2 (4.9) 2 (3.7) 6 (8.8) 9 (10.0) Left v entricular hyper trophy , n (%) 0 (0) 0 (0) 1 (1.9) 0 (0) 2 (2.2) D iabetes mellitus, n (%) 1 (5.9) 3 (7.3) 3 (5.6) 4 (5.9) 9 (10.0) ACE-inhibitor use, n (%) 1 (5.9) 4 (9.8) 2 (3.7) 10 (14.7) 12 (13.3) Beta-blocker use, n (%) 3 (17.6) 3 (7.3) 4 (7.4) 10 (14.7) 13 (14.4) Any antihyper tensiv e medication use, n (%) 4 (23.5) 9 (22.0) 9 (16.7) 19 (27.9) 27 (30.0) Car dio vascular risk (scor e 0-50) 19.3 ±11.0 19.0 ±10.2 15.6 ±10.3 21.4 ±12.2 23.7 ±10.6 Time inter val betw
een index sting and
ser um sampling (months) 4.1 (2.3-7.3) 6.9 (3.0-9.2) 4.3 (2.3-6.9) 4.6 (2.3-11.6) 5.3 (2.1-8.7) YJV -sI gE (kU A/L) 8.23 (2.00-25.15) 4.09 (1.65-11.96) 4.97 (1.53-10.53) 4.62 (1.46-17.68) 2.52 (0.81-7.67) Total IgE (kU A/L) 100.00 (43.95-128.00) 67.80 (32.50-154.50) 66.25 (33.75-123.25) 88.9 (38.60-158.00) 49.95 (19.78-109.25) BsT (μg/L) 4.62 (3.05-5.68) 5.23 (3.43-6.25) 4.76 (3.65-6.32) 5.47 (4.24-8.08) 8.03 (5.28-18.80) MH (μmol/mol cr eatinine) 83.00 (59.50-119.00) 97.00 (71.00-113.00) 92.50 (72.00-120.25) 102.00 (78.00-143.00) 115.00 (83.50-184.00) MIMA (mmol/mol cr eatinine) 1.50 (1.13-2.18) 1.40 (1.28-2.10) 1.40 (1.23-1.75) 2.50 (1.70-3.40) 2.50 (1.70-3.43) ApoB (g/L) 1.04 ±0.36 1.05 ±0.28 1.10 ±0.29 1.15 ±0.34 1.10 ±0.30 Data is pr esented as means with standard de viations , median with interquar tile ranges and frequencies with per centages . Ab br eviations: A poB , A polipopr otein B; BsT , baseline ser um
tryptase; ISM, indolent systemic mastoc
ytosis; MH, meth
ylhistamine; MIMA, meth
ylimidaz
ole acetic acid; SR; systemic r
eaction; YJV
; y
ellow jac
ket venom
Table 3. Selection of variables for the prediction model of the severity grade based on univariate analysis. N B 95%CI P-value Age (years) 270 0.019 0.009-0.030 <0.001 Male gender* 270 0.119 -0.183-0.421 0.439 Diagnosis or exclusion of ISM 253 1.421 1.047-1.795 <0.001 Diagnosis or exclusion of Urticaria Pigmentosa 270 1.227 0.585-1.870 <0.001 History of respiratory disease* 270 -0.034 -0.479-0.410 0.880 History of MI/Stroke 270 0.556 -0.031-1.143 0.063 Cardiovascular risk (score 0-50) 270 0.022 0.009-0.035 0.001 Beta-blocker use* 270 0.202 -0.259-0.663 0.388 ACE-inhibitor use 270 0.364 -0.122-0.850 0.142 Any antihypertensive medication use 270 0.244 -0.103-0.591 0.167 YJV-sIgE (kUA/L) # 268 -0.113 -0.261-0.018 0.093 Total IgE (kUA/L) # 268 -1.201 -1.366-1.054 0.006 sIgE-total IgE ratio #* 267 0.005 -1.113-1.124 0.929 BsT (μg/L) # 270 1.113 0.718-1.599 <0.001 MH (μmol/mol creatinine)# 268 2.075 1.543-2.790 <0.001 MIMA (mmol/mol creatinine) # 88 1.892 0.568-4.339 0.001 ApoB (g/L)* 250 0.305 -0.198-0.809 0.234 Time interval between index sting and serum
sampling (months) #*
270 0.046 -0.164-0.274 0.652
Abbreviations: ApoB, Apolipoprotein B; B, regression coefficient; BsT, baseline serum tryptase; CI, confidence interval; ISM, indolent systemic mastocytosis; MH, methylhistamine; MIMA, methylimidazole acetic acid; SR; systemic reac-tion; YJV; yellow jacket venom. *The variable was not tested in multivariate regression analysis because of a P value > 0.20 in univariate regression analysis. #Backtransformed values.
Risk factors for severe systemic reactions to a Yj field sting
In the population where the diagnosis of ISM was established or excluded (N=253), sig-nificant independent predictors for the severity grade were ISM (β= 0.415, P<0.001) and age (β= 0.219, P<0.001). This prediction model could explain 23.0% of the variance of the severity grade, see Table 4. Factors not found to independently predict the reaction sever-ity were bsT (β=0.177, P=0.054), history of MI or stroke (β=0.111, P=0.054), cardiovascular risk score (β=0.017, P=0.881), ACE-inhibitor use (β=0.029, P=0.643), any antihyperten-sive medication use (β=0.007, P=0.920), UP (β=-0.014, P=0.842), level of MH (β=0.071, P=0.318), level of total IgE (β=-0.042, P=0.473) or level of sIgE (β=0.044, P=0.541).
8 Table 4. Prediction models for the severity grade in the whole study group, and for only those with
a definite diagnosis (either confirmed ISM or those without clinical suspicion of ISM).
Study population Predictor B 95%CI P-value
N=268, ISM excluded. R2=0.221 Age 0.016 0.005-0.026 0.003 History of MI/Stroke 0.546 0.004-1.087 0.048 BsT# 0.793 0.409-1.282 <0.001 MH# 1.477 1.067-2.046 0.019 N=253, ISM included. R2=0.230 Age 0.020 0.010-0.030 <0.001 ISM 1.380 1.016-1.744 <0.001
Abbreviations: ApoB, Apolipoprotein B; B, regression coefficient; BsT, baseline serum tryptase; CI, confidence interval; ISM, indolent systemic mastocytosis; MH, methylhistamine; MIMA, methylimidazole acetic acid; R2, explained
vari-ance; SR, systemic reaction; YJV, yellow jacket venom. #Backtransformed values.
In the total study population, also including patients for whom the diagnosis of ISM was in-conclusive (N=17), ISM was not included in the prediction model. Significant independent predictors for the severity grade were age (β= 0.173, P=0.003), bsT (β= 0.365, P <0.001), level of MH (β= 1.165, P=0.019) and history of MI or stroke (β= 0.111, P=0.048). This prediction model explained 22.1% of the variance of the severity grade. MIMA was only tested in a sub-group with available data (N=88), but it was not found to be a significant independent predictor for the severity grade (B=-0.374, P=0.384).
In linear regression analysis, there was no collinearity between the bsT concentration and ISM (data not shown). The analysis of a potential interaction between the level of bsT in patients with and without ISM was not significant (P=0.106 for the tryptase/ISM interac-tion term in the model).
Additionally, in patients not suspected of systemic mastocytosis with bsT levels within the normal range (<10.0μg/L; n=206), the association with the severity grade in univari-ate analysis (B=0.950, 95%CI=0.184-2.212, P=0.009) disappeared when corrected for age (B=0.597, 95%CI=-0.034-1.635, P=0.067). Thus, the level of bsT did not independently predict the severity grade in non-ISM patients with bsT levels within the normal range, since this effect was abrogated by including age in the model.
DiScuSSion
With the identified clinical risk factors, we are able to predict only 23.0% of the severity grade of systemic reactions to yellow jacket stings. Independent risk factors for severe sting reactions were diagnosis of ISM and older age. ISM was shown to be the largest independent risk factor for predicting reaction severity. This result confirms ISM to be the most important clinical risk factor for reaction severity to YJV.
In the study group where the diagnosis or exclusion of ISM was inconclusive, older age, a higher bsT level, a higher MH level and a history of cardiovascular events were shown to be independent predictors of reaction severity. However, the level of bsT, MH level and history of cardiovascular events are likely to represent ISM, since these factors were not significant predictors when ISM was included in the model.
Strikingly, we found that bsT level within the normal range (<10.0μg/L) does not predict reaction severity in patients without ISM, after adjusting for age. This is in contrast to a previous study(10), in which, however, ISM was not taken into account. Thus, bsT seems to merely be an indicator of ISM and increasing age, and it is not an independent de-terminant of reaction severity. Notably, the bsT level have previously been shown to be inappropriately elevated in older and overweight patients.(30)
No role for beta-blockers or ACE-inhibitors could be found in predicting the severity of reaction, in line with a recent review article.(31) Similarly, the level of MIMA was not shown to be an independent predictor in a sub-group analysis. This result is not likely to be caused by a lack of power, since the level of MIMA was shown to be a significant factor in the univariate analysis.
Total IgE was not an independent predictor for the severity grade after adjusting for ISM. It has previously been suggested that patients with stinging insect allergy and high levels of total IgE generally have milder systemic reactions, whereas patients with low levels of total IgE generally have more severe systemic reactions.(5) However, a more recent study correcting for additional factors, such as age and level of baseline serum tryptase, no such relationship for vespula venom allergy was found.(32) Thus, an increased level of total IgE could possibly be linked to an unknown diagnosis of ISM or increasing age, which is probably why total IgE is not an independent predictor of reaction severity. It has previously been shown that the presence of venom sIgE is significantly associated with a history of systemic reactions to Hymenoptera stings. However, the level of venom sIgE was not related to severity.(33) This is in agreement with our results.
8
In contrast to a previous study, which showed a relationship between the severity grade and the level of PAF-AH, (34) we could not show a relationship between the severity grade and ApoB. However, this previous study did not take ISM into account. Moreover, PAF and PAF-AH have previously been shown to be linked to cardiovascular disease.(35) Thus the influence of PAF and/or PAF-AH on the severity of reaction could be difficult to demon-strate in a population with pre-existing cardiovascular disease.
According to a previous study, it is possible that some patients classified as being in the non-ISM group, without UP and without an increased level of bsT, may nevertheless have unidentified ISM.(36) However, this previous study used a higher bsT cut-off value (11.4 ng/ml), had a highly selected study population and only included patients with severe systemic reactions. In addition, this previous study did not determine levels of MH and/or MIMA. Moreover, a previous study from our own center (29) showed that the risk of ISM is very low in patients without UP and a bsT below 10 µg/l.
To date, the majority of factors determining the severity of reaction remains unknown. This could be explained by the fact that systemic reactions to stinging insects take place under specific individual circumstances, with varying augmenting factors present for each occurrence. Furthermore, the clinical outcome of a severe reaction could be influenced by prompt treatment with an adrenaline auto-injector.
A possible limitation of this study is that the data was collected from patient charts, which could have led to an underestimation of minor risk factors such as hypertension and hypercholesterolemia due to the registration method. However, serious cardiovascular events were not predictive of the reaction severity when including ISM in the model. A larger impact on reaction severity by minor cardiovascular risk factors, as compared to serious cardiovascular events is improbable. Thus, it is unlikely that minor cardiovascular risk factors would be associated with reaction severity if another data collection method was used.
The strengths of this study were the determination of the diagnosis of ISM with the gold standard bone marrow biopsy, that tryptase was determined in all subjects and that many probable factors were included in the model. The inclusion of a comprehensive number of factors is important for accurate interpretation of the impact of individual factors on the reaction severity.
In conclusion, the majority of factors determining reaction severity to YJV remains un-known. ISM is the most important determinant of severe systemic reactions to yellow jacket stings. Serum baseline tryptase is not an independent predictor of the reaction
severity, but merely reflects the impact of ISM. Thus, ISM and age are the most important known independent factors in the risk assessment of severe reactions to yellow jacket stings.
acknowledgements
The authors thank P.M. Kluin of the Department of pathology for critically revising the bone marrow biopsies, and A.B. Mulder of the Department of laboratory medicine for immunophenotyping and C-KIT mutation analysis.
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