Abstract
Background
There is controversy whether taking β‐blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT).
Methods
In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking β‐blockers or ACEI show more systemic AE during VIT compared to patients without such treatment.
Results
In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took β‐blockers, 11.9% ACEI, 5.0% β‐blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43–1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of β‐blockers or ACEI (OR: 1.14, 95% CI: 0.89–1.46, p = 0.29). In total, 210 (17.7%) patients were re‐stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took β‐blockers, none an ACEI.
Conclusions
This trial provides robust evidence that taking β‐blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).
Keywords: ACE inhibitor, adverse event, beta‐blocker, systemic insect sting reaction, venom immunotherapy
Patients under antihypertensive treatment with β‐blockers and angiotensin‐converting enzyme inhibitor (ACEI) do not have a higher risk for severe insect sting reactions. The intake of β‐blockers and ACEI does not increase the frequency of systemic adverse events during venom immunotherapy (VIT). Results suggest that β‐blockers and ACEI do not impair VIT effectiveness.
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; VIT, venom immunotherapy.
1. INTRODUCTION
Insect stings by Hymenoptera species are very common with data indicating that 56.6–94.5% of the general population has been stung at least once in their lifetime.1 Systemic sting reactions (SSRs) have been reported in 2.3–5.4% of adults in European and US epidemiological studies.2, 3, 4 Hymenoptera venom allergy is a potentially life‐threatening disease, and venom immunotherapy (VIT) is the only treatment that can potentially prevent further SSR.5 It is effective in 77–84% of patients treated with honeybee venom6, 7 and in 91–96% of patients receiving vespid venom.6, 7 There are two well‐established risk factors for severe SSR: higher age8, 9, 10 and elevated tryptase levels >11.4 mg/L indicating clonal mast cell disorders.8, 9, 11 The major risk factor for systemic adverse events (AE) during VIT is treatment with bee venom.12, 13 There has been an ongoing debate over decades whether antihypertensive (AHT) treatment with β‐blockers and/or ACE inhibitors (ACEI) is a risk factor for the development of more severe SSR and whether it increases the number of (more severe) AE during VIT. The global prevalence of arterial hypertension in the adult population ranges from 26.4–27.7%, and 40.7% of patients older than 35 years suffer from hypertension.14, 15 Overall, ACEI or angiotensin receptor blockers are the most commonly used blood pressure‐lowering agents followed by diuretics and β‐blockers in high‐income countries.14 Given that higher age is a major risk factor for severe SSR, it is very likely that these patients also take antihypertensive medication. Replacing or discontinuing antihypertensive medication is cumbersome, time‐consuming, and may even be harmful. This could prevent patients from receiving potentially life‐saving VIT. Available data are controversial and invariably originate from case reports or studies with underpowered designs to evaluate the effect of antihypertensive drugs.8, 16, 17 We hypothesized that the risk of β‐blockers and/or ACEI for AE during VIT could have been overestimated, and the alleged higher risk for more severe sting reactions could have been biased by patients’ age. We therefore initiated an open, prospective, observational, multicenter study, recruiting 1,425 patients in 26 centers from eight European countries.
2. METHODS
2.1. Objectives
The primary objective of this study was to evaluate whether patients under antihypertensive treatment with β‐blockers or ACEI show more systemic AE during VIT compared with patients without antihypertensive therapy.
Secondary objectives included the evaluation of whether patients under antihypertensive treatment (β‐blockers or ACEI) have more severe SSR and whether prevalence of cardiovascular diseases or hypertension is associated with the risk of more severe SSR and more frequent systemic AE during VIT. Furthermore, we evaluated whether bee venom, high sIgE levels, high tryptase levels, or quicker up‐dosing protocols are correlated with a higher frequency of systemic AE. In addition, the effectiveness of VIT was monitored by the outcome of sting challenges or field stings, and these results were compared between patients with and without antihypertensive treatment.
2.2. Study design and oversight
The study was conducted as an open, prospective, observational, multicenter study (Clinicaltrials.gov number NCT04269629). Patients were recruited in 26 centers in eight European countries. The study was approved by the ethics committee of the sponsor of the study (Medical University of Graz; approval no. 26–442 ex 13/14) as well as local ethics committees in each country, and patients gave their written, informed consent.
Legally competent male and female patients aged 35 to 85 years with a history of a SSR (≥ grade I according to the classification by Ring and Messmer18) were eligible for the study. Absolute contraindications to VIT according to the EAACI guidelines such as active multisystem autoimmune disorders, active malignant disease, and pregnancy5 as well as pre‐treatment with omalizumab were exclusion criteria.
After giving their written informed consent, patients were included after carefully reviewing all inclusion and exclusion criteria at Visit 1. All data concerning the index sting reaction, laboratory parameters like specific immunoglobulin E (sIgE) and tryptase levels, and skin test results were recorded as well as concomitant diseases and medication. If patients agreed to receive VIT, data concerning the up‐dosing phase (premedication, venom preparation, up‐dosing protocol, systemic AE (classification by Ring and Messmer18), changes in concomitant diseases, and medication) were recorded at Visit 2. There was no standard up‐dosing protocol used for VIT. All centers used their own in‐house protocols including conventional, cluster, ultrarush, and rush protocols.5 One year after reaching the maintenance dose, Visit 3 was performed. At this visit, changes in premedication, venom preparation, concomitant diseases, and medication were recorded as well as systemic AE during the maintenance phase and, if applicable, the outcome of field stings and/or sting challenges. No additional study‐related visits were required. All procedures (diagnosis and treatment of Hymenoptera venom allergy) had to be in concordance with current EAACI guidelines5, 19, 20 and were conducted individually by each study center.
2.3. Statistics
2.3.1. Sample size calculation
It was assumed that 24% of the patients would be on β‐blockers and/or ACEI. A χ2 test with a two‐sided 5% significance level has an 80% power to detect the difference between the group without antihypertensive medication with 6% systemic AE during VIT and the group on β‐blockers and/or ACEI with 12.3% systemic AE during VIT (OR =2.2) when the sample sizes are 631 and 200 (a total sample size of 831), respectively. The drop‐out rate included study drop‐outs (30%) who did not start VIT and study drop‐outs (10%) who did not finish VIT. This resulted in a drop‐out rate of 37% and a required number of 1,319 patients.
2.3.2. Statistical analysis
All patients participating in this study belong to one of the following two groups for analysis: the group with antihypertensive treatment (β‐blockers and/or ACEI) and the group without such treatment. The analyses concerning the outcome “systemic adverse event” are based on the patients who completed the up‐dosing phase of immunotherapy, while analyses concerning the outcome “systemic sting reaction” are based on all patients included in the study.
The primary outcome and secondary outcomes were analyzed using logistic linear mixed models with a random intercept. This model type takes into account the clustered structure of the data, that is, observations clustered in the different participating centers. Parameters having a p‐value < 0.15 in the univariable model analysis were kept for further analysis with multivariable models. For further parameter reduction, the Bayesian information criterion (BIC) was calculated as a measure of the relative quality of the models. However, age and taking antihypertensive treatment were always kept in the multivariable models for the outcome “systemic adverse event” as well as for the outcome “systemic sting reaction.” For these outcomes, complete case model analyses were performed, if missing data in parameters of interest were rare (<1%). Otherwise, missing at random was assumed, and multiple imputations were conducted with 50 imputations taking into account the cluster design. The level of significance was set at 0.05.
All analyses were performed using the statistical software R (version 3.6.3) with the lme4 package (version 1.1‐23) to carry out multilevel modeling and the MICE package for the multiple imputation analysis (version 3.8.0).21, 22
3. RESULTS
3.1. Patients
From August 2014 until January 2018, a total of 1,425 patients were included in the study: 330 of these patients were included in Austria, 41 in the Czech Republic, 68 in Germany, 254 in Italy, 269 in Poland, 279 in Slovenia, 44 in Spain, and 140 in Turkey. The demographic data of the patients are shown in Table 1. Seventy‐five patients refused VIT, and eight patients were lost to follow‐up, and therefore, Visit 2 was performed with 1,342 patients. The majority of patients returned to the clinics for the first annual checkup; Visit 3 was performed with 1,186 patients.
TABLE 1.
Demographic data. The percentages refer to the total number of observations. Missing data are not explicitly stated in the table. Age at Visit 1 was the age at index sting, age at Visit 2 was the age when venom immunotherapy was started
|
Visit 1 (n = 1,425) pre‐treatment |
Visit 2 (n = 1,342) up‐dosing phase |
Visit 3 (n = 1,186) maintenance phase |
|
|---|---|---|---|
| Age range (mean age) [years] | 35–80 (52) | 35–84 (54) | 36–85 (55) |
| Sex, n (%) | |||
| Male | 810 (56.8) | 774 (57.7) | 679 (57.3) |
| Female | 615 (43.2) | 568 (42.3) | 507 (42.7) |
| Grade of SSR (index sting), n (%) | |||
| Grade I | 122 (8.6) | .. | .. |
| Grade II | 700 (49.1) | .. | .. |
| Grade III | 589 (41.3) | .. | .. |
| Grade IV | 14 (1.0) | .. | .. |
| Antihypertensive treatment, n (%) | |||
| No medication | 1,035 (72.6) | 1,001 (74.6) | 886 (74.7) |
| β‐blockers | 148 (10.4) | 123 (9.2) | 105 (8.9) |
| ACEI | 169 (11.9) | 159 (11.9) | 136 (11.5) |
| β‐blockers and ACEI | 71 (5.0) | 58 (4.3) | 55 (4.6) |
| Cardiovascular disease, n (%) | |||
| No disease | 845 (59.3) | 801 (59.7) | 715 (60.3) |
| Coronary heart disease or hypertension | 571 (40.1) | 533 (39.7) | 463 (39.0) |
| Causal venom, n (%) | |||
| Bee | 320 (22.5) | 351 (26.2) | 297 (25.0) |
| Vespid | 838 (58.8) | 923 (68.8) | 829 (69.9) |
| Bee & vespid | 206 (14.5) | 67 (5.0) | 57 (4.8) |
| Basal tryptase level, n (%) | |||
| ≤11.4 µg/L | 1,159 (81.3) | 1,092 (81.4) | 972 (82.0) |
| >11.4 µg/L | 127 (8.9) | 121 (9.0) | 108 (9.1) |
Of all patients included, 388 (27.2%) took antihypertensive drugs: 10.4% took β‐blockers, 11.9% ACEI, and 5.0% β‐blockers and ACEI, respectively. Ninety‐three (7.0%) patients who underwent VIT had a systemic adverse event, and these reactions were predominantly mild (Table 2). Only one patient suffered from a Grade III reaction with flush and bronchospasm. Large local reactions (LLR) were observed in 348 (26.3%) patients undergoing VIT.
TABLE 2.
Details of adverse events during VIT. The percentages refer to the total number of adverse events (n = 93). Missing data are not explicitly stated in the table. Classification according to Ring and Messmer18
| Grade I | Grade II | Grade III | total | |
|---|---|---|---|---|
| Adverse events, n (%) | 54 (58.1) | 38 (40.9) | 1 (1.1) | 93 (100.0) |
| Up‐dosing protocol, n (%) | ||||
| Conventional | 2 (2.2) | 3 (3.2) | 0 (0.0) | 5 (5.4) |
| Cluster, ultrarush | 27 (29.0) | 17 (18.3) | 1 (1.1) | 45 (48.4) |
| Rush | 23 (24.7) | 16 (17.2) | 0 (0.0) | 39 (41.9) |
| Premedication, n (%) | ||||
| No | 21 (22.6) | 15 (16.1) | 0 (0.0) | 36 (38.7) |
| Yes | 33 (35.5) | 23 (24.7) | 1 (1.1) | 57 (61.3) |
| Tryptase level, n (%) | ||||
| >11.4 µg/L | 7 (7.5) | 5 (5.4) | 1 (1.1) | 13 (14.0) |
| Treatment with β‐blockers and/or ACEI, n (%) | ||||
| No | 43 (46.2) | 30 (32.3) | 1 (1.1) | 74 (79.6) |
| β‐blockers | 1 (1.1) | 3 (3.2) | 0 (0.0) | 4 (4.3) |
| ACEI | 8 (8.6) | 5 (5.4) | 0 (0.0) | 13 (14.0) |
| β‐blockers and ACEI | 2 (2.2) | 0 (0.0) | 0 (0.0) | 2 (2.2) |
3.2. Primary outcome
Of all patients who underwent VIT, 338 (25.2%) took β‐blockers and/or ACEI. Only 19 (5.6%) patients, who were taking β‐blockers or ACEI, experienced a systemic AE compared to 74 (7.4%) patients not taking such drugs resulting in an odds ratio (OR) of 0.74 (95% confidence interval (CI): 0.43–1.22, p = 0.25; Table 3). In detail, 4 of 123 (3.3%) had systemic AE taking β‐blockers, 13 of 157 (8.3%) experienced systemic AE under ACEI treatment, and 2 of 58 (3.5%) had systemic AE taking β‐blockers and ACEI (p = 0.15). All systemic AE in patients with antihypertensive treatment were mild‐to‐moderate reactions. The most severe reaction occurred in a patient not taking AHT drugs (Table 2).
TABLE 3.
Impact of decisive parameters on the frequency of systemic adverse events during VIT
| Parameter | Categories | No systemic reaction | Systemic reaction | OR (95% CI)a | p‐value | OR (95% CI)b | p‐value |
|---|---|---|---|---|---|---|---|
| Age at starting date of VIT | 1240 (93.0) | 93 (7.0) | 0.98 (0.96–1.00) | 0.09 | 0.99 (0.96–1.01) | 0.20 | |
| Antihypertensive treatment with β‐blockers and/or ACEI | No | 920 (92.6) | 74 (7.4) | 1.00 | 0.25 | 1.00 | 0.61 |
| Yes | 319 (94.4) | 19 (5.6) | 0.74 (0.43–1.22) | 0.87 (0.49–1.52) | |||
| Cardiovascular disease | No | 734 (92.1) | 63 (7.9) | 1.00 | 0.11 | .. | .. |
| Yes | 498 (94.3) | 30 (5.7) | 0.69 (0.43–1.08) | .. | |||
| Bee venom | No | 879 (95.8) | 39 (4.3) | 1.00 | <0.001 | 1.00 | <0.001 |
| Yes | 360 (87.0) | 54 (13.0) | 3.39 (2.20–5.27) | 3.35 (2.17–5.16) | |||
| Tryptasec | ≤11.4 µg/L | 1010 (93.2) | 74 (6.8) | 1.00 | 0.16 | .. | .. |
| >11.4 µg/L | 107 (89.2) | 13 (10.8) | 1.54 (0.83–2.90) | .. | |||
| Verified mastocytosisc | No | 1,144 (93.1) | 85 (6.9) | 1.00 | 0.41 | .. | .. |
| Yes | 29 (87.9) | 4 (12.1) | 1.71 (0.57–5.14) | .. | |||
| sIgE levels (bee venom) | >0.35–3.5 kU/l | 96 (85.0) | 17 (15.0) | 1.00 | 0.99 | .. | .. |
| >3.5–17.5 kU/l | 97 (85.1) | 17 (14.9) | 0.97 (0.46–2.06) | .. | |||
| >17.5 kU/l | 45 (84.9) | 8 (15.1) | 0.92 (0.34–2.31) | .. | |||
| sIgE levels (vespid venom) | >0.35–3.5 kU/l | 270 (94.1) | 17 (5.9) | 1.00 | 0.15 | .. | .. |
| >3.5–17.5 kU/l | 281 (96.9) | 9 (3.1) | 0.52 (0.22–1.17) | .. | |||
| >17.5 kU/l | 148 (97.4) | 4 (2.6) | 0.42 (0.12–1.17) | .. | |||
| Grading Ring‐Messmer (initial sting reaction) | 1&2 | 714 (93.3) | 51 (6.7) | 1.00 | 0.66 | .. | .. |
| 3&4 | 526 (92.6) | 42 (7.4) | 1.10 (0.72–1.69) | .. | |||
| Premedication with H1‐antihistamine | No | 606 (94.3) | 37 (5.8) | 1.00 | 0.07 | .. | .. |
| Yes | 634 (91.9) | 56 (8.1) | 1.67 (0.96–3.18) | .. | |||
| Up‐dosing protocol | Conventional | 104 (95.4) | 5 (4.6) | 1.00 | 0.50 | .. | .. |
| Rush, cluster, ultrarush | 1128 (93.1) | 84 (6.9) | 1.40 (0.54–4.23) | .. |
no adjustments.
multivariable model.
Data imputation for univariable model.
3.3. Secondary outcomes
3.3.1. Adverse events
The prevalence of cardiovascular diseases or hypertension was no risk factor for systemic AE during VIT (p = 0.11). Bee venom caused more systemic AE during VIT: 13.0% of patients treated with bee venom had systemic reactions, but only 4.3% of patients treated with vespid venom (p < 0.001) (Table 3). We did not detect a statistically significant effect of elevated basal tryptase levels on the frequency of systemic AE during VIT: 6.8% of patients with normal tryptase levels compared with 10.8% of patients with elevated tryptase levels had systemic AE (p = 0.16). There was still no effect on systemic AE, when the analysis was performed separately for bee venom– and vespid venom–allergic patients (p = 0.23 and p = 0.18, respectively). Verified mastocytosis was also not a risk factor: Only 12.1% of patients with verified mastocytosis had a systemic reaction compared with 6.9% without mastocytosis (p = 0.41). Neither high sIgE levels to bee venom nor high sIgE levels to vespid venom correlated with a higher frequency of systemic AE during VIT (p = 0.99 and p = 0.15, respectively).
The severity of the initial sting reaction had no influence on the frequency of systemic AE during VIT: systemic AE occurred in 51 (6.7%) patients with a previous Grade I or II reaction and in 42 (7.4%) patients with a severe (Grade III or IV) initial sting reaction (p = 0.66). Premedication with oral non‐sedative antihistamines was taken by half of the patients during the up‐dosing phase, but this had no effect on the frequency of systemic AE (p = 0.07); however, the frequency of LLR was lower in patients taking premedication as compared with those not taking antihistamines (23.5% vs. 29.3%; p < 0.001).
Quicker up‐dosing protocols (conventional vs. rush, cluster, and ultrarush) did not cause more frequent systemic AE during VIT (p = 0.50). Nevertheless, large local reactions were seen more frequently when quicker up‐dosing protocols were used (OR: 8.72; 95% CI: 3.59–24.37; p < 0.001).
The parameters age at starting date of VIT, antihypertensive treatment, and bee venom were kept for further analysis in a multivariable model: The risk of a systemic adverse event during VIT was still 3.4 times (OR 3.35; 95% CI: 2.17–5.16) higher for patients treated with bee venom, compared with patients treated with vespid venom (p < 0.001).
A separate data analysis for bee and vespid VIT regarding the parameters age and antihypertensive treatment did not lead to different results: There was still no effect on the frequency of systemic AE.
During the first year of the maintenance phase, systemic AE occurred in only 20 (1.7%) patients. Systemic adverse reactions were mild or moderate in 17 patients; three bee venom–allergic patients had a Grade III reaction with loss of consciousness or bronchospasm. None of them took β‐blockers or ACEI, but one patient with loss of consciousness suffered from systemic mastocytosis. Taking AHT drugs did not increase the frequency of systemic AE (p = 0.99). The intake of antihistamine premedication decreased from about 50.0% during the up‐dosing phase to about 20.0% during the maintenance phase.
3.3.2. Systemic sting reactions
Taking β‐blockers or ACEI had no influence on the severity of the initial sting reaction: 41.7% of patients not taking AHT drugs and 44.1% of patients under antihypertensive treatment had a severe SSR (Grade III or IV; p = 0.29) (Table 4). The proportions of severe SSR did not differ significantly between patients taking β‐blockers, ACEI, and β‐blockers and ACEI with 43.9, 47.9, and 35.2% respectively (p = 0.14). The prevalence of cardiovascular diseases or hypertension appeared to be a risk factor (p = 0.04). However, this result was biased by patients’ age; when patients’ age was taken into consideration, the effect of cardiovascular disease on the severity of SSR vanished (p = 0.91).
TABLE 4.
Impact of decisive parameters on the severity of the systemic (index) sting reactions
| Parameter | categories | Grade 1&2 | Grade 3&4 | OR (95% CI)a | p‐value | OR (95% CI)b | p‐value |
|---|---|---|---|---|---|---|---|
| Age at index sting | 822 (57.7) | 603 (44.3) | 1.02 (1.01–1.04) | <0.001 | 1.02 (1.01–1.04) | <0.001 | |
| Antihypertensive treatment with β‐blockers and/or ACEI | no | 603 (58.3) | 432 (41.7) | 1.00 | 0.29 | 1.00 | 0.70 |
| yes | 217 (55.9) | 171 (44.1) | 1.14 (0.89–1.46) | 0.95 (0.72–1.24) | |||
| Cardiovascular disease | no | 502 (59.4) | 343 (40.6) | 1.00 | 0.04 | .. | .. |
| yes | 313 (54.8) | 258 (45.2) | 1.27 (1.01–1.60) | .. | |||
| Bee venomc | no | 488 (58.2) | 350 (41.8) | 1.00 | 0.50 | .. | .. |
| yes | 298 (56.7) | 228 (43.4) | 0.92 (0.72–1.17) | .. | |||
| Tryptase c , d | ≤ 11.4 µg/L | 672 (58.0) | 487 (42.0) | 1.00 | <0.001 | 1.00 | <0.001 |
| > 11.4 µg/L | 46 (36.2) | 81 (63.8) | 2.37 (1.61–3.50) | 2.43 (1.63–3.64) | |||
| Verified mastocytosisc | no | 765 (58.3) | 548 (41.7) | 1.99 | <0.001 | .. | .. |
| yes | 11 (29.7) | 26 (70.3) | 3.73 (1.74–7.98) | .. |
no adjustments.
multivariable model.
Data imputation for univariable model.
Data imputation for multivariable model.
We additionally investigated whether bee venom or elevated basal tryptase levels or verified mastocytosis are associated with more severe SSR. Severe sting reactions occurred in 43.4% of patients stung by bees and 41.8% of patients reacting to vespid stings (p = 0.50). Elevated basal tryptase levels were associated with more severe sting reactions: 42.0% of patients with normal tryptase levels but 63.8% with elevated tryptase levels had a systemic reaction Grade III or IV (OR: 2.37; 95% CI: 1.61–3.50; p < 0.001). The risk for a severe reaction was even 3.7‐fold higher for patients with verified mastocytosis compared to patients without mastocytosis (p < 0.001).
The parameters age at index sting, treatment with β‐blockers or ACEI, and tryptase levels were further analyzed in a multivariable model: Antihypertensive treatment still had no influence on the severity of the initial sting reaction (OR: 0.95; 95% CI: 0.72–1.24; p = 0.70), and patients with elevated basal tryptase levels still had a 2.4 times higher risk of developing a severe SSR compared with patients with normal tryptase levels (p < 0.001).
3.3.3. Effectiveness of VIT
The effectiveness of VIT can solely be monitored by the outcome of sting challenges or field stings. Sting challenges were performed in 18 patients; 192 patients experienced field stings within the first year of the maintenance phase. In total, 210 (17.7%) patients were stung, and 91.0% of patients tolerated the sting without systemic symptoms. Thirty‐four (16.2%) patients suffered from a LLR. Of the patients with SSR, 12 experienced a grade I reaction, and among these, two took β‐blockers. Five patients had a grade II reaction, and one of them took a β‐blocker, while two had a Grade III reaction, and one patient took a β‐blocker. None of the patients with therapy failure took an ACEI. 191 patients tolerated the sting; among these, 20 (10.5%) took a β‐blocker, 23 (12.0%) an ACEI, and 10 (5.2%) both drugs. Taking antihypertensive drugs did not increase the risk for therapy failure (p = 0.72).
4. DISCUSSION
This open, prospective, observational, multicenter study is the first multicenter study primarily focusing on the potential effect of β‐blockers and ACEI on systemic AE during VIT and the severity of SSR. It is by far the largest study, with 388 insect venom–allergic patients under antihypertensive drugs, and the first study with appropriate sample size estimation to calculate the patients’ risk. It therefore provides robust evidence that taking β‐blockers or ACEI does not increase the risk of systemic AE or aggravate sting reactions in patients with insect venom allergy.
Available data so far originated from studies with underpowered designs to evaluate the effect of antihypertensive drugs.8, 12, 15, 16, 17 Previously published reports evaluating the influence of β‐blockers on AE have already shown that β‐blocker medication was not associated with a higher prevalence of (more severe) systemic AE12, 23, 24, 25; however, although usually hundreds of patients were included, the low number of patients under β‐blocker therapy provided only statistically fragile evidence. We could now show that in 181 patients, taking β‐blockers did not increase the risk for systemic AE, and if AE occurred, they were not more severe.
Taking ACEI was reported to be an independent predictor for systemic AE26 and temporary discontinuation of ACEI therapy was recommended.27 However, ACEI also appeared to be safe with VIT,25 and although one small study reported more severe AE in patients taking ACEI, no significant difference in the number of treatment doses of epinephrine was observed.28 Another study reported an even lower frequency of AE in patients taking antihypertensive treatment, although not statistically significant.29 This is in agreement with our results; VIT was safe in patients taking ACEI.
Whether β‐blockers and ACEI are able to aggravate anaphylaxis is still a controversial issue. A systematic review and meta‐analysis revealed that evidence of an increased risk of more severe anaphylaxis in patients who take β‐blockers and ACEI was tenuous owing to the heterogeneous control of confounding variables.30 Importantly, higher age is an established risk factor for more severe sting reactions.8, 9, 10 Previous data had already suggested that older patients are more likely to take β‐blockers and ACEI and that older age was the relevant predictor for severe anaphylaxis16 or SSR.9 We were able to demonstrate in 219 patients taking β‐blockers and in 240 patients taking ACEI that higher age, but not taking antihypertensive drugs, was a major risk factor for severe anaphylaxis. This is in conflict with data from the anaphylaxis registry of the German‐speaking countries: In the first report,17 a moderately increased risk for more severe anaphylaxis particularly in patients taking both, β‐blockers and ACEI, was detected. More recently,31 it was reported that patients receiving β‐blockers and ACEI had a higher risk of developing severe cardiovascular symptoms during venom‐induced anaphylaxis. There may be several reasons explaining the different findings. Most importantly, due to the previous strict recommendation of stopping β‐blockers and ACEI in insect venom–allergic patients, these drugs were only maintained in highly selected patients with severe cardiovascular problems. Those patients may have more severe SSR caused by their underlying disease but not by the intake of their medication. No adjustment was made for cardiovascular diseases as a potential confounder. Furthermore, they did not state the exact number of patients taking β‐blockers and ACEI in both reports. One could speculate that if the patient number was small, a random effect could have been observed due to the underpowered study design.
It was also hypothesized that AE could be refractory to emergency treatment and that epinephrine may cause paradoxical treatment effects due to concomitant β‐blocker therapy.32 Recent data suggest that patients with β‐blockers do not require increased doses of epinephrine.33 In our study, epinephrine was rarely used to treat AE, indicating that VIT was very safe. In detail, in 19 patients, epinephrine was administered to treat low‐to‐moderate adverse reactions. It is, however, important to note that only two patients taking β‐blockers required epinephrine: one had a Grade I reaction and was taking β‐blockers and ACEI, the other had a Grade II reaction and was only taking a β‐blocker. Importantly, these patients tolerated emergency treatment well and responded quickly. Therefore, the beneficial effects of β‐blockers by far outweigh the hypothetical negative effects.
Treatment with ACE inhibitors or β‐blockers during VIT was considered as contraindicated for years; therefore, ACEI and β‐blocker therapy was usually stopped and only maintained in patients with severe cardiovascular diseases. These highly selective samples of patients may have biased previous study results. Over recent years, guidelines have become less restrictive, resulting in more patients taking antihypertensive drugs with VIT. This may explain why older studies sometimes reported a higher risk for AE,12 while more recent data suggested that taking ACEI and β‐blockers is safe.25 The situation is similar in terms of the effectiveness of VIT: While one study reported a higher risk of VIT failure in a small number of highly selected patients,7 others did not detect such a risk.29, 34 In our study, the effectiveness of VIT was comparable in patients with or without antihypertensive drugs. Interestingly, none of the patients who relapsed took ACEI.
Patients treated with bee venom had an approximately 3‐fold higher risk for systemic AE. This is in accordance with previously published data of multicenter studies.12, 35 We could also show in a large number of patients receiving VIT that elevated basal tryptase levels and mastocytosis were no risk factors for systemic AE. It is also already known that patients with mastocytosis usually tolerate VIT well.36 Interestingly, we calculated almost the same OR for systemic AE in patients with elevated serum tryptase (OR 1.54) compared to a previously published multicenter study (OR 1.56).12 While the risk was statistically significant in the study by Rueff et al.,12 we did not observe such a risk. We did not use logarithmic transformation of data, which may explain the different statistical outcomes. Additionally, we could confirm that severe sting reactions12, 35 and high specific IgE25 did not influence the frequency of systemic AE.
Limitations of the study: The number of patients who experienced more severe AE during VIT requiring epinephrine treatment was very low. Only two patients taking β‐blockers received epinephrine and no conclusion can be drawn as to whether epinephrine was less effective or caused paradoxical effects in patients taking β‐blockers.
The effect of age on the severity of SSR may have been underestimated in our study. Only patients aged 35 to 85 years were included because it was assumed that 24% of this age group would take β‐blockers or ACEI. We still observed an age effect. However, we could not compare severity of SSR between our age group and younger patients. Monitoring VIT effectiveness by sting challenge was optional for study centers and the evaluation was primarily based on the reported outcome of field stings. Therefore, results should be interpreted with caution, as patients may not have correctly identified the stinging insect.
This study provides robust evidence that β‐blockers and ACEI do not increase the frequency of systemic AE during VIT. The number of AE was even lower compared with patients not taking antihypertensive treatment (5.6% and 7.4%, respectively; OR: 0.74; CI: 0.43–1.22); moreover, β‐blockers and ACEI did not aggravate the severity of insect sting reactions.
CONFLICT OF INTEREST
Dr. Sturm reports grants from ALK‐Abelló, personal fees from ALK‐Abelló, personal fees from Allergopharma, personal fees from Novartis, personal fees from Mylan, personal fees from Stallergenes, personal fees from Bencard, outside the submitted work. Dr. Herzog has nothing to disclose. Dr. Aberer has nothing to disclose. Dr. Alfaya reports personal fees from ALK‐Abelló, outside the submitted work. Dr. Antolín‐Amérigo reports personal fees from Astra‐Zeneca, personal fees from GSK, personal fees from MSD, personal fees from Novartis, personal fees from MEDA‐Mylan, personal fees from FAES, personal fees from Leti, personal fees from Sanofi‐Genzyme, personal fees from ALK‐Abelló, outside the submitted work. Dr. Bonadonna has nothing to disclose. Dr. Boni has nothing to disclose. Dr. Bozek has nothing to disclose. Dr. Chelminska has nothing to disclose. Dr. Ernst has nothing to disclose. Dr. Frelih has nothing to disclose. Dr. Gawlik has nothing to disclose. Dr. Gelincik has nothing to disclose. Dr. Hawranek reports personal fees from ALK‐Abelló, personal fees from Novartis, personal fees from Takeda, personal fees from Bencard, personal fees from Lofarma, outside the submitted work. Dr. Hoetzenecker has nothing to disclose. Dr. Jiménez Blanco has nothing to disclose. Dr. Kita has nothing to disclose. Dr. Kendirlinan has nothing to disclose. Dr. Kosnik has nothing to disclose. Dr. Laipold has nothing to disclose. Dr. Lang reports non‐financial support from Bencard, non‐financial support from ALK‐Abelló, non‐financial support from Thermo Fisher Scientific, outside the submitted work. Dr. Marchi has nothing to disclose. Dr. Mauro has nothing to disclose. Dr. Nittner‐Marszalska has nothing to disclose. Dr. Poziomkowska‐Gęsicka has nothing to disclose. Dr. Pravettoni has nothing to disclose. Dr. Preziosi has nothing to disclose. Dr. Quercia has nothing to disclose. Dr. Reider has nothing to disclose. Dr. Rosiek‐Biegus has nothing to disclose. Dr. Ruiz‐Leon has nothing to disclose. Dr. Schrautzer has nothing to disclose. Dr. Serrano has nothing to disclose. Dr. Sin A. has nothing to disclose. Dr. Sin B.A. has nothing to disclose. Dr. Stoevesandt has nothing to disclose. Dr. Trautmann reports personal fees from ALK‐Abelló, outside the submitted work. Dr. Vachová has nothing to disclose. Dr. Arzt‐Gradwohl has nothing to disclose.
AUTHOR CONTRIBUTION
Conceptualization: GJS and CS; Supervision: GJS; Project administration: LAG; Investigation: GJS, TAA, DAA, PB, EB, AB, MC, BE, NF, RG, AG, TH, WH, AJB, KK, RK, MK, KL, RL, FM, MM, MNM, IPG, VP, DP, OQ, NR, MRB, BRL, CS, PS, AS, BAS, JS, AT, MV, LAG; Formal analysis: SAH; Methodology: SAH, KL; Writing‐original draft: GJS, SAH and LAG; Writing‐review & editing: WA, TAA, DAA, PB, EB, AB, MC, BE, NF, RG, AG, TH, WH, AJB, KK, RK, MK, RL, FM, MM, MNM, IPG, VP, DP, OQ, NR, MRB, BRL, CS, PS, AS, BAS, JS, AT, MV; Funding acquisition: GJS. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
ACKNOWLEDGEMENTS
We thank Anna Carabelli, MD (SD Allergologia Clinica, Azienda Ospedaliero‐Universitaria Pisana, Pisa, Italy), Georg Klein, MD (Department of Dermatology, General Hospital Ordensklinikum Linz GmbH Elisabethinen, Linz, Austria), Antonia Kragten (Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria), José Julio Laguna, MD (Allergy Unit, Hospital Central de la Cruz Roja. Faculty of Medicine, Alfonso X El Sabio University, ARADyAL, Madrid, Spain), Carmen Moreno‐Aguilar, MD (Maimonides Institute for research in Biomedicine of Cordoba (IMIBIC), Avenida Menéndez Pidal S/N, Córdoba, Spain and Unidad de GestiónClínica de Inmunoalergia&ARADyAL research network, Reina Sofía University Hospital, Córdoba, Spain), Barbara Rogala, MD, PhD (Clinical Department of Internal Diseases, Dermatology, and Allergology, Medical University of Silesia, Zabrze, Poland), Cecilia Spina, MD (Haematology and Bone‐Marrow Transplant Unit, Department of Medicine, Verona University, Verona, Italy), Ceyda TunakanDalgıç, MD(Department of Internal Medicine, Division of Allergy and Immunology, Medical Faculty, Ege University, Izmir, Turkey) as well as Daniella Winter, MD (Department of Dermatology, General Hospital Ordensklinikum Linz GmbH Elisabethinen, Linz, Austria) for their valuable help.
Funding information
The study was funded by the Medical University of Graz.
REFERENCES
- 1.Antonicelli L, Bilo MB, Bonifazi F. Epidemiology of Hymenoptera allergy. Curr Opin Allergy Clin Immunol. 2002;2(4):341‐346. [DOI] [PubMed] [Google Scholar]
- 2.Golden DB, Marsh DG, Kagey‐Sobotka A, et al. Epidemiology of insect venom sensitivity. JAMA 1989;262(2):240‐244. [PubMed] [Google Scholar]
- 3.Bilo BM, Bonifazi F. Epidemiology of insect‐venom anaphylaxis. Curr Opin Allergy Clin Immunol. 2008;8(4):330‐337. [DOI] [PubMed] [Google Scholar]
- 4.Bokanovic D, Aberer W, Griesbacher A, Sturm GJ. Prevalence of hymenoptera venom allergy and poor adherence to immunotherapy in Austria. Allergy 2011;66(10):1395‐1396. [DOI] [PubMed] [Google Scholar]
- 5.Sturm GJ, Varga EM, Roberts G, et al. EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy. Allergy 2018;73(4):744‐764. [DOI] [PubMed] [Google Scholar]
- 6.Muller U, Helbling A, Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety. J Allergy Clin Immunol. 1992;89(2):529‐535. [DOI] [PubMed] [Google Scholar]
- 7.Rueff F, Vos B, Elberink JO, et al. Predictors of clinical effectiveness of Hymenoptera venom immunotherapy. Clin Exp Allergy 2014. [DOI] [PubMed] [Google Scholar]
- 8.Rueff F, Przybilla B, Bilo MB, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase‐a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol. 2009;124(5):1047‐1054. [DOI] [PubMed] [Google Scholar]
- 9.Arzt L, Bokanovic D, Schwarz I, et al. Hymenoptera stings in the head region induce impressive, but not severe sting reactions. Allergy 2016;71(11):1632‐1634. [DOI] [PubMed] [Google Scholar]
- 10.Stoevesandt J, Hain J, Kerstan A, Trautmann A. Over‐ and underestimated parameters in severe Hymenoptera venom‐induced anaphylaxis: cardiovascular medication and absence of urticaria/angioedema. J Allergy Clin Immunol. 2012;130(3):698‐704 e691. [DOI] [PubMed] [Google Scholar]
- 11.Ludolph‐Hauser D, Rueff F, Fries C, Schopf P, Przybilla B. Constitutively raised serum concentrations of mast‐cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001;357(9253):361‐362. [DOI] [PubMed] [Google Scholar]
- 12.Rueff F, Przybilla B, Bilo MB, et al. Predictors of side effects during the buildup phase of venom immunotherapy for Hymenoptera venom allergy: the importance of baseline serum tryptase. J Allergy Clin Immunol. 2010;126(1):105‐111 e105. [DOI] [PubMed] [Google Scholar]
- 13.Sturm G, Kranke B, Rudolph C, Aberer W. Rush Hymenoptera venom immunotherapy: a safe and practical protocol for high‐risk patients. J Allergy Clin Immunol. 2002;110(6):928‐933. [DOI] [PubMed] [Google Scholar]
- 14.Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high‐, middle‐, and low‐income countries. JAMA 2013;310(9):959‐968. [DOI] [PubMed] [Google Scholar]
- 15.Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365(9455):217‐223. [DOI] [PubMed] [Google Scholar]
- 16.Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol. 2004;114(2):371‐376. [DOI] [PubMed] [Google Scholar]
- 17.Nassiri M, Babina M, Dolle S, Edenharter G, Rueff F, Worm M. Ramipril and metoprolol intake aggravate human and murine anaphylaxis: evidence for direct mast cell priming. J Allergy Clin Immunol. 2015;135(2):491‐499. [DOI] [PubMed] [Google Scholar]
- 18.Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977;1(8009):466‐469. [DOI] [PubMed] [Google Scholar]
- 19.Bilo BM, Rueff F, Mosbech H, Bonifazi F, Oude‐Elberink JN. EAACI Interest Group on Insect venom hypersensitivity. diagnosis of hymenoptera venom allergy. Allergy 2005;60(11):1339‐1349. [DOI] [PubMed] [Google Scholar]
- 20.Bonifazi F, Jutel M, Bilo BM, Birnbaum J, Muller U. Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice. Allergy 2005;60(12):1459‐1470. [DOI] [PubMed] [Google Scholar]
- 21.Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed‐effects models using lme4. J Stat Softw. 2015;67(1):48. [Google Scholar]
- 22.van Buuren S, Groothuis‐Oudshoorn K. mice: Multivariate imputation by chained equations in R. J Stat Softw. 2011;45(3):67. [Google Scholar]
- 23.Hepner MJ, Ownby DR, Anderson JA, Rowe MS, Sears‐Ewald D, Brown EB. Risk of systemic reactions in patients taking beta‐blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol. 1990;86(3 Pt 1):407‐411. [DOI] [PubMed] [Google Scholar]
- 24.Muller UR, Haeberli G. Use of beta‐blockers during immunotherapy for Hymenoptera venom allergy. J Allergy Clin Immunol. 2005;115(3):606‐610. [DOI] [PubMed] [Google Scholar]
- 25.Stoevesandt J, Hain J, Stolze I, Kerstan A, Trautmann A. Angiotensin‐converting enzyme inhibitors do not impair the safety of Hymenoptera venom immunotherapy build‐up phase. Clin Exp Allergy. 2014;44(5):747‐755. [DOI] [PubMed] [Google Scholar]
- 26.Bernkopf K, Ronsch H, Spornraft‐Ragaller P, Neumeister V, Bauer A. Safety and tolerability during build‐up phase of a rush venom immunotherapy. Ann Allergy Asthma Immunol. 2016;116(4):360‐365. [DOI] [PubMed] [Google Scholar]
- 27.Stumpf JL, Shehab N, Patel AC. Safety of Angiotensin‐converting enzyme inhibitors in patients with insect venom allergies. Ann Pharmacother. 2006;40(4):699‐703. [DOI] [PubMed] [Google Scholar]
- 28.Carlson GS, Wong PH, White KM, Quinn JM. Evaluation of angiotensin‐converting enzyme inhibitor and angiotensin receptor blocker therapy in immunotherapy‐associated systemic reactions. J Allergy Clin Immunol Pract. 2017;5(5):1430‐1432. [DOI] [PubMed] [Google Scholar]
- 29.Stoevesandt J, Hosp C, Kerstan A, Trautmann A. Hymenoptera venom immunotherapy while maintaining cardiovascular medication: safe and effective. Ann Allergy Asthma Immunol. 2015;114(5):411‐416. [DOI] [PubMed] [Google Scholar]
- 30.Tejedor‐Alonso MA, Farias‐Aquino E, Pérez‐Fernández E, Grifol‐Clar E, Moro‐Moro M, Rosado‐Ingelmo A. Relationship between anaphylaxis and use of beta‐blockers and angiotensin‐converting enzyme inhibitors: a systematic review and meta‐analysis of observational studies. J Allergy Clin Immunol Pract. 2019;7(3):879‐897.e875. [DOI] [PubMed] [Google Scholar]
- 31.Francuzik W, Ruëff F, Bauer A, et al. Phenotype and risk factors of venom‐induced anaphylaxis: a case‐control study of the European Anaphylaxis Registry. J Allergy Clin Immunol. 2020;147(2):653–662. [DOI] [PubMed] [Google Scholar]
- 32.Lang DM. Anaphylactoid and anaphylactic reactions. Hazards of beta‐blockers. Drug Saf. 1995;12(5):299‐304. [DOI] [PubMed] [Google Scholar]
- 33.White JL, Greger KC, Lee S, et al. Patients taking β‐blockers do not require increased doses of epinephrine for anaphylaxis. J Allergy Clin Immunol Pract. 2018;6(5):1553‐1558.e1551. [DOI] [PubMed] [Google Scholar]
- 34.Rueff F, Przybilla B, Bilo MB, et al. Clinical effectiveness of hymenoptera venom immunotherapy: a prospective observational multicenter study of the European academy of allergology and clinical immunology interest group on insect venom hypersensitivity. PLoS One 2013;8(5):e63233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Mosbech H, Muller U. Side‐effects of insect venom immunotherapy: results from an EAACI multicenter study. European Academy of Allergology and Clinical Immunology. Allergy 2000;55(11):1005‐1010. [DOI] [PubMed] [Google Scholar]
- 36.Bonadonna P, Gonzalez‐de‐Olano D, Zanotti R, et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract. 2013;1(5):474‐478. [DOI] [PubMed] [Google Scholar]