In this study, we compared a purified aqueous extract and the corresponding nonpurified aqueous preparation under the same build-up protocol in bee venom allergic patients with a normal baseline mast cell tryptase concentration. Eighty patients with a history of a systemic reaction were enrolled for immunotherapy using a 5-day rush protocol. Patients treated with the purified extract and those treated with the non purified aqueous extract who developed a systemic reaction underwent maintenance therapy with the purified aluminium hydroxide adsorbed preparations. Patients treated with the nonpurified aqueous extract who did not experience a systemic reaction during the rush phase underwent the maintenance phase with that extract. Systemic reactions during the build-up phase occurred significantly more often in patients treated with nonpurified aqueous extract than in those treated with the corresponding purified aqueous preparations. During the one-year maintenance phase, no systemic reactions occurred in either of the groups. Neither age nor baseline mast cell tryptase concentration presented a significant correlation with the occurrence of a systemic reaction during the treatment, while the type of extract did. In conclusion, nonpurified aqueous extracts induced more frequent systemic reactions than the purified aqueous preparations, during the same rush protocol. The efficacy seemed to be comparable.
Subcutaneous VIT with a standard dose of 100
As PA extracts and the corresponding NPA extracts in HBV-allergic patients have not been compared so far, this study aims to prospectively compare treatment safety in terms of SRs by administering PA and the corresponding NPA bee-venom extracts during the same rush phase in patients with a normal bSTC and evaluate the safety of depot versus NPA extracts during a one-year maintenance phase.
Consecutive HBV-allergic patients with a history of a SR ≥ Mueller grade II [
The Local Ethics Committee approved the Study Protocol and patients gave their written informed consent.
The following extracts were used for treatment: (1) the traditional NPA HBV preparations (Pharmalgen ALK-Abellò aqueous extracts, HØrsholm, Denmark), reconstituted in albumin-containing saline diluent; (2) a PA HBV preparation (Aquagen SQ, ALK-Abellò); (3) a purified aluminium-adsorbed HBV depot preparation (Alutard SQ, ALK-Abellò). All preparations contain 100
The patients underwent a 5-day rush VIT regimen (Table
Protocol of VIT build-up rush phase.
Day | Dose | mL administered | Conc | |
---|---|---|---|---|
1 | 1 | 0.10 | 0,01 | 0,1 |
2 | 0.10 | 0,1 | 1 | |
3 | 0.10 | 1 | 10 | |
4 | 0.20 | 2 | 10 | |
2 | 5 | 0.30 | 3 | 10 |
6 | 0.35 | 3,5 | 10 | |
7 | 0.35 | 3,5 | 10 | |
3 | 8 | 0.10 | 10 | 100 |
9 | 0.15 | 15 | 100 | |
10 | 0.15 | 15 | 100 | |
4 | 11 | 0.20 | 20 | 100 |
12 | 0.25 | 25 | 100 | |
13 | 0.25 | 25 | 100 | |
5 | 14 | 0.30 | 30 | 100 |
15 | 0.35 | 35 | 100 | |
16 | 0.35 | 35 | 100 |
Only those patients with a history of anaphylaxis undergoing rush VIT were hospitalised in our clinic. The other patients were kept on an outpatient regimen on the day of treatment. Injections were administered in our clinic by the same allergist. SRs to VIT injections were Mueller classified [
Development of an SR during the rush-phase necessitated suspending treatment until the patient made a complete recovery, after which a depot extract was used. In the event of a large local or a mild SR, the VIT dosage was maintained. Weekly interval injections up to the standard maintenance dosage were then administered.
Patients were instructed to immediately report any suspected delayed VIT-related reactions experienced at home.
The use of hospital sting challenges remains an ethical issue in Italy and is generally avoided for testing VIT efficacy. This being the case, patients were instructed to report details of any reaction to a field sting and any pharmacological treatment. To assess treatment efficacy in non beekeepers, only those stings typically attributable to bees, recognisable by the embedded stinger at the sting site, were considered.
Statistical analysis was carried out using SPSS statistical software (vers. 13) (SPSS Chicago, IL, USA). Differences between the two groups in outcome variables (i.e., occurrence of SRs) were assessed using Fisher’s exact test (whenever an expected cell value was <5) and the
The power calculation assumed a difference between PA and NPA treated subjects in the incidence of SRs of at least 65% less (relative risk reduction). This assumption provided 80% power at an alpha level of 0.05 for a sample size of at least 40 evaluable patients per group. Sample size calculation was performed using GPower Statistical Software ver 3.03 (Germany).
Ninety-seven consecutive patients with a history of an SR to HB stings were evaluated for the study, of whom 17 (17.5%) were excluded on the grounds of a bSTC ≥ 11.5
Demographic and clinical data of patients included in the study.
Group A (Nonpurified) | Group B (purified) | ||
---|---|---|---|
Sex (male/female) | 34/6 | 30/10 | 0.8 |
Age, years, mean (SD) | 42 (17) | 42 (16) | 0.8 |
Mueller classification | |||
Grade I | 0 | 0 | 0.7 |
Grade II | 7 | 9 | |
Grade III | 15 | 13 | |
Grade IV | 18 | 18 |
Study flow for the build-up phase of VIT.
Baseline serum tryptase level (
The cumulative doses during the tolerated 5-day rush-phase was 223.11
Systemic reaction during the build-up phase of VIT.
Build-up 5-day rush phase | |||
Group | No. of patient | VIT day | SR* |
(A) Aqueous non-purified | 2 | 2 | II |
1 | 2 | I | |
3 | 3 | II | |
3 | 3 | I | |
1 | 4 | I | |
1 | 5 | I | |
(B) Aqueous purified | 1 | 3 | I |
*According to Mueller classification [
Study flow for the build-up and maintenance phases of VIT.
Maintenance dose was 100
The mean (SD) value of bSTC was 5 (±2.3)
Baseline serum tryptase level in patients who developed a systemic reaction (SR) during the build-up phase of VIT in comparison with those who did not.
No patient was re-stung during the build-up phase. Thirteen out of the 29 (44.8%) NPA extract treated patients were re-stung during the one year maintenance phase without developing a reaction.
Fifteen out of the 51 patients (13.6%) treated with the PAHA extract during the maintenance phase were re-stung without side effects, of whom one developed a mild SR during VIT.
While probably being the most effective form of allergen immunotherapy currently available to physicians [
This is the first study comparing the safety of purified and the corresponding non-purified aqueous venom preparations in terms of SRs in HBV-allergic patients with a normal bSTC under the same build-up protocol. We studied HV-venom-allergic patients as their risk of developing an SR during VIT is greater than that of vespid-allergic patients [
Patients with a bSTC ≥ 11.5
In this study, we compared the same build-up protocol in two homogeneous groups of patients who were treated with two different extracts from the same company. We have demonstrated that patients treated with the non-purified HBV experienced significantly more SRs than those treated with the purified HBV preparation, due to a higher occurrence of SRs during the build-up phase. In fact, during the same 5-day rush phase, 27.5% of the NPA-extracts-treated patients developed an SR compared with 2.5% of the PA-extract-treated subjects (
Patients who had SRs during the build-up phase were switched to the PAHA extract from the NPA solution, as were those treated with the PA extract whether they had experienced an SR or not. During the one-year maintenance phase, no SRs occurred in either group. Though there was no control group, our data indirectly confirm the safer profile of the PAHA extracts. In fact, all those patients who experienced PA- or NPA-induced SRs during the rush phase could have benefited from being switched to the same dosage of a PAHA preparation and have subsequently achieved the 100
To date, the only study which compares PA and PAHA extracts with the corresponding NPA preparations dates back to 1986 and was done in yellow-jacket-venom- (YJV-) allergic patients. The authors demonstrated that PA-induced SRs were milder than those caused by NPA preparations, but more frequent with the PAHA extracts [
Another study of HBV-allergic patients, in which the safety of the PA and PAHA extracts and of three different induction protocols were compared, demonstrated that depot cluster VIT was better tolerated than PA rush VIT, which in turn was less well tolerated than the PA cluster protocol [
The efficacy of the PA and PAHA preparations is supported by studies implementing sting challenges in HBV- and YJV-allergic patients and is comparable to that of non-purified extracts [
Our study suffers from a few limitations which need to be taken into account from a results point of view. Firstly, we conducted an unblinded open trial. Despite this, the main outcome was the incidence of SRs which should be considered as the “hard” end point. Also, the clinical definition of SR is well defined and accepted with a low margin to subjectivity. Secondly, the sample size required to verify the trial hypothesis was calculated in advance and the relative risk reduction (RRR) in the number of SRs we observed (−91%) in the purified extract-treated patients was far greater than the RRR forecast in calculation of the sample size (−65%).
In conclusion, our study demonstrates the superiority of the PA extract in HBV-allergic subjects over the corresponding non-purified extracts under the same rush incremental phase.
Though similar in terms of their efficacy, HB PA extracts are safer option than NPA preparations for specialists who perform rush VIT, followed by maintenance treatment with the PAHA preparation. The use of the HB depot extracts for the conventional incremental and maintenance phases could be proposed as a workable solution for specialists with less experience in managing VIT.
Moreover, in patients with SRs caused by both PA and NPA extracts, the switch to a PAHA extract could be safely made and allow the generally adequate maintenance dose of 100
ALK-Abellò Italy partially supported this study by providing study medication. The authors wish to extend their thanks to Massimo Milani for his statistical support and to Paul Bowerbank for his assistance in reviewing the English of the paper.