eMJA: Westall et al, Adverse events associated with rush Hymenoptera venom immunotherapy

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Adverse events associated with rush Hymenoptera venom immunotherapy

Glen P Westall, Frank C K Thien, Dan Czarny, Robyn E O'Hehir and Jo A Douglass

MJA 2001; 174: 227-230

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Abstract - Methods - Results - Discussion - References - Authors' details

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Abstract

Objectives: To determine the incidence and nature of adverse events associated with the induction of rush Hymenoptera venom immunotherapy.
Design: Retrospective descriptive case study.
Setting: The asthma and allergy unit at a major metropolitan teaching hospital, between 1 January 1989 and 30 June 1999.
Patients: All patients with anaphylaxis to stings of Hymenoptera insects who received rush venom immunotherapy as inpatients.
Outcome measures: Hypersensitivity reactions to venom administration, including angioedema, skin rashes, hypotension and asthma, as well as any other adverse events related to the inpatient stay.
Results: 68 venom-allergic patients received 73 courses of rush immunotherapy; 89% were desensitised to honey bee venom, 10% to yellow jacket wasp venom, and one to paper wasp venom. Hypersensitivity reactions occurred after 36 subcutaneous injections (3.8% of all injections given) in 26 patients (38%).
Conclusion: In our cohort, immunotherapy was accompanied by a high incidence of adverse systemic events during the induction phase. Immunotherapy should only be given by experienced staff in centres where there are facilities for resuscitation.

Stinging-insect anaphylaxis is most often caused by bee and wasp stings, but may also occur as a reaction to ants, march flies, ticks and other insects.¹ The insect order Hymenoptera includes the vespids (yellow jacket or European wasp, and paper wasps) and the apids (honey bees). Clinical manifestations after wasp and bee stings include hypersensitivity reactions that can be fatal. There is a minimal degree of immunogenic cross-reactivity between bee and wasp venoms.² Australian Bureau of Statistics mortality figures after bee stings give a rate of 0.086 per million population per year, or approximately one death per year.³

An anaphylactic reaction to insect venom is an absolute indication for venom immunotherapy (see Box 1), as this is protective in more than 80%-90% of individuals in preventing future severe reactions.⁴ The first commercial venom extracts became available in 1979 and since then indications and treatment schedules have been refined. A number of different dosing schedules for immunotherapy are used, including conventional (induction immunotherapy over several weeks as an outpatient), rush (induction over several days) and ultrarush (induction over several hours) immunotherapy.^5-7 In rush protocols, patients are given higher venom doses in a shorter period of time compared with conventional protocols, reaching maintenance dose (100 µg) more quickly and thus offering the patient earlier protection.⁸ At our allergy clinic, patients usually receive rush immunotherapy.

We performed a retrospective analysis of case records of insect-allergic patients to describe and ascertain the incidence of adverse events associated with inpatient rush Hymenoptera immunotherapy.

Methods

We chose the period 1 January 1989 to 30 June 1999 for our retrospective, descriptive study. Patients were identified by searching hospital records of discharge diagnosis, and we reviewed the records of all patients admitted to the Alfred Asthma and Allergy Unit for rush venom immunotherapy. The cohort therefore represented a highly selected group of venom-allergic individuals. The field sting that caused anaphylaxis was classified according to the system proposed by Mueller (Box 2).⁹ The causative insect was identified from the history and subsequently confirmed by detection of serum-specific IgE by skin-prick tests or blood-specific IgE serological testing.¹⁰ If blood-specific IgE tests were negative or unavailable, venom-specific IgE was sought by skin-prick tests with 100 µg/mL of honey bee, yellow jacket wasp and paper wasp venom; if these tests were negative patients underwent intradermal testing to serial 10-fold dilutions of venom. For diagnosis and immunotherapy, a freeze-dried venom of honey bees (Apis mellifera), paper wasps (Polistes sp.), or yellow jacket wasps (Vespula sp.) was reconstituted in albumin-saline (Bayer Australia Ltd, Pymble, NSW). Patients then had immunotherapy with the venoms corresponding to their sensitivity. Patients were treated over five days as inpatients at the Alfred Hospital, where full emergency resuscitation facilities were available, and with intravenous access being maintained at all times. Escalating doses of venom (0.1 µg to 100 µg) were injected subcutaneously. A total of 13 injections were given 60 minutes apart, and a nurse closely observed the patient after each injection. The patient's general practitioner continued maintenance immunotherapy according to a protocol provided by the Asthma and Allergy Unit. For patients who were unable to attain the recommended maintenance dose of 100 µg of venom, the patient's GP was provided with a treatment schedule on how to increase the dose, up to the maintenance dose.

We compared the group of patients who developed hypersensitivity reactions to venom during the course of their induction immunotherapy with a group of patients who had no such reaction to look for any predictive variables. For each group, mean age, sex, stinging insect, severity of initial reaction, atopic status, presence of asthma, and blood-specific IgE to stinging insect was compared.

Statistical analysis

Statistical analysis was performed with the SAS software package.¹¹ Means and proportions were compared by standard tests (

², t tests and Wilcoxon 2-sample test). The 0.05 level of significance was used throughout the analysis and all P values reported are two-sided.

Ethical approval

The study was approved by the Alfred Hospital Ethics Committee.

Results

Clinical features

Patient demographics and clinical features are shown in Box 2. During the study period, 68 venom-allergic patients received a total of 73 courses of rush immunotherapy (949 injections). When asked about the causative stinging insect, 58 patients identified honey bee, six identified yellow jacket wasp and one identified the paper wasp. All of these responses were confirmed with either positive skinprick tests or blood-specific IgE testing to the same insect. Only three patients could not identify the stinging insect. Of the five patients who received two courses of immunotherapy, two initially complied poorly with the initial course and developed severe anaphylaxis when they were stung again, and three patients ran out of maintenance bee venom during a national shortage. One patient who was taking a

-blocker (a contraindication to immunotherapy) changed to an alternative antihypertensive medication before beginning immunotherapy.

Immunotherapy

Complications during treatment were recorded as being either IgE mediated (hypersensitivity reaction) or non-IgE mediated (no hypersensitivity reaction); details are shown in Box 3. Allergic complications occurred at all stages of the rush protocol. All patients developed local reactions at the site of injection. Systemic hypersensitivity reactions occurred after 36 of the 949 injections (3.8%) in 26 of the 68 patients (38%). Recurrent adverse reactions prevented 14% of individuals attaining the recommended maintenance dose (100 mg) during their hospital admission.

Among patients who had non-IgE-mediated complications, two developed gram-negative sepsis, possibly from infected intravenous sites, and one was initially incorrectly given paper wasp rather than yellow jacket wasp venom.

Discussion

We found that allergic adverse events during rush immunotherapy were common, occurring in 38% of patients treated, with a risk of allergic reaction per immunotherapy injection of 3.8%.

There are very few Australian reports looking at the management of insect venom allergy;^1,3,12,13 most such reports come from the United States and Europe.^6,14-17 The most striking difference between our findings and those of overseas studies was in the causative insect. In the US and Europe, most courses of insect immunotherapy are prescribed for wasp allergy, while we found that almost 90% of people assessed for desensitisation in our unit had honey bee allergy. This marked difference most likely reflects Australia's geographical location and thus differing local fauna. In particular, the European (yellow jacket) wasp has only been common in Australia in the past 10 years. The importance of this observation relates to marked differences in the efficacy and the rates of adverse events of bee and wasp immunotherapy.¹⁸

In our study, the risk of an allergic adverse event and the rate of administration of adrenaline per injection (1.4%) are higher than those reported in other centres that use rapid immunotherapy regimens.^6,14-19 However, we treated a considerably higher proportion of patients with honey bee venom than these centres. This is relevant because previous reports have described a higher incidence of side effects in patients treated with honey bee venom owing to its greater potency,⁴ and our findings support these conclusions. A second explanation for the increased use of adrenaline may lie in our unit's policy of early identification and aggressive treatment of any allergic reactions to venom preparations.

Previous investigators have shown that there is a strong correlation between a severe initial sting (Mueller grade IV) and subsequent propensity to develop hypersensitivity reactions after deliberate sting challenges.²⁰ We found no correlation between an initial Mueller grade IV sting and subsequent likelihood of developing anaphylaxis during immunotherapy (P = 0.63). As in other studies looking at predictors of side-effects during treatment,¹⁸ we found no association with atopic status or the serum level of venom-specific IgE. The trend for increased adverse events in females that we observed has been previously reported,^4,18 despite a predominance of males receiving desensitisation therapy. The finding that two patients developed gram-negative septicaemia led us to introduce a policy of moving the intravenous cannula every 48 hours.

One problem with treating insect stings described in the literature is the importance of correctly identifying the stinging insect. This was not a significant problem with our cohort, with only three patients being unsure of the insect at their initial assessment. This may reflect the presence of a "stinger" at the sting site being indicative of honey bee stings and thus aiding identification.²¹

Over the period examined, 68 patients were treated with a rush immunotherapy protocol, with 86% of patients reaching maintenance dose by the time they were discharged. The maintenance dose is reached within a few days with rush therapy, compared with three months with conventional regimens. The safety and cost-effectiveness of rush therapy have been previously documented,²² and tolerance to rush immunotherapy has been reported to be equal to or better than that for conventional protocols.⁷ Because allergic reactions occurred within one hour of each injection, we advise general practitioners who administer maintenance injections to observe patients for an hour after each injection.

In conclusion, our retrospective review of rush immunotherapy shows a large proportion of reactions to honey bees in Australia compared with Europe and the USA. However, there are only minimal differences in diagnosis, investigation and management compared with overseas practice. The incidence of adverse events during induction was more common with bee venom immunotherapy. Our rush protocol is convenient for the patients who often live in rural areas and would find weekly trips to our unit for outpatient immunotherapy disruptive. Our results support the recommendations that Hymenoptera venom immunotherapy should only be given by experienced staff, in centres where there are facilities for resuscitation.²³

References

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(Received 11 Sep 2000, accepted 18 Jan 2001)

Authors' details

Department of Allergy, Asthma and Clinical Immunology, The Alfred and Monash University, Melbourne, VIC.
Glen P Westall, MRCP, MB BS, Registrar;
Frank C K Thien, FRACP, MD, Physician;
Dan Czarny, FRACP, FRCP, Physician and Associate Professor;
Robyn E O'Hehir, FRACP, PhD, Professor and Director;
Jo A Douglass, FRACP, MD, Head, Asthma and Allergy Unit.

Reprints will not be available from the authors.
Correspondence: Dr J A Douglass, Department of Allergy, Asthma and Clinical Immunology, The Alfred and Monash University, Commercial Road, Prahran, VIC 3181.
j.douglassATalfred.org.au

©MJA 2001