Risk Factors for Systemic Reactions to Allergen Immunotherapy

Alfredo Iglesias-Cadarso; Pilar Hernández-Weigand

Curr Opin Allergy Clin Immunol. 2011;11(6):579-585. 

Purpose of review To update safety information regarding allergen-specific immunotherapy (ASIT) in clinical practice and highlight the risk factors associated with the adverse reactions, product and each dose.
Recent findings Efforts in recent years have focused on increasing our understanding of the efficacy and safety of ASIT, especially the sublingual variety (SLIT), in multicenter studies. Moreover, new Clinical Practice Guidelines (CPGs) and an international consensus concerning ASIT have been published recently. Although no deaths as a result of subcutaneous immunotherapy or SLIT have been reported in the last 2 years, systemic reactions mainly arising from administration errors still appear. Recent studies support the safety of new forms of specific immunotherapy.
Summary An understanding of the risk factors for each patient, product and dose, and the implementation of CPGs are the main factors that could improve the safety of ASIT. The standardization of all procedures for prescribing and administering ASIT, and the systematic collection of standardized safety data in a multicenter database (postmarketing surveillance), may be required to generate new information on the safety of ASIT.

Why Do We Even Care About Safety of Allergy Shots?

Allergen-specific immunotherapy (ASIT), both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT), has been shown to be effective for the treatment of allergic respiratory disease in randomized controlled trials and meta-analyses.  Indeed, SCIT is the treatment of choice for preventing anaphylaxis in patients with systemic reactions to hymenoptera (bee stings).

The greatest drawback to the more widespread use of ASIT is the associated risk of severe side-effects, as the dose which has been shown to be well tolerated and effective in a group of patients may not be so for a specific patient. Here again, everyone is different and what may be the best dose for one patient, may cause an adverse reaction for someone else.

Systemic reactions are those which produce symptoms and signs far from the administration site. They may be immediate systemic reaction (ISR), appearing in the first 30 min postadministration, or delayed systemic reaction (DSR), occurring after the first 30 min, with the former tending to be more severe.

The incidence of systemic reactions has been estimated at between 1 and 34% of patients and around 0.2–0.3% of doses, depending on the type of study, patient, diagnosis, extract or treatment scheme.  

Historical reviews of ASIT-related mortalityhighlighted severe or poorly controlled asthma and administration errors as the main causes of fatal systemic reactions. These findings led to the drafting of Clinical Practice Guidelines (CPGs) for ASIT treatment,and their subsequent updates, in the 1990s. Adherence to such guidelines is the main reason behind the reduced frequency and severity of systemic reactions in the past 20 years. The statistics regarding mortality and systemic reactions prior to these CPGs are no longer applicable.

Let’s look at some individual factors that increase your chances of a systemic reaction to an allergy shot!

• What do you put in my serum? No specific allergen is currently thought to produce higher mortality or a greater chance of a large local reaction.
• Very few fatal reactions to pure hymenoptera venom immunotherapy (VIT) have been reported. Indeed, several studieshave found a lower incidence of systemic reactions with hymenoptera vaccines, with bee vaccines being tolerated worse than wasp vaccines.
• Systemic reactions appear to be more frequent when aqueous extracts are used.  This is presumably due to the fact that the allergen is absorbed very quickly after it’s injected.

Dose-related Risk Factors

• Administration errors are the main identifiable and avoidable cause of ASIT-related systemic reactions, including SLIT. (SLIT is the oral allergy drops)
• Any delay in the treatment of a systemic reaction increases its severity. This is why I instruct my nurses to give epinephrine first, then call.
• Although CPGs provide recommendations to avoid such errors, they continue to occur with a greater than expected frequency. 
• I could write a book on the types of errors that occur with the dose of allergy shots.  Would this be a best-seller or what?
• Research has shown that a large local reaction does not predict the occurance of a more severe systemic reaction; a concept that can be difficult to grasp for patients.  (see below)

Dosing Scheme

In the case of SCIT with airborne allergens, the use of fast regimens (rush and cluster) has been associated with a higher number of systemic reactions, although more recent studies have shown their safety to be similar to that of conventional schemes. Patients tend to like the rapid schedule because they can avoid the prolonged build-up of conventional treatment. 

Omalizumab (Xolair) has been used to reduce the systemic reaction incidence in patients receiving SCIT with inhaled allergens and VIT (venom shots),  with good results.

It is possible, but not confirmed, that systemic reactions increase during the pollen season, but patients generally do not decrease their dose at this time.

Prior Reactions

Together with poorly controlled asthma, the presence of a prior systemic reaction during AIT is the main risk factor associated with a new systemic reaction. 

There is currently no evidence that the dose adjustments recommended in clinical guidelines reduce recurrent systemic reaction in a patient.

Premedication with antihistamines or omalizumab has been shown to be useful in some studies, although such treatment is not recommended as standard.

Local reactions do not predict the appearance of a systemic reaction, although some studies have suggested them to be a risk factor.  The dose adjustments subsequent to major local reactions recommended in the clinical guidelines do not reduce the frequency of future systemic reactions. For additional information regarding the safety of allergy shots, refer to the reference below:

• Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127:S1-S55.
  •• Latest and extended update of the Joint Task Force (AAAAI-ACAAI) on Practice Parameters concerning all aspects of allergen-specific immunotherapy.