Original Article
Systemic reactions to subcutaneous immunotherapy: Effects of dosing and aeroallergen content

https://doi.org/10.1016/j.anai.2019.06.021Get rights and content

Abstract

Background

Systemic reactions are a known risk of subcutaneous immunotherapy (SCIT) for aeroallergens.

Objective

To identify the dose of SCIT that results in the most systemic reactions to SCIT (SCITSRs) and other risk factors for SCITSRs.

Methods

We performed a retrospective review of all SCIT encounters from 2013 to 2017 at a multisite allergy/immunology practice. SCITSRs were identified from the electronic health record through immunotherapy encounters in which epinephrine was administered. Collected data included patient demographics, the dose of immunotherapy at the time of the SCITSR, the presence or absence of asthma, and aeroallergen content. The control group was generated randomly from the same cohort during the same period.

Results

There were 86,949 SCIT visits, with 81 SCITSRs (0.9 per 1000 injections). A total of 77.8% of reactions occurred at a dose of 1:1 0.1 mL and above. The presence of cat (81.5% vs 63.0%, P = .01), dog (67.9% vs 37.0%, P < .001), and grass extracts (85.2% vs 67.5%, P = .01) were associated with SCITSRs. Asthma was not significantly associated with SCITSRs. The presence of dust mites, trees, weeds, and molds was not associated with SCITSRs. There were no months or seasons where SCITSRs were more likely to occur. Individuals who experienced SCITSRs had a mean (SD) higher number of included aeroallergenic groups compared with controls (5.86 [1.88] vs 5.00 [1.92], P < .001).

Conclusion

Risk factors for SCITSRs in a multisite allergy/immunology practice included administration of the highest immunotherapy doses; inclusion of cat, dog, and grass extracts; and the number of aeroallergenic groups included in the extract. This information helps further characterize risk for patients receiving SCIT.

Introduction

Subcutaneous immunotherapy (SCIT) is effective for allergic rhinitis, allergic conjunctivitis, and allergic asthma.1 Local reactions are the most common adverse effect associated with SCIT,1 although systemic reactions to SCIT (SCITSRs) are the most serious adverse effect.1 The rate of SCITSRs with a conventional dosing schedule is reported to be 0.1% to 0.2% per injection.1, 2 It is generally accepted that the potential benefits of SCIT for select atopic conditions outweigh this risk of SCITSRs.3, 4

Several risk factors for SCITSRs have been reported. Perhaps the best known risk factor is uncontrolled asthma, and 86% of practices in a American Association of Allergy, Asthma, and Immunology (AAAAI)/American College of Asthma, Allergy, and Immunology survey reported routine screening for poorly controlled asthma before administering SCIT.1, 5, 6 Studies have been mixed regarding whether seasonal exposure to pollen is a risk factor for SCITSRs.1 A practice survey found that allergy practices stepping down on pollen dosing during the specific pollen season were less likely to report severe systemic reactions.7 Two other studies, however, did not find an increase in systemic reactions during the pollen season.8, 9 The size and number of positive skin test results and aeroallergen type have also been suggested to predict SCITSRs,10 but these data have also been mixed.11

Data regarding whether the dose of immunotherapy is related to SCITSRs are limited, with some literature reporting an increased risk of an SCITSR during the build-up phase.12, 13 Authors of a prospective study regarding immunotherapy reactions concluded that although reactions were most likely to occur during the build-up period, reactions could occur at any time and at any concentration during the build-up period.8

Given the conflicting data regarding risk factors for SCITSRs, we undertook a retrospective study of patients receiving SCIT administered following a conventional dosing schedule in a hospital-owned, multisite, outpatient allergy practice to determine whether specific dose or aeroallergen content are associated with SCITSRs. We also analyzed the patient cohort to determine whether asthma, sex, month of the year, and presence of asthma were associated with SCITSRs.

We performed a retrospective case-control study of all SCITSRs in patients receiving SCIT per a conventional dosing schedule (Table 1) occurring at the Rochester Regional Health outpatient allergy offices in Rochester, New York, from 2013 to 2017. Systemic reactions to venom immunotherapy and SCITSRs per the cluster-dosing schedule were excluded. Delayed SCITSRs occurring after the 30-minute wait period and not treated in our office were also excluded. SCIT was administered in recommended doses from the AAAAI practice parameters1 (see Table 2 for specific aeroallergen content and concentration). The standardized office build-up protocol consisted of 21 steps (Table 1), with patients coming every 2 to 14 days for build-up dosing. SCITSRs were identified from the electronic medical record (Hyperspace, Epic Systems Corporation, Verona, Wisconsin) from SCIT encounters in which epinephrine was administered. The control group was generated from patients undergoing SCIT during the same period who did not experience SCITSRs through the randomization feature in Microsoft Excel software (Microsoft Corporation, Redmond, Washington). Information collected from SCITSRs and control groups included age, sex, type and number of aeroallergen groups included in immunotherapy extracts, and the presence of absence of asthma. In patients with asthma, control status was confirmed before administering SCIT with screening questions regarding symptoms and use of a β-agonist. Aeroallergen groups were defined as the following: cat, dog, dust mites (Dermatophagoides farinae, Dermatophagoides pteronyssinus), roach, trees, grasses, weeds, and molds. For the SCITSR group, the month of reaction and dose of immunotherapy was also collected.

Programs used for analysis included IBM SPSS Statistics, version 24 for Windows (IBM Inc, Armonk, New York) and Microsoft Excel software (Microsoft Corporation). Demographics and outcome variables are summarized using descriptive statistics (numbers, percentages, means, and SDs). Bivariate analysis included the Fisher exact test for dichotomous variables. Continuous variables were only slightly skewed. Parametric and nonparametric tests were performed, and results for both were similar. Parametric results are reported. An α < .05 was considered statistically significant.

Section snippets

Results

From 2013 to 2017, there were 86,949 SCIT encounters in 2931 patients. Of these encounters, 81 patients experienced an SCITSR (0.09% or 0.9 per 1000 injections). When patients who experienced an SCITSR were compared with the control group, no difference was found between the groups in sex or age at the start of SCIT (Table 3). The mean (SD) age of the 162 patients was 24.7 (16.0) years, with ages ranging from 3 to 69 years. Of the 182 patients, 100 (61.7%) were female and 62 (38.2%) were male.

Discussion

SCIT is an effective therapeutic option for patients with allergic rhinitis, allergic conjunctivitis, and allergic asthma.1 Although SCIT is generally well tolerated, SCITSRs occur approximately 0.1% to 0.2% of the time, and deaths have been reported.6 Beyond poorly controlled asthma, studies examining risk factors for SCITSRs have yielded mixed results to date. Our study sought to identify whether dosing or aeroallergen content of SCIT extracts was associated with SCITSRs, along with the

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Disclosures: Dr Ramsey is on the speaker’s bureau for Regeneron. Dr Mustafa is on the speaker’s bureau for Genentech, Teva, Astra-Zeneca, Regeneron, and CSL Behrin. No other disclosures were reported.

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