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Local and systemic reactions to subcutaneous allergen immunotherapy
Ann Allergy Asthma Immunol 116 (2016) 349e353
Contents lists available at ScienceDirect
Local and systemic reactions to subcutaneous allergen immunotherapy Ten years’ experience in a pediatric clinic Hikmet Tekin Nacaroglu, MD *; Semiha Bahceci Erdem, MD *; Ozlem Sumer, MD *; Sait Karaman, MD *; Canan Sule Unsal Karkıner, MD *; Suna Asilsoy, MD y; Ilker Gunay, MD *; Demet Can, MD * * Department y
of Pediatric Allergy and Immunology, Dr Behcet Uz Children’s Hospital, Izmir, Turkey Division of Pediatric Allergy and Immunology, Dokuz Eylul University Hospital, Izmir, Turkey
A R T I C L E
I N F O
Article history: Received for publication December 4, 2015. Received in revised form January 1, 2016. Accepted for publication January 18, 2016.
A B S T R A C T
Background: Local and especially systemic reactions are important problems in subcutaneous immunotherapy (SCIT). Local and systemic reactions develop in 0.7% to 4% and 0.2% of all injections, respectively. Objective: To evaluate the frequency of and risk factors for reactions developing in pediatric patients undergoing SCIT. Methods: Local and systemic reactions developing after 14,308 injections between 2003 and 2013 were retrospectively evaluated in the current study using the Subcutaneous Immunotherapy Systemic Reaction Grading System, as recommended by the World Allergy Organization. The type of allergic disease, allergens producing a sensitivity, allergen immunotherapy content, adjuvant content, and the effects of treatment phase on the frequency of adverse effects were investigated. Results: Of 319 patients, local reactions occurred in 11.9%, wide local reactions occurred in 5%, and systemic reactions occurred in 4.7%. A local reaction was observed in 0.38% of all injections, whereas a systemic reaction was observed in 0.1% of all injections. Local reactions were most frequent in the build-up phase, and systemic reactions were most frequent in the maintenance phase (P ¼ .01). Side reactions were more common in patients undergoing SCIT with multiple allergens (P ¼ .002) and house dust mite (P ¼ .001). No statistically significant difference was found between adjuvant content and adverse effect frequency (P ¼ .32). Conclusions: The frequencies of local and wide local reactions during SCIT were lower than expected. Although systemic reactions were frequently seen, no fatal reaction was observed in the current study. House dust mite SCIT and multiple allergen use increased the risk of reaction. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Subcutaneous immunotherapy (SCIT) is a treatment method aimed at controlling the administration of allergens that produce sensitivity in increasing doses and cause patients to develop immune tolerance. Although SCIT prevents new sensitization in allergic patients, it also affects the natural course of the disease and prevents asthma development in patients with allergic rhinitis.1 Although the benefits of SCIT are apparent, the presence of local and especially systemic reactions limits its use. The adjuvants used to provide slow release in depot allergen extracts, such as calcium phosphate and aluminum hydroxide, also play a
Reprints: Hikmet Tekin Nacaroglu, MD, Department of Pediatric Allergy and Immunology, Dr Behcet Uz Children’s Hospital, Izmir, Turkey; E-mail: tekin212@ gmail.com. Disclosures: Authors have nothing to disclose.
role in the development of adverse effects.2 Local reactions are seen in 26% to 86% of patients and are observed in 0.7 to 4.0% per course of therapy.3 Although the risk of developing a systemic reaction is 0.1% to 0.2% for each injection, a rate between 0.06% and 3.2% has been reported in previous studies.4e6 The rate of a near-fatal reaction between 2008 and 2012 was reported as 1 in 1 million injections in surveillance studies conducted by the American Academy of Allergy, Asthma and Immunology (AAAAI).7 Although fatal reactions are rare, 1 to 2 fatal cases were reported in 2.5 million injections.8 Increasing knowledge related to local or systemic reactions would clarify the limits of immunotherapy applications in allergy practice. The primary aim in the current study was to determine the frequency and severity of reactions developing in patients who have undergone SCIT. The secondary aim was to investigate the risk factors associated with the development of adverse reactions.
http://dx.doi.org/10.1016/j.anai.2016.01.015 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Methods Patient Population Patients who underwent SCIT with a diagnosis of asthma, allergic rhinitis and/or conjunctivitis, or asthma plus allergic rhinitis and/or rhinoconjunctivitis in the allergy polyclinic between 2003 and 2013 were included in the study. The diagnosis of asthma and allergic rhinitis was performed according to international guidelines.9,10 Sensitivity to allergens was determined by skin prick tests and/or measurement of specific IgE levels in the serum. The indications and contraindications for immunotherapy were evaluated according to the recommendations of the AAAAI.7,8 Informed consent forms were obtained from all patients before initiation of immunotherapy. The study was approved by the Dr Behçet Uz Children’s Hospital of Ethics Committee. Allergen Immunotherapy Standardized depot extracts commercially available in Turkey for this study included Allergopharma (Reinbeck, Germany), ALKAbello (Madrid, Spain), and Stallergens (Antony Cedex, France). Allergopharma contains aluminum hydroxide, and Stallergenes contains calcium phosphate. The build-up dose for immunotherapy was 0.1 mL of 100 SQ/mL (ALK-Abellò) or 0.1 mL of 0.01 IR/mL (Stallergens) for calcium phosphateeadsorbed allergen extracts and 0.2 mL of 5 TU/mL for aluminum hydroxideeabsorbed extracts. Dosages were increased weekly. The usual maximum dose was 0.8 mL of 100,000 SQ/mL or 10 IR/mL for calcium phosphateeadsorbed allergen extracts and 1 mL of 5,000 TU/mL for aluminum hydroxideeabsorbed extracts. In the build-up phase, injections were performed weekly for 24 weeks and subsequently biweekly for 3 months; in the maintenance phase, injections were performed monthly and completed in 4 years. Immunotherapy doses were changed accordingly by the recommendations of the manufacturer. Patients were observed for 30 minutes after each injection, and local and systemic reactions were recorded. The immunotherapies were applied subcutaneously by physicians and experienced nurses in the polyclinic. Current symptoms and responses to previous doses of immunotherapy were reviewed before administering the next dose. In the presence of systemic and wide local reactions, appropriate treatment was administered, and the following dose of immunotherapy was determined by the Allergen Immunotherapy: A Practice Parameter Third Update and recommendations of the manufacturer.12 Grading of Reactions A total of 14,308 injections were evaluated for reactions and adverse events in 319 patients. Edema and/or erythema 2 to 5 cm developing at the site of injection after subcutaneous allergen injection was defined as a local reaction, and edema and/or erythema larger than 5 cm was defined as a wide local reaction. Systemic adverse effects were classified according to the grading system recommended by the World Allergy Organization as follows: grade 1, reactions developing in only 1 organ, such as the skin, conjunctiva, or upper respiratory tract system; grade2, presence of findings in more than 1 system, resence of asthma (<40% decrease in forced expiratory volume in 1 second and peak expiratory flow, presence of response to inhaler bronchodilator treatment), or presence of gastrointestinal involvement; grade 3, presence of findings in more than 1 system, presence of asthma (<40% decrease in forced expiratory volume in 1 second and peak expiratory flow, absence of response to inhaler bronchodilator treatment), or presence of gastrointestinal involvement; grade4, presence of respiratory failure and hypotension independent of the presence of loss of consciousness; or grade 5, death.4 The type of allergic disease, the offending antigen, antigen and adjuvant content, and dose and
timing of the reaction within the treatment course were analyzed against the type and frequency of the adverse events. Statistical Analysis Data were analyzed using the SPSS statistical software for Windows, version 15.0 (SPSS Inc, Chicago, Illinois). Values for continuous variables are presented as mean (SD) or median (interquartile range) based on the normality of the distribution. The t test was used to compare the normal and homogeneous distributions of parametric values. The c2 and Mann-Whitney tests were used to compare nonparametric values. Multivariate logistic regression analysis was used to determine risk factors that affect the development of adverse effects related to SCIT. P < .05 was considered statistically significant. Results A total of 319 patients (221 boys and 98 girls) were included in the study. The mean (SD) age at the time of diagnosis was 109 (39) months, and the mean (SD) age at initiation of immunotherapy was 156 (47) months. Of the 319 patients, 118 (37.5%) had asthma, 111 (35.2%) had allergic rhinitis and/or rhinoconjunctivitis, and 86 (27.3%) had a diagnoses of asthma plus allergic rhinitis and/or rhinoconjunctivitis. Although 106 patients (33.2%) were monosensitized, 213 (66.8%) were polysensitized according to the skin prick test. Allergens producing a sensitivity were house dust mites in 156 patients (48.9%), Alternaria in 29 patients (9.1%), animal dander in 59 patients (18.5%), grass pollen in 181 patients (56.7%), mixed cereal pollens (Avena, Hordeum, Secale, Triticum) in 165 patients (51.7%), tree mixes (Alnus, Betula, Corylus) in 22 patients (6.9%), olive pollens in 112 patients (35.1%), and weed pollens (Artemisia, Chenopodium, Pariteria, Plantago) in 54 patients (16.9%). Although the content of immunotherapy was a single allergen in 73 patients (22.9%), it was composed of multiple allergens in 246 patients (77.1%). SCIT was performed with house dust mites in 128 patients (40.1%), grass pollen in 180 patients (56.4%), and olive pollen in 91 patients (28.5%) (Table 1). A total of 14,308 injections were administered to 319 patients during the study period (mean [SD] duration of follow up, 67 [39] months). Of the 319 patients, local reactions were observed in 38 patients (11.9 %), wide local reactions were observed in 16 patients (5%), and systemic reactions were observed in 15 patients (4.7%). Local reactions were observed in 0.38% of all injections, and systemic reactions were observed in 0.1% of all injections (Table 1). Forty-four adverse effects (63.8%) were observed in the build-up phase, and 25 (36.2%) were observed in the maintenance phase. Most local reactions (76.3%) occurred during the build-up phase (P ¼ .01). There was no statistical difference between the total percentage of local reactions and wide local reactions during the build-up phase (76.3% vs 75%; P ¼ .29). Systemic reactions (80%) were more likely to occur during the maintenance phase (P ¼ .001) (Table 2). Multiple logistic regression analysis revealed that local reactions were 1.8-fold more common (P ¼ .01; 95% confidence interval [CI], 0.08e0.76) in the build-up phase, whereas systemic reactions were 14.6-fold more common (P ¼ .001; 95% CI, 3.15e67.6) in the maintenance phase (Table 3). Skin involvement, bronchospasm, and hypotension were observed in 13 (86.6%), 10 (66.9%), and 2 (13.3%) patients with systemic reactions, respectively. Twenty percent of patients with systemic reactions had a grade 1 reaction and 80% had a grade 2 reaction. SCIT was terminated in cases with grade 2 reactions, whereas cases with grade 1 reactions tolerated the treatment at lower doses. Epinephrine injection was needed only once for each patients with grade 2 reactions. Adverse reactions were observed in 23.7% of patients with comorbid asthma: 18.9% with allergic rhinitis with or without conjunctivitis and 23.3% with both asthma and allergic rhinitis with
H.T. Nacaroglu et al. / Ann Allergy Asthma Immunol 116 (2016) 349e353 Table 1 Characteristics of the Study Participantsa
351
Table 3 Proven Risk Factors for the Development of Adverse Effects During Immunotherapy
Characteristic
Finding
b
Risk Factor
OR (95% CI)
P value
coefficient Female/male sex Age at diagnosis, mean (SD), mo Age at initiation of SCIT, mean, mo Distribution of diagnosis Asthma Allergic rhinitis and/or rhinoconjunctivitis Asthma plus allergic rhinitis and/or rhinoconjunctivitis Eosinophil count, mean (SD)/mm3 Eosinophils, mean (SD), % IgE, mean (SD), IU/L Allergen-specific IgE respiratory panel level, mean (SD), IU/L Sensitization Monoallergen Multiple allergen SCIT allergens Monoallergen Multiple allergens Allergen content of SCIT House dust mites Grass pollens Olive pollens Adjuvant content of SCIT Aluminum hydroxide Calcium phosphate Distribution of adverse effects Local reaction Wide local reaction Systemic reaction Frequency of adverse effects according to No. of injections, % Local reaction Systemic reaction a
98 (29.7)/221 (70.3) 109 (39) 156 (47) 118 111 86 350 7.2 274 10.3
(37.5) (35.2) (27.3) (430) (5.87) (462) (46.7)
106 (33.2) 213 (66.8) 73 (22.9) 246 (77.1) 128 (40.1) 180 (56.4) 91 (28.5) 168 (52.7) 151 (47.3) 38/319 (11.9) 16/319 (5) 15/319 (4.7) 0.38 0.1
Data are expressed as number (percentage) unless otherwise indicated.
or without conjunctivitis. No statistically significant difference was found between local reaction and type of allergic disease (P ¼ .61). The wide local side reactions were significantly higher in patients with asthma (P ¼ .03). Systemic reactions were significantly higher in patients with asthma and allergic rhinitis and/or conjunctivitis (P ¼ .047) (Table 2). Multiple logistic regression analysis revealed Table 2 Risk Factors Associated With Adverse Events Risk factor
Diagnosis Asthma Rhinoconjunctivitis Asthma plus rhinoconjunctivitis P value Sensitization Monoallergen Multiple allergens P value Content of SCIT Monoallergen Multiple allergens P value Adjuvant content of SCIT Aluminum hydroxide Calcium phosphate P value Time when reaction occurred Initiation phase Maintenance phase P value
1.348
1.8 (0.08e0.76)
.01
2.681
14.6 (3.15e67.6)
.001
0.958
1.7 (0.16e0.88)
.02
1.555
4.7 (1.11e19.9)
.04
Abbreviations: CI, confidence interval; OR, odds ratio; SCIT, subcutaneous immunotherapy. a Local reactions were edema and/or erythema of 2 to 5 cm. b Wide local reactions were edema and/or erythema larger than 5 cm.
that the diagnosis of asthma increased the probability of a wide local reaction 1.7-fold (P ¼ .02; 95% CI, 0.16e0.88); however, it had no effect on the development of a systemic reaction (P ¼ .11; 95% CI, 0.84e4.96) (Table 3). Calcium phosphate was the adjuvant in 151 (43.7%) of the allergen extracts; aluminum hydroxide was the adjuvant in 168 (52.7 %). A reaction was observed in 23.8% of the extracts that contained calcium phosphate as the adjuvant and 19.2% of extracts that contained aluminum hydroxide. No statistically significant difference was observed between the adjuvant content and the frequency of adverse effects (P ¼ .32) (Table 2). No statistically significant difference was observed between monoallergen or multiple allergen sensitization and adverse effects (P ¼ .76). No statistically significant difference was found between the type of sensitizing allergen and adverse effect (Table 4). It was determined that monoallergen or multiple allergen sensitization (P ¼ .38) and the sensitizing allergen had no effect on local reaction development. No significant differences were observed between the development of a local reaction and adjuvant content (P ¼ .49), number of allergens (P ¼ .053), or allergen content (P > .05) used in immunotherapy (Tables 2, 4, and 5). No significant differences were
Table 4 Comparison of Adverse Effects According to the Sensitizing Allergen
Total with adverse effects, No. (%)
Total with a local reaction, No. (%)
Total with a wide local reaction, No. (%)
28 (23.7) 21 (18.9) 20 (23.3)
12 (10.2) 16 (14.4) 10 (11.6)
11 (9.3) 3 (2.7) 2 (2.3)
.64
.61
.03
.047
24 (22.6) 45 (21.1) .76
15 (14.2) 23 (10.8) .38
11 (5.2) 5 (4.7) .86
4 (3.8) 11 (5.2) .58
6 (8.7) 63 (25.6) .002
4 (10.5) 34 (13.8) .053
2 (2.7) 14 (5.7) .31
0 15 (6.1) .03
Total with a systemic reaction, No. (%)
5 (4.2) 2 (1.8) 8 (9.3)
29 (19.2) 40 (23.8) .32
22 (13.1) 16 (10.6) .49
8 (4.8) 8 (5.3) .83
10 (6.0) 5 (3.3) .27
44 (63.8) 25 (36.2) .001
29 (76.3) 9 (23.7) .02
12 (75.0) 4 (25.0) .29
3 (20.0) 12 (80.0) .001
Abbreviation: SCIT, subcutaneous immunotherapy.
Observation of local reactions at the initial phasea Observation of systemic reactions at the maintenance phase Effect of asthma on the development of a wide local reactionb Development of a wide local reaction in SCIT with house dust mitesb
Content of allergen
House dust mite Present Absent P value Grass pollens Present Absent P value Olive pollens Present Absent P value Weed pollens Present Absent P value Animal dander Present Absent P value Alternaria Present Absent P value
Total with adverse effects, No. (%)
Total with a local reaction, No. (%)
Total with a wide local reaction, No. (%)
Total with a systemic reaction, No. (%)
39 (25.0) 30 (18.4) .15
19 (12.2) 19 (11.7) .89
13 (8.3) 3 (3.8) .08
7 (4.5) 8 (4.9) .86
35 (19.3) 34 (24.6) .26
20 (11.0) 18 (13.0) .59
6 (3.3) 10 (7.2) .11
9 (5.0) 6 (4.3) .79
21 (18.8) 48 (23.2) .36
11 (9.8) 27 (13.0) .40
5 (4.5) 11 (5.3) .74
5 (4.5) 10 (4.8) .88
10 (18.5) 59 (22.3) .54
6 (11.1) 32 (12.1) .84
1 (1.9) 15 (5.7) .24
3 (5.6) 12 (4.5) .74
12 (20.3) 57 (21.9) .79
5 (8.5) 33 (12.7) .37
5 (8.5) 11 (4.2) .18
2 (3.4) 13 (5.0) .60
3 (10.3) 66 (22.8) .12
2 (5.3) 36 (12.4) .38
1 (3.4) 15 (5.2) .68
0 15 (5.2) .21
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Table 5 Comparison of Adverse Effects According to the Allergen Content of Immunotherapy Content of allergen
House dust mites Present Absent P value Grass pollens Present Absent P value Olive pollens Present Absent P value Weed pollens Present Absent P value
Total with adverse effects, No. (%)
Total with local reaction, No. (%)
Total with wide local reaction, No. (%)
Total with systemic reaction, No. (%)
36 (28.1) 33 (17.3) .02
17 (13.3) 21 (11.0) .54
13 (10.2) 3 (1.6) .001
6 (4.7) 9 (4.7) .99
35 (19.4) 34 (24.5) .28
20 (11.1) 18 (12.9) .62
6 (3.3) 10 (7.2) .12
9 (5.0) 6 (4.3) .78
16 (17.6) 53 (23.2) .27
7 (7.7) 31 (13.6) .14
5 (5.5) 11 (4.8) .80
4 (4.4) 11 (4.8) .87
10 (18.5) 59 (22.0) .54
2 (50.0) 36 (11.4) .07
0 16 (5.1) .64
1 (25.0) 14 (4.4) .54
observed between the development of wide local reactions and monoallergen or multiple allergen sensitization (P ¼ .86), adjuvant content (P ¼ .83), or number of allergens (P ¼ .31) used in immunotherapy (Tables 2 and 4). Although the incidence of wide local reactions increased in mite immunotherapy (P ¼ .001), no significant differences were found for other allergens (P > .05) (Table 5). According to multiple logistic regression analysis, the probability of developing a wide local reaction was increased by 4.7-fold in mite immunotherapy (P ¼ .04; 95% CI, 1.11e19.9) (Table 3). No statistically significant differences were observed between the development of a systemic reaction and monoallergen or multiple allergen sensitization (P ¼ .58), sensitizing allergen (P > .05), adjuvant content (P ¼ .27), or allergen content (P > .05) (Tables 2 and 4). Although no systemic reaction was observed in patients SCIT with a single allergen, systemic side reactions were observed in patients SCIT with multiple allergens (6.1%) (P ¼ .03) (Table 2). Discussion In the current study, a total of 14,308 injections were administered to 319 patients, and systemic reactions were observed in 15 patients (4.7%) per course of therapy. Similar to other studies in the literature, systemic reactions were observed in 0.1% of all injections.6,7 Twenty percent of patients in which a systemic reaction developed had grade 1 reactions, and 80% had grade 2 reactions; fatal reactions were not observed in any patient. In the studies conducted by the AAAAI, the rate of systemic reaction was determined as 1 in 1,000 injections, whereas the rate of fatal reactions was 1 in 2 million injections.6,7,11e13 Similarly, in a Cochrane review, 1 reaction requiring adrenalin use after SCIT was reported in approximately 770 injections.14,15 In our study, 1 reaction requiring epinephrine injection after SCIT is needed in approximately 1190 injections. In the literature, although the incidence of systemic reactions changes according to the selected protocol, rates ranging between 0.06% and 3.2% have been reported; this rate is 0.1% to 0.2% for each injection.2,4,7,11,14 In a retrospective study that evaluated nonfatal systemic reactions, including more than 4,000 patients and 435,845 allergy immunotherapy doses, the rate of systemic reactions in all injections was reported as 0.06% during the first 10 years and as 0.01% during the second 10 years.16 In another review that included studies published during the last 15 years that reported the rates of systemic reactions, the rate of reaction for each injection in conventional protocols was 0.2%.4 In a study conducted in Turkey that included 108 children who were followed up with
the diagnosis of asthma and/or allergic rhinitis and who were sensitive to pollen or house dust mites, a total of 4,783 doses of SCIT were administered, and the rate of early systemic reaction was 0.1%.2 A history of asthma, multiple allergen sensitization, the formula and standardization of the allergen extract, dose errors, performing an injection during an acute exacerbation, performing an injection from a new bottle, and an accelerated immunotherapy protocol are reported to be among the risk factors for systemic reactions that may develop after allergen immunotherapy. Despite many preventive procedures, the factors that produce a predisposition to these reactions and determine the type and severity of these reactions have not yet been completely defined.11e18 The focus for the development of systemic reactions is the presence of asthma. Hejjaoui et al18 found that bronchial reactions in patients who received only pollen allergy immunotherapy were more common in patients who have asthma. In addition, in other studies, the presence of asthma was reported as a risk factor for systemic and fatal reactions during allergy immunotherapy.12,17e19 When the association between the severity of asthma and reactions developing after immunotherapy was examined, uncontrolled asthma was reported as a risk factor. In another study that followed up patients undergoing immunotherapy for 12 years, it was reported that most fatal cases were observed in patients with uncontrolled asthma.20,21 On the other hand, Dursun et al22 reported that the incidence of systemic reactions increased in patients with asthma, although the asthma was stable and well-controlled. In the current study, although the incidence of wide local reactions was significantly higher in patients with asthma, the presence of asthma was not found to be a risk factor for the development of systemic reactions. In studies investigating the association between the allergen extract used in immunotherapy and adverse effects, the incidence of systemic reactions was similar with pollen extract and house dust mites extract; therefore, the type of allergen was not a risk factor for the development of systemic reactions.22,23 In the current study, although the incidence of wide local reactions during immunotherapy with house dust mites was significantly high, no significant difference was found in the incidence of systemic reactions according to the allergen content, similar to the literature. When the association between adverse effects and period of immunotherapy was evaluated in 2 surveys conducted by the AAAAI, the investigators found 17 deaths and reported that more than 75% of the patients had asthma; half of the reactions were observed in the build-up phase, and reactions were observed within 30 minutes after injection in more than 80% of cases. In a survey conducted between 1990 and 2001, 58% of fatal reactions requiring emergency epinephrine therapy were observed during the maintenance phase.17e26 Although Nettis et al,23 Arifhodzic et al,27 and Epstein et al8 reported greater systemic reactions in the build-up phase, Dursun et al22 reported more systemic reactions in the maintenance phase, and Moreno et al24 and Tinkelman et al28 observed systemic reactions at similar rates in both the build-up and maintenance phases. In the current study, although the development of local reactions was significantly higher in the build-up phase, the incidence of systemic reactions was 14.6-fold higher in the maintenance phase. Systemic reactions are more common in the maintenance phase, which might be associated with increased cumulative doses of allergens. In a review that included 38 studies related to SCIT, it was reported that the risk of adverse effects increased in patients when accelerated protocols were used and in patients with high sensitivity.17,19 In the current study, all patients were in a conventional immunotherapy program; therefore, the risk of adverse effects according to protocols could not be compared. Depending on the type of immunotherapy, local reactions are frequently seen at the
H.T. Nacaroglu et al. / Ann Allergy Asthma Immunol 116 (2016) 349e353
site of injection. Although there are differences among studies, it was reported that local reactions developed in 26% to 82% of patients and 0.7% to 4% of all injections.3 In a study conducted by Nelson et al,29 a local reaction was observed at a rate of 4% in immunotherapy with pollen extracts and at a rate of 5.2% in immunotherapy with acarus mixtures, and most of the reactions were observed in the build-up phase. In the current study, the rate of wide local reactions was lower compared with those reported in the literature; wide local reactions were observed in 11.9% of patients and 0.38% of all injections. Calcium phosphate and aluminum hydroxide are used as adjuvants for allergy immunotherapy. Many studies have compared the effects and adverse effects of immunologic adjuvants, and in most studies, it was reported that allergy immunotherapy that contained calcium phosphate causes fewer reactions.30 In the current study, no association was found between adjuvant content and the incidence of adverse effects. In previous studies comparing the frequency of systemic reactions in patients with monoallergen and multiple allergen immunotherapy, it was reported that, generally, more adverse effects were observed in allergy immunotherapy with multiple allergens.31e33 The study of Barth et al33 found the frequency of local adverse effects to be 0.7% in immunotherapy with monoallergens and 1.5% in immunotherapy with multiallergens. They reported that 11 systemic reactions developed in 8 patients, no fatal reactions were observed, and the frequency of systemic reactions was 0.2% in immunotherapy with monoallergens and 0.5% in immunotherapy with multiallergens. In the current study, adverse effects were observed in 8.7% of patients undergoing immunotherapy with monoallergens and 25.6% of patients undergoing immunotherapy with multiallergens. Although no systemic adverse effects were observed in patients undergoing immunotherapy with monoallergens, systemic adverse effects were observed in 6.1% of patients undergoing immunotherapy with multiallergens. The limitations of our study are the risk factors that could not be evaluated, such as uncontrolled asthma, sensitization level, previous reactions to allergen immunotherapy, dosing and administration errors, epinephrine administration being delayed or not given, and inadequate waiting times after injections. In conclusion, local, wide local, and systemic reactions are observed at certain rates during SCIT during childhood. Therefore, the immunotherapy method and technique should be carefully selected, and to minimize the incidence of adverse effects, the known risk factors should be reviewed, and patient selection and close follow-up of patients’ clinical and immunologic parameters are important. In addition, immunotherapy should be applied in centers that have medical instruments and educated personnel who can undertake the responsibility of treatment in cases of a possible systemic reaction. In the current study, the frequency of local and wide local reactions during SCIT was lower than expected. Although the frequency of systemic reactions in the current study is similar to the frequencies reported in the literature, no fatal reaction was observed in any patient. It is important to determine predisposing factors to prevent the development of reactions during SCIT treatment. References [1] Malling HJ, Weeke B. Position paper: ımmunotherapy. Allergy. 1993;48:9e35. [2] Can D, Demir E, Tanaç R, et al. Immediate adverse reactions to immunotherapy. J Investig Allergol Clin Immunol. 2003;13:177e180. [3] Adamic K, Zidarn M, Bajrovic N, Erzen R, Kopac P, Music E. The local and systemic side-effects of venom and inhaled-allergen subcutaneous immunotherapy. Wien Klin Wochenschr. 2009;121:357e360. [4] Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: the World Allergy Organization subcutaneous immunotherapy
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12] [13] [14]
[15] [16]
[17] [18] [19]
[20]
[21]
[22] [23]
[24]
[25] [26] [27]
[28]
[29]
[30]
[31] [32]
[33]
353
systemic reaction grading system. J Allergy Clin Immunol. 2010;125: 569e574. Winther L, Arnved J, Malling HJ, Nolte H, Mosbech H. Side effects of allergen specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy. 2006;36:254e260. Gastaminza G, Algorta J, Audicana M, Etxenagusia M, Fernandez E, Munoz D. Systemic reactions to immunotherapy: influence of composition and manufacturer. Clin Exp Allergy. 2003;33:470e474. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008-2012: an update on fatal and nonfatal systemic allergic reactions. J Allergy Clin Immunol Pract. 2014;2:161e167. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. Immediate and delayed-onset systemic reactions after subcutaneous immunotherapy injections: ACAAI/AAAAI surveillance study of subcutaneous immunotherapy: year 2. Ann Allergy Asthma Immunol. 2011;107:426e431. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2014 (revised). http://www.ginasthma.org. Accessed June 10, 2015. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63:8e160. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized, prospective, singleor double-blind, placebo-controlled studies. Clin Ther. 2000;22:342e350. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127:1e55. Kannan JA, Epstein TG. Immunotherapy safety: what have we learned from surveillance surveys? Curr Allergy Asthma Rep. 2013;13:381e388. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;24:1. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;4:8. Ragusa VF, Massolo A. Non-fatal systemic reactions to subcutaneous immunotherapy: a 20-year experience comparison of two 10-year periods. Eur Ann Allergy Clin Immunol. 2004;36:52e55. Windom HH, Lockey RF. An update on the safety of specific immunotherapy. Curr Opin Allergy Clin Immunol. 2008;8:571e576. Stewart GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol. 1992;90:567e578. Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions occurring during immunotherapy with standardized pollen extracts. J Allergy Clin Immunol. 1992;89:925e933. Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions and fatalities associated with allergen immunotherapy. Ann Allergy Asthma Immunol. 2001;87:47e55. Bernstein DI, Wanner M, Borish L, Liss GM; Immunotherapy Committee of the AAAAI. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004;113:1129e1136. Dursun AB, Sin BA, Öner F, Mısırlıgil Z. The safety of allergen immunotherapy (IT) in Turkey. J Investig Allergol Clin Immunol. 2006;16:123e128. Nettis E, Giordano D, Pannofino A, Ferrannini A, Tursi A. Safety of inhalant allergen immunotherapy with mass units-standardized extracts. Clin Exp Allergy. 2002;32:1745e1749. Moreno C, Cuesta Herranz J, Fernandez Tavora L, Alvarez Cuesta E; Immunotherapy Committee, Sociedad Española de Alergología e Inmunología Clínica. Immunotherapy safety: a prospective multicenter monitoring study of biologically standardized therapeutic vaccines for allergic diseases. Clin Exp Allergy. 2004;34:513e514. Bousquet J, Michel FB. Safety considerations in assessing the role of immunotherapy in allergic disorders. Drug Saf. 1994;10:5e17. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol. 2006;117:169e175. Arifhodzic N, Behbehani N, Duwaisan AR, Al-Mosawi M, Khan M. Safety of subcutaneous specific immunotherapy with pollen allergen extracts for respiratory allergy. Int Arch Allergy Immunol. 2003;132:258e262. Tinkelman DG, Cole WQ, Tunno J. Immunotherapy: a one year prospective study to evaluate risk factors of systemic reactions. J Allergy Clin Immunol. 1995;95:8e14. Nelson BL, Dupont LA, Reid MJ. Prospective survey of local and systemic reactions to immunotherapy with pollen extracts. Ann Allergy. 1986;56: 331e334. Leynadier F, Banoun L, Dollois B, et al. Immunotherapy with a calcium phosphate adsorbed five-grass-pollen extract in seasonal rhinoconjunctivitis: a double-blind, placebo- controlled study. Clin Exp Allergy. 2001;31:988e996. Ravi A, Rank MA. Reducing and managing systemic reactions to immunotherapy. Curr Opin Allergy Clin Immunol. 2013;13:651e655. Copenhaver CC, Parker A, Patch S. Systemic reactions with aeroallergen cluster immunotherapy in a clinical practice. Ann Allergy Asthma Immunol. 2011;107:441e447. Barth C, Anero F, Pfaar O, Klimek L, Hörmann K, Stuck BA. Safety aspects of subcutaneous immunotherapy with multiple allergens a retrospective analysis on polysensitized patients. Eur Arch Otorhinolaryngol. 2010;267: 1873e1879.
Contents lists available at ScienceDirect
Local and systemic reactions to subcutaneous allergen immunotherapy Ten years’ experience in a pediatric clinic Hikmet Tekin Nacaroglu, MD *; Semiha Bahceci Erdem, MD *; Ozlem Sumer, MD *; Sait Karaman, MD *; Canan Sule Unsal Karkıner, MD *; Suna Asilsoy, MD y; Ilker Gunay, MD *; Demet Can, MD * * Department y
of Pediatric Allergy and Immunology, Dr Behcet Uz Children’s Hospital, Izmir, Turkey Division of Pediatric Allergy and Immunology, Dokuz Eylul University Hospital, Izmir, Turkey
A R T I C L E
I N F O
Article history: Received for publication December 4, 2015. Received in revised form January 1, 2016. Accepted for publication January 18, 2016.
A B S T R A C T
Background: Local and especially systemic reactions are important problems in subcutaneous immunotherapy (SCIT). Local and systemic reactions develop in 0.7% to 4% and 0.2% of all injections, respectively. Objective: To evaluate the frequency of and risk factors for reactions developing in pediatric patients undergoing SCIT. Methods: Local and systemic reactions developing after 14,308 injections between 2003 and 2013 were retrospectively evaluated in the current study using the Subcutaneous Immunotherapy Systemic Reaction Grading System, as recommended by the World Allergy Organization. The type of allergic disease, allergens producing a sensitivity, allergen immunotherapy content, adjuvant content, and the effects of treatment phase on the frequency of adverse effects were investigated. Results: Of 319 patients, local reactions occurred in 11.9%, wide local reactions occurred in 5%, and systemic reactions occurred in 4.7%. A local reaction was observed in 0.38% of all injections, whereas a systemic reaction was observed in 0.1% of all injections. Local reactions were most frequent in the build-up phase, and systemic reactions were most frequent in the maintenance phase (P ¼ .01). Side reactions were more common in patients undergoing SCIT with multiple allergens (P ¼ .002) and house dust mite (P ¼ .001). No statistically significant difference was found between adjuvant content and adverse effect frequency (P ¼ .32). Conclusions: The frequencies of local and wide local reactions during SCIT were lower than expected. Although systemic reactions were frequently seen, no fatal reaction was observed in the current study. House dust mite SCIT and multiple allergen use increased the risk of reaction. Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Subcutaneous immunotherapy (SCIT) is a treatment method aimed at controlling the administration of allergens that produce sensitivity in increasing doses and cause patients to develop immune tolerance. Although SCIT prevents new sensitization in allergic patients, it also affects the natural course of the disease and prevents asthma development in patients with allergic rhinitis.1 Although the benefits of SCIT are apparent, the presence of local and especially systemic reactions limits its use. The adjuvants used to provide slow release in depot allergen extracts, such as calcium phosphate and aluminum hydroxide, also play a
Reprints: Hikmet Tekin Nacaroglu, MD, Department of Pediatric Allergy and Immunology, Dr Behcet Uz Children’s Hospital, Izmir, Turkey; E-mail: tekin212@ gmail.com. Disclosures: Authors have nothing to disclose.
role in the development of adverse effects.2 Local reactions are seen in 26% to 86% of patients and are observed in 0.7 to 4.0% per course of therapy.3 Although the risk of developing a systemic reaction is 0.1% to 0.2% for each injection, a rate between 0.06% and 3.2% has been reported in previous studies.4e6 The rate of a near-fatal reaction between 2008 and 2012 was reported as 1 in 1 million injections in surveillance studies conducted by the American Academy of Allergy, Asthma and Immunology (AAAAI).7 Although fatal reactions are rare, 1 to 2 fatal cases were reported in 2.5 million injections.8 Increasing knowledge related to local or systemic reactions would clarify the limits of immunotherapy applications in allergy practice. The primary aim in the current study was to determine the frequency and severity of reactions developing in patients who have undergone SCIT. The secondary aim was to investigate the risk factors associated with the development of adverse reactions.
http://dx.doi.org/10.1016/j.anai.2016.01.015 1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Methods Patient Population Patients who underwent SCIT with a diagnosis of asthma, allergic rhinitis and/or conjunctivitis, or asthma plus allergic rhinitis and/or rhinoconjunctivitis in the allergy polyclinic between 2003 and 2013 were included in the study. The diagnosis of asthma and allergic rhinitis was performed according to international guidelines.9,10 Sensitivity to allergens was determined by skin prick tests and/or measurement of specific IgE levels in the serum. The indications and contraindications for immunotherapy were evaluated according to the recommendations of the AAAAI.7,8 Informed consent forms were obtained from all patients before initiation of immunotherapy. The study was approved by the Dr Behçet Uz Children’s Hospital of Ethics Committee. Allergen Immunotherapy Standardized depot extracts commercially available in Turkey for this study included Allergopharma (Reinbeck, Germany), ALKAbello (Madrid, Spain), and Stallergens (Antony Cedex, France). Allergopharma contains aluminum hydroxide, and Stallergenes contains calcium phosphate. The build-up dose for immunotherapy was 0.1 mL of 100 SQ/mL (ALK-Abellò) or 0.1 mL of 0.01 IR/mL (Stallergens) for calcium phosphateeadsorbed allergen extracts and 0.2 mL of 5 TU/mL for aluminum hydroxideeabsorbed extracts. Dosages were increased weekly. The usual maximum dose was 0.8 mL of 100,000 SQ/mL or 10 IR/mL for calcium phosphateeadsorbed allergen extracts and 1 mL of 5,000 TU/mL for aluminum hydroxideeabsorbed extracts. In the build-up phase, injections were performed weekly for 24 weeks and subsequently biweekly for 3 months; in the maintenance phase, injections were performed monthly and completed in 4 years. Immunotherapy doses were changed accordingly by the recommendations of the manufacturer. Patients were observed for 30 minutes after each injection, and local and systemic reactions were recorded. The immunotherapies were applied subcutaneously by physicians and experienced nurses in the polyclinic. Current symptoms and responses to previous doses of immunotherapy were reviewed before administering the next dose. In the presence of systemic and wide local reactions, appropriate treatment was administered, and the following dose of immunotherapy was determined by the Allergen Immunotherapy: A Practice Parameter Third Update and recommendations of the manufacturer.12 Grading of Reactions A total of 14,308 injections were evaluated for reactions and adverse events in 319 patients. Edema and/or erythema 2 to 5 cm developing at the site of injection after subcutaneous allergen injection was defined as a local reaction, and edema and/or erythema larger than 5 cm was defined as a wide local reaction. Systemic adverse effects were classified according to the grading system recommended by the World Allergy Organization as follows: grade 1, reactions developing in only 1 organ, such as the skin, conjunctiva, or upper respiratory tract system; grade2, presence of findings in more than 1 system, resence of asthma (<40% decrease in forced expiratory volume in 1 second and peak expiratory flow, presence of response to inhaler bronchodilator treatment), or presence of gastrointestinal involvement; grade 3, presence of findings in more than 1 system, presence of asthma (<40% decrease in forced expiratory volume in 1 second and peak expiratory flow, absence of response to inhaler bronchodilator treatment), or presence of gastrointestinal involvement; grade4, presence of respiratory failure and hypotension independent of the presence of loss of consciousness; or grade 5, death.4 The type of allergic disease, the offending antigen, antigen and adjuvant content, and dose and
timing of the reaction within the treatment course were analyzed against the type and frequency of the adverse events. Statistical Analysis Data were analyzed using the SPSS statistical software for Windows, version 15.0 (SPSS Inc, Chicago, Illinois). Values for continuous variables are presented as mean (SD) or median (interquartile range) based on the normality of the distribution. The t test was used to compare the normal and homogeneous distributions of parametric values. The c2 and Mann-Whitney tests were used to compare nonparametric values. Multivariate logistic regression analysis was used to determine risk factors that affect the development of adverse effects related to SCIT. P < .05 was considered statistically significant. Results A total of 319 patients (221 boys and 98 girls) were included in the study. The mean (SD) age at the time of diagnosis was 109 (39) months, and the mean (SD) age at initiation of immunotherapy was 156 (47) months. Of the 319 patients, 118 (37.5%) had asthma, 111 (35.2%) had allergic rhinitis and/or rhinoconjunctivitis, and 86 (27.3%) had a diagnoses of asthma plus allergic rhinitis and/or rhinoconjunctivitis. Although 106 patients (33.2%) were monosensitized, 213 (66.8%) were polysensitized according to the skin prick test. Allergens producing a sensitivity were house dust mites in 156 patients (48.9%), Alternaria in 29 patients (9.1%), animal dander in 59 patients (18.5%), grass pollen in 181 patients (56.7%), mixed cereal pollens (Avena, Hordeum, Secale, Triticum) in 165 patients (51.7%), tree mixes (Alnus, Betula, Corylus) in 22 patients (6.9%), olive pollens in 112 patients (35.1%), and weed pollens (Artemisia, Chenopodium, Pariteria, Plantago) in 54 patients (16.9%). Although the content of immunotherapy was a single allergen in 73 patients (22.9%), it was composed of multiple allergens in 246 patients (77.1%). SCIT was performed with house dust mites in 128 patients (40.1%), grass pollen in 180 patients (56.4%), and olive pollen in 91 patients (28.5%) (Table 1). A total of 14,308 injections were administered to 319 patients during the study period (mean [SD] duration of follow up, 67 [39] months). Of the 319 patients, local reactions were observed in 38 patients (11.9 %), wide local reactions were observed in 16 patients (5%), and systemic reactions were observed in 15 patients (4.7%). Local reactions were observed in 0.38% of all injections, and systemic reactions were observed in 0.1% of all injections (Table 1). Forty-four adverse effects (63.8%) were observed in the build-up phase, and 25 (36.2%) were observed in the maintenance phase. Most local reactions (76.3%) occurred during the build-up phase (P ¼ .01). There was no statistical difference between the total percentage of local reactions and wide local reactions during the build-up phase (76.3% vs 75%; P ¼ .29). Systemic reactions (80%) were more likely to occur during the maintenance phase (P ¼ .001) (Table 2). Multiple logistic regression analysis revealed that local reactions were 1.8-fold more common (P ¼ .01; 95% confidence interval [CI], 0.08e0.76) in the build-up phase, whereas systemic reactions were 14.6-fold more common (P ¼ .001; 95% CI, 3.15e67.6) in the maintenance phase (Table 3). Skin involvement, bronchospasm, and hypotension were observed in 13 (86.6%), 10 (66.9%), and 2 (13.3%) patients with systemic reactions, respectively. Twenty percent of patients with systemic reactions had a grade 1 reaction and 80% had a grade 2 reaction. SCIT was terminated in cases with grade 2 reactions, whereas cases with grade 1 reactions tolerated the treatment at lower doses. Epinephrine injection was needed only once for each patients with grade 2 reactions. Adverse reactions were observed in 23.7% of patients with comorbid asthma: 18.9% with allergic rhinitis with or without conjunctivitis and 23.3% with both asthma and allergic rhinitis with
H.T. Nacaroglu et al. / Ann Allergy Asthma Immunol 116 (2016) 349e353 Table 1 Characteristics of the Study Participantsa
351
Table 3 Proven Risk Factors for the Development of Adverse Effects During Immunotherapy
Characteristic
Finding
b
Risk Factor
OR (95% CI)
P value
coefficient Female/male sex Age at diagnosis, mean (SD), mo Age at initiation of SCIT, mean, mo Distribution of diagnosis Asthma Allergic rhinitis and/or rhinoconjunctivitis Asthma plus allergic rhinitis and/or rhinoconjunctivitis Eosinophil count, mean (SD)/mm3 Eosinophils, mean (SD), % IgE, mean (SD), IU/L Allergen-specific IgE respiratory panel level, mean (SD), IU/L Sensitization Monoallergen Multiple allergen SCIT allergens Monoallergen Multiple allergens Allergen content of SCIT House dust mites Grass pollens Olive pollens Adjuvant content of SCIT Aluminum hydroxide Calcium phosphate Distribution of adverse effects Local reaction Wide local reaction Systemic reaction Frequency of adverse effects according to No. of injections, % Local reaction Systemic reaction a
98 (29.7)/221 (70.3) 109 (39) 156 (47) 118 111 86 350 7.2 274 10.3
(37.5) (35.2) (27.3) (430) (5.87) (462) (46.7)
106 (33.2) 213 (66.8) 73 (22.9) 246 (77.1) 128 (40.1) 180 (56.4) 91 (28.5) 168 (52.7) 151 (47.3) 38/319 (11.9) 16/319 (5) 15/319 (4.7) 0.38 0.1
Data are expressed as number (percentage) unless otherwise indicated.
or without conjunctivitis. No statistically significant difference was found between local reaction and type of allergic disease (P ¼ .61). The wide local side reactions were significantly higher in patients with asthma (P ¼ .03). Systemic reactions were significantly higher in patients with asthma and allergic rhinitis and/or conjunctivitis (P ¼ .047) (Table 2). Multiple logistic regression analysis revealed Table 2 Risk Factors Associated With Adverse Events Risk factor
Diagnosis Asthma Rhinoconjunctivitis Asthma plus rhinoconjunctivitis P value Sensitization Monoallergen Multiple allergens P value Content of SCIT Monoallergen Multiple allergens P value Adjuvant content of SCIT Aluminum hydroxide Calcium phosphate P value Time when reaction occurred Initiation phase Maintenance phase P value
1.348
1.8 (0.08e0.76)
.01
2.681
14.6 (3.15e67.6)
.001
0.958
1.7 (0.16e0.88)
.02
1.555
4.7 (1.11e19.9)
.04
Abbreviations: CI, confidence interval; OR, odds ratio; SCIT, subcutaneous immunotherapy. a Local reactions were edema and/or erythema of 2 to 5 cm. b Wide local reactions were edema and/or erythema larger than 5 cm.
that the diagnosis of asthma increased the probability of a wide local reaction 1.7-fold (P ¼ .02; 95% CI, 0.16e0.88); however, it had no effect on the development of a systemic reaction (P ¼ .11; 95% CI, 0.84e4.96) (Table 3). Calcium phosphate was the adjuvant in 151 (43.7%) of the allergen extracts; aluminum hydroxide was the adjuvant in 168 (52.7 %). A reaction was observed in 23.8% of the extracts that contained calcium phosphate as the adjuvant and 19.2% of extracts that contained aluminum hydroxide. No statistically significant difference was observed between the adjuvant content and the frequency of adverse effects (P ¼ .32) (Table 2). No statistically significant difference was observed between monoallergen or multiple allergen sensitization and adverse effects (P ¼ .76). No statistically significant difference was found between the type of sensitizing allergen and adverse effect (Table 4). It was determined that monoallergen or multiple allergen sensitization (P ¼ .38) and the sensitizing allergen had no effect on local reaction development. No significant differences were observed between the development of a local reaction and adjuvant content (P ¼ .49), number of allergens (P ¼ .053), or allergen content (P > .05) used in immunotherapy (Tables 2, 4, and 5). No significant differences were
Table 4 Comparison of Adverse Effects According to the Sensitizing Allergen
Total with adverse effects, No. (%)
Total with a local reaction, No. (%)
Total with a wide local reaction, No. (%)
28 (23.7) 21 (18.9) 20 (23.3)
12 (10.2) 16 (14.4) 10 (11.6)
11 (9.3) 3 (2.7) 2 (2.3)
.64
.61
.03
.047
24 (22.6) 45 (21.1) .76
15 (14.2) 23 (10.8) .38
11 (5.2) 5 (4.7) .86
4 (3.8) 11 (5.2) .58
6 (8.7) 63 (25.6) .002
4 (10.5) 34 (13.8) .053
2 (2.7) 14 (5.7) .31
0 15 (6.1) .03
Total with a systemic reaction, No. (%)
5 (4.2) 2 (1.8) 8 (9.3)
29 (19.2) 40 (23.8) .32
22 (13.1) 16 (10.6) .49
8 (4.8) 8 (5.3) .83
10 (6.0) 5 (3.3) .27
44 (63.8) 25 (36.2) .001
29 (76.3) 9 (23.7) .02
12 (75.0) 4 (25.0) .29
3 (20.0) 12 (80.0) .001
Abbreviation: SCIT, subcutaneous immunotherapy.
Observation of local reactions at the initial phasea Observation of systemic reactions at the maintenance phase Effect of asthma on the development of a wide local reactionb Development of a wide local reaction in SCIT with house dust mitesb
Content of allergen
House dust mite Present Absent P value Grass pollens Present Absent P value Olive pollens Present Absent P value Weed pollens Present Absent P value Animal dander Present Absent P value Alternaria Present Absent P value
Total with adverse effects, No. (%)
Total with a local reaction, No. (%)
Total with a wide local reaction, No. (%)
Total with a systemic reaction, No. (%)
39 (25.0) 30 (18.4) .15
19 (12.2) 19 (11.7) .89
13 (8.3) 3 (3.8) .08
7 (4.5) 8 (4.9) .86
35 (19.3) 34 (24.6) .26
20 (11.0) 18 (13.0) .59
6 (3.3) 10 (7.2) .11
9 (5.0) 6 (4.3) .79
21 (18.8) 48 (23.2) .36
11 (9.8) 27 (13.0) .40
5 (4.5) 11 (5.3) .74
5 (4.5) 10 (4.8) .88
10 (18.5) 59 (22.3) .54
6 (11.1) 32 (12.1) .84
1 (1.9) 15 (5.7) .24
3 (5.6) 12 (4.5) .74
12 (20.3) 57 (21.9) .79
5 (8.5) 33 (12.7) .37
5 (8.5) 11 (4.2) .18
2 (3.4) 13 (5.0) .60
3 (10.3) 66 (22.8) .12
2 (5.3) 36 (12.4) .38
1 (3.4) 15 (5.2) .68
0 15 (5.2) .21
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Table 5 Comparison of Adverse Effects According to the Allergen Content of Immunotherapy Content of allergen
House dust mites Present Absent P value Grass pollens Present Absent P value Olive pollens Present Absent P value Weed pollens Present Absent P value
Total with adverse effects, No. (%)
Total with local reaction, No. (%)
Total with wide local reaction, No. (%)
Total with systemic reaction, No. (%)
36 (28.1) 33 (17.3) .02
17 (13.3) 21 (11.0) .54
13 (10.2) 3 (1.6) .001
6 (4.7) 9 (4.7) .99
35 (19.4) 34 (24.5) .28
20 (11.1) 18 (12.9) .62
6 (3.3) 10 (7.2) .12
9 (5.0) 6 (4.3) .78
16 (17.6) 53 (23.2) .27
7 (7.7) 31 (13.6) .14
5 (5.5) 11 (4.8) .80
4 (4.4) 11 (4.8) .87
10 (18.5) 59 (22.0) .54
2 (50.0) 36 (11.4) .07
0 16 (5.1) .64
1 (25.0) 14 (4.4) .54
observed between the development of wide local reactions and monoallergen or multiple allergen sensitization (P ¼ .86), adjuvant content (P ¼ .83), or number of allergens (P ¼ .31) used in immunotherapy (Tables 2 and 4). Although the incidence of wide local reactions increased in mite immunotherapy (P ¼ .001), no significant differences were found for other allergens (P > .05) (Table 5). According to multiple logistic regression analysis, the probability of developing a wide local reaction was increased by 4.7-fold in mite immunotherapy (P ¼ .04; 95% CI, 1.11e19.9) (Table 3). No statistically significant differences were observed between the development of a systemic reaction and monoallergen or multiple allergen sensitization (P ¼ .58), sensitizing allergen (P > .05), adjuvant content (P ¼ .27), or allergen content (P > .05) (Tables 2 and 4). Although no systemic reaction was observed in patients SCIT with a single allergen, systemic side reactions were observed in patients SCIT with multiple allergens (6.1%) (P ¼ .03) (Table 2). Discussion In the current study, a total of 14,308 injections were administered to 319 patients, and systemic reactions were observed in 15 patients (4.7%) per course of therapy. Similar to other studies in the literature, systemic reactions were observed in 0.1% of all injections.6,7 Twenty percent of patients in which a systemic reaction developed had grade 1 reactions, and 80% had grade 2 reactions; fatal reactions were not observed in any patient. In the studies conducted by the AAAAI, the rate of systemic reaction was determined as 1 in 1,000 injections, whereas the rate of fatal reactions was 1 in 2 million injections.6,7,11e13 Similarly, in a Cochrane review, 1 reaction requiring adrenalin use after SCIT was reported in approximately 770 injections.14,15 In our study, 1 reaction requiring epinephrine injection after SCIT is needed in approximately 1190 injections. In the literature, although the incidence of systemic reactions changes according to the selected protocol, rates ranging between 0.06% and 3.2% have been reported; this rate is 0.1% to 0.2% for each injection.2,4,7,11,14 In a retrospective study that evaluated nonfatal systemic reactions, including more than 4,000 patients and 435,845 allergy immunotherapy doses, the rate of systemic reactions in all injections was reported as 0.06% during the first 10 years and as 0.01% during the second 10 years.16 In another review that included studies published during the last 15 years that reported the rates of systemic reactions, the rate of reaction for each injection in conventional protocols was 0.2%.4 In a study conducted in Turkey that included 108 children who were followed up with
the diagnosis of asthma and/or allergic rhinitis and who were sensitive to pollen or house dust mites, a total of 4,783 doses of SCIT were administered, and the rate of early systemic reaction was 0.1%.2 A history of asthma, multiple allergen sensitization, the formula and standardization of the allergen extract, dose errors, performing an injection during an acute exacerbation, performing an injection from a new bottle, and an accelerated immunotherapy protocol are reported to be among the risk factors for systemic reactions that may develop after allergen immunotherapy. Despite many preventive procedures, the factors that produce a predisposition to these reactions and determine the type and severity of these reactions have not yet been completely defined.11e18 The focus for the development of systemic reactions is the presence of asthma. Hejjaoui et al18 found that bronchial reactions in patients who received only pollen allergy immunotherapy were more common in patients who have asthma. In addition, in other studies, the presence of asthma was reported as a risk factor for systemic and fatal reactions during allergy immunotherapy.12,17e19 When the association between the severity of asthma and reactions developing after immunotherapy was examined, uncontrolled asthma was reported as a risk factor. In another study that followed up patients undergoing immunotherapy for 12 years, it was reported that most fatal cases were observed in patients with uncontrolled asthma.20,21 On the other hand, Dursun et al22 reported that the incidence of systemic reactions increased in patients with asthma, although the asthma was stable and well-controlled. In the current study, although the incidence of wide local reactions was significantly higher in patients with asthma, the presence of asthma was not found to be a risk factor for the development of systemic reactions. In studies investigating the association between the allergen extract used in immunotherapy and adverse effects, the incidence of systemic reactions was similar with pollen extract and house dust mites extract; therefore, the type of allergen was not a risk factor for the development of systemic reactions.22,23 In the current study, although the incidence of wide local reactions during immunotherapy with house dust mites was significantly high, no significant difference was found in the incidence of systemic reactions according to the allergen content, similar to the literature. When the association between adverse effects and period of immunotherapy was evaluated in 2 surveys conducted by the AAAAI, the investigators found 17 deaths and reported that more than 75% of the patients had asthma; half of the reactions were observed in the build-up phase, and reactions were observed within 30 minutes after injection in more than 80% of cases. In a survey conducted between 1990 and 2001, 58% of fatal reactions requiring emergency epinephrine therapy were observed during the maintenance phase.17e26 Although Nettis et al,23 Arifhodzic et al,27 and Epstein et al8 reported greater systemic reactions in the build-up phase, Dursun et al22 reported more systemic reactions in the maintenance phase, and Moreno et al24 and Tinkelman et al28 observed systemic reactions at similar rates in both the build-up and maintenance phases. In the current study, although the development of local reactions was significantly higher in the build-up phase, the incidence of systemic reactions was 14.6-fold higher in the maintenance phase. Systemic reactions are more common in the maintenance phase, which might be associated with increased cumulative doses of allergens. In a review that included 38 studies related to SCIT, it was reported that the risk of adverse effects increased in patients when accelerated protocols were used and in patients with high sensitivity.17,19 In the current study, all patients were in a conventional immunotherapy program; therefore, the risk of adverse effects according to protocols could not be compared. Depending on the type of immunotherapy, local reactions are frequently seen at the
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site of injection. Although there are differences among studies, it was reported that local reactions developed in 26% to 82% of patients and 0.7% to 4% of all injections.3 In a study conducted by Nelson et al,29 a local reaction was observed at a rate of 4% in immunotherapy with pollen extracts and at a rate of 5.2% in immunotherapy with acarus mixtures, and most of the reactions were observed in the build-up phase. In the current study, the rate of wide local reactions was lower compared with those reported in the literature; wide local reactions were observed in 11.9% of patients and 0.38% of all injections. Calcium phosphate and aluminum hydroxide are used as adjuvants for allergy immunotherapy. Many studies have compared the effects and adverse effects of immunologic adjuvants, and in most studies, it was reported that allergy immunotherapy that contained calcium phosphate causes fewer reactions.30 In the current study, no association was found between adjuvant content and the incidence of adverse effects. In previous studies comparing the frequency of systemic reactions in patients with monoallergen and multiple allergen immunotherapy, it was reported that, generally, more adverse effects were observed in allergy immunotherapy with multiple allergens.31e33 The study of Barth et al33 found the frequency of local adverse effects to be 0.7% in immunotherapy with monoallergens and 1.5% in immunotherapy with multiallergens. They reported that 11 systemic reactions developed in 8 patients, no fatal reactions were observed, and the frequency of systemic reactions was 0.2% in immunotherapy with monoallergens and 0.5% in immunotherapy with multiallergens. In the current study, adverse effects were observed in 8.7% of patients undergoing immunotherapy with monoallergens and 25.6% of patients undergoing immunotherapy with multiallergens. Although no systemic adverse effects were observed in patients undergoing immunotherapy with monoallergens, systemic adverse effects were observed in 6.1% of patients undergoing immunotherapy with multiallergens. The limitations of our study are the risk factors that could not be evaluated, such as uncontrolled asthma, sensitization level, previous reactions to allergen immunotherapy, dosing and administration errors, epinephrine administration being delayed or not given, and inadequate waiting times after injections. In conclusion, local, wide local, and systemic reactions are observed at certain rates during SCIT during childhood. Therefore, the immunotherapy method and technique should be carefully selected, and to minimize the incidence of adverse effects, the known risk factors should be reviewed, and patient selection and close follow-up of patients’ clinical and immunologic parameters are important. In addition, immunotherapy should be applied in centers that have medical instruments and educated personnel who can undertake the responsibility of treatment in cases of a possible systemic reaction. In the current study, the frequency of local and wide local reactions during SCIT was lower than expected. Although the frequency of systemic reactions in the current study is similar to the frequencies reported in the literature, no fatal reaction was observed in any patient. It is important to determine predisposing factors to prevent the development of reactions during SCIT treatment. References [1] Malling HJ, Weeke B. Position paper: ımmunotherapy. Allergy. 1993;48:9e35. [2] Can D, Demir E, Tanaç R, et al. Immediate adverse reactions to immunotherapy. J Investig Allergol Clin Immunol. 2003;13:177e180. [3] Adamic K, Zidarn M, Bajrovic N, Erzen R, Kopac P, Music E. The local and systemic side-effects of venom and inhaled-allergen subcutaneous immunotherapy. Wien Klin Wochenschr. 2009;121:357e360. [4] Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: the World Allergy Organization subcutaneous immunotherapy
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12] [13] [14]
[15] [16]
[17] [18] [19]
[20]
[21]
[22] [23]
[24]
[25] [26] [27]
[28]
[29]
[30]
[31] [32]
[33]
353
systemic reaction grading system. J Allergy Clin Immunol. 2010;125: 569e574. Winther L, Arnved J, Malling HJ, Nolte H, Mosbech H. Side effects of allergen specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy. 2006;36:254e260. Gastaminza G, Algorta J, Audicana M, Etxenagusia M, Fernandez E, Munoz D. Systemic reactions to immunotherapy: influence of composition and manufacturer. Clin Exp Allergy. 2003;33:470e474. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008-2012: an update on fatal and nonfatal systemic allergic reactions. J Allergy Clin Immunol Pract. 2014;2:161e167. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. Immediate and delayed-onset systemic reactions after subcutaneous immunotherapy injections: ACAAI/AAAAI surveillance study of subcutaneous immunotherapy: year 2. Ann Allergy Asthma Immunol. 2011;107:426e431. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2014 (revised). http://www.ginasthma.org. Accessed June 10, 2015. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63:8e160. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized, prospective, singleor double-blind, placebo-controlled studies. Clin Ther. 2000;22:342e350. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127:1e55. Kannan JA, Epstein TG. Immunotherapy safety: what have we learned from surveillance surveys? Curr Allergy Asthma Rep. 2013;13:381e388. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;24:1. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2010;4:8. Ragusa VF, Massolo A. Non-fatal systemic reactions to subcutaneous immunotherapy: a 20-year experience comparison of two 10-year periods. Eur Ann Allergy Clin Immunol. 2004;36:52e55. Windom HH, Lockey RF. An update on the safety of specific immunotherapy. Curr Opin Allergy Clin Immunol. 2008;8:571e576. Stewart GE, Lockey RF. Systemic reactions from allergen immunotherapy. J Allergy Clin Immunol. 1992;90:567e578. Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions occurring during immunotherapy with standardized pollen extracts. J Allergy Clin Immunol. 1992;89:925e933. Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions and fatalities associated with allergen immunotherapy. Ann Allergy Asthma Immunol. 2001;87:47e55. Bernstein DI, Wanner M, Borish L, Liss GM; Immunotherapy Committee of the AAAAI. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004;113:1129e1136. Dursun AB, Sin BA, Öner F, Mısırlıgil Z. The safety of allergen immunotherapy (IT) in Turkey. J Investig Allergol Clin Immunol. 2006;16:123e128. Nettis E, Giordano D, Pannofino A, Ferrannini A, Tursi A. Safety of inhalant allergen immunotherapy with mass units-standardized extracts. Clin Exp Allergy. 2002;32:1745e1749. Moreno C, Cuesta Herranz J, Fernandez Tavora L, Alvarez Cuesta E; Immunotherapy Committee, Sociedad Española de Alergología e Inmunología Clínica. Immunotherapy safety: a prospective multicenter monitoring study of biologically standardized therapeutic vaccines for allergic diseases. Clin Exp Allergy. 2004;34:513e514. Bousquet J, Michel FB. Safety considerations in assessing the role of immunotherapy in allergic disorders. Drug Saf. 1994;10:5e17. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol. 2006;117:169e175. Arifhodzic N, Behbehani N, Duwaisan AR, Al-Mosawi M, Khan M. Safety of subcutaneous specific immunotherapy with pollen allergen extracts for respiratory allergy. Int Arch Allergy Immunol. 2003;132:258e262. Tinkelman DG, Cole WQ, Tunno J. Immunotherapy: a one year prospective study to evaluate risk factors of systemic reactions. J Allergy Clin Immunol. 1995;95:8e14. Nelson BL, Dupont LA, Reid MJ. Prospective survey of local and systemic reactions to immunotherapy with pollen extracts. Ann Allergy. 1986;56: 331e334. Leynadier F, Banoun L, Dollois B, et al. Immunotherapy with a calcium phosphate adsorbed five-grass-pollen extract in seasonal rhinoconjunctivitis: a double-blind, placebo- controlled study. Clin Exp Allergy. 2001;31:988e996. Ravi A, Rank MA. Reducing and managing systemic reactions to immunotherapy. Curr Opin Allergy Clin Immunol. 2013;13:651e655. Copenhaver CC, Parker A, Patch S. Systemic reactions with aeroallergen cluster immunotherapy in a clinical practice. Ann Allergy Asthma Immunol. 2011;107:441e447. Barth C, Anero F, Pfaar O, Klimek L, Hörmann K, Stuck BA. Safety aspects of subcutaneous immunotherapy with multiple allergens a retrospective analysis on polysensitized patients. Eur Arch Otorhinolaryngol. 2010;267: 1873e1879.