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Immunotherapy and new treatments
Abstract
Purpose of review
This review comes at a time where new techniques in immunotherapy administration are being developed, new innovations are being incorporated to standard techniques, and new regulations are being adopted regarding the creation and storage of allergen extracts. Prior to the release of updated practice parameters regarding allergic rhinitis and immunotherapies, this review article provides a synopsis of current recommendations, a comparison of the practices in the United States and those of Europe, and an examination of experimental methods that are being studied.
Recent findings
This article seeks to review and discuss the various methods of administration, build up schedules, efficacy, effect on other atopic symptoms, and safety associated with allergen immunotherapy.
Summary
Innovations in standard techniques, such as new allergoids for SCIT, appear to be effective in improving symptoms and increasing IgG levels for grass allergens. Data for newer techniques is less clear. There appears to be increased treatment-related adverse events for ILIT, worse symptom scores compared with placebo for IDIT, and insufficient studies regarding the effectiveness of EPIT for aeroallergens. New regulations seek to standardize the documentation, storage, and creation of allergen extracts.
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Aim
To systematically compare the efficacy and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in children with allergic rhinitis (AR).
Methods
PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to March 2, 2023. Outcomes included symptom scores (SSs), medication scores (MSs), symptom and medication scores (SMSs), new sensitizations, development of asthma, improvement, and treatment-related adverse events (TRAEs). The quality of the included studies was assessed by the modified Jadad scale and Newcastle-Ottawa scale (NOS). Meta-regression was carried out to explore the source of heterogeneity. Subgroup analysis was further conducted in terms of study design [randomized controlled trials (RCTs), cohort studies], allergen [house dust mites (HDMs), grass pollen], treatment duration (≥ 24, 12-23 or < 12 months), allergen immunotherapy (AIT) modality (drops or tablets), and AIT protocol [continuous, pre-seasonal, co-seasonal, or after the grass pollen season (GPS)]. Sensitivity analysis was conducted for all outcomes. A Bayesian framework and a Monte Carlo Markov Chain (MCMC) model were developed for indirect comparison.
Results
Totally 50 studies with 10813 AR children were included, with 4122 treated with SLIT, 1852 treated with SCIT, and 4839 treated with non-SLIT or non-SCIT therapy. For direct comparison, the SLIT group had a similar SS to the SCIT group [pooled standardized mean difference (SMD): 0.41, 95% confidence interval (CI): -0.46, 1.28, P = 0.353]. Comparable MSs were observed in the SLIT and SCIT groups (pooled SMD: 0.82, 95%CI: -0.88, 2.53, P = 0.344). For indirect comparison, no significant differences were found in SSs (pooled SMD: 1.20, 95% credibility interval (CrI): -1.70, 4.10), MSs (pooled SMD: 0.57, 95%CrI: -1.20, 2.30), SMSs (pooled SMD: 1.80, 95%CrI: -0.005, 3.60), new sensitizations [pooled relative risk (RR): 0.34, 95%CrI: 0.03, 3.58], and development of asthma (pooled RR: 0.68, 95%CrI: 0.01, 26.33) between the SLIT and SCIT groups; the SLIT group illustrated a significantly lower incidence of TRAEs than the SCIT group (pooled RR: 0.17, 95%CrI: 0.11, 0.26).
Conclusion
Considering both efficacy and safety, SLIT might be a more favorable AIT than SCIT in the treatment of pediatric AR, which may serve as a decision-making reference for clinicians.
Systematic review registration
PROSPERO (CRD42023460693).
Background
A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid‐A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short‐course treatment of grass‐pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial.
Methods
In this exploratory, randomized, double‐blind, placebo‐controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre‐seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18–65 years) with moderate‐to‐severe SAR with or without asthma that was well‐controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ‐S) and allergen‐specific IgG4 response.
Results
The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ‐S for the extended regimen (mean change −0.72, p = .02). Both regimens were well‐tolerated.
Conclusions
This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well‐tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.
IgE-mediated atopic diseases such as allergic rhinitis and rhinoconjunctivitis are common chronic diseases in the western world. Allergen immunotherapy (AIT) plays a fundamental role in the treatment of allergic patients by modulating the underlying immune mechanisms. Though this treatment is integrated in practice-patterns globally, many differences are found in the application of AIT on the national or international level due to heterogeneous methods, and clinical recommendations are given in different parts of the world.
This review from authors in Europe and the United States highlights differences and similarities in important aspects of AIT application in the 2 global regions. First, the regulatory situation differs regarding marketing authorization and licensing. Secondly, differences are elaborated in manufacturing practices, marketing distribution and formulations of AIT products. Thirdly, clinical administration patterns in the current guidelines show similarities in indications and contraindications of AIT, but also are divergent in some practical aspects.
Informing the readership on similarities, as well as differences of standards in AIT in the United States and Europe, the authors highlight the unmet need of thorough harmonization of standards of AIT, as it is the only disease modifying treatment option available for patients with allergic rhinitis and rhinoconjunctivitis.
Background:
Subcutaneous immunotherapy (SCIT) is a well-validated and effective disease modification treatment for house dust mites (HDM)-induced allergic rhinitis (AR). Long-term post-treatment comparisons in children and adults treated with SCIT have rarely been published. This study aimed to evaluate the long-term efficacy of HDM-SCIT administered under a cluster schedule in children compared to adults.
Methods:
This was an open-design, observational, long-term clinical follow-up study on children and adults with perennial AR treated with HDM-SCIT. The follow-up consisted of a three-year treatment duration plus a post-treatment follow-up of over three years.
Results:
Patients in the pediatric (n = 58) and adult (n = 103) groups completed a post-SCIT follow-up of over three years. The total nasal symptom score (TNSS), combined symptom medication score (CSMS), and rhinoconjunctivitis quality-of-life questionnaire (RQLQ) score decreased significantly at T1 (three-year SCIT completed) and T2 (follow-up completed) in the pediatric and adult groups. In both groups, the improvement rate of TNSS (T0-T1) was moderately correlated with the baseline TNSS (r = 0.681, p < 0.001 and r = 0.477, p < 0.001 for children and adults, respectively). Only in the pediatric group, TNSS was significantly lower at T2 compared with that right after SCIT cessation (T1) (p = 0.030).
Conclusions:
Children and adults with HDM-induced perennial AR could achieve a sustainable post-treatment efficacy for over three years (up to 13 years) following a three-year SCIT. Patients with relatively severe nasal symptoms at baseline may benefit more from SCIT. Children who have completed an adequate course of SCIT may gain further improvement in nasal symptoms after SCIT cessation.
Allergen immunotherapy (AIT) is the only disease-modifying treatment in allergy. However clinical trials as well as real-life studies revealed poor treatment adherence. This article is intended to provide an overview of the current literature of the last 10 years, to outline reasons for poor treatment adherence in AIT and to provide possible solutions for improving adherence.
Background
Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli (eg. allergens, irritants, microbes). The role of environmental allergens (aeroallergens) in triggering AD remains unclear.
Objective
Systematically synthesize evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD.
Methods
As part of the 2022 AAAAI/ACAAI JTFPP AD Guideline update, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, GREAT and Web of Science (all databases) to December 2021 for randomized controlled trials (RCTs) comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard of care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares and adverse events. Raters independently screened, extracted data and assessed risk of bias in duplicate. We synthesized intervention effects using Frequentist and Bayesian random-effects models. The GRADE approach determined quality of the evidence.
Results
23 RCTs including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing AD (SCORAD; RR 1.53 [95%CI 1.31-1.78]; 26% to 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index (DLQI) by 4 points or more (RR 1.44 [1.03-2.01]; 39% to 56%, absolute difference 17%; both outcomes moderate-certainty). Both routes of AIT increased adverse events (RR 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high-certainty). AIT’s effect on sleep disturbance and eczema flares were very uncertain. Subgroup and sensitivity analyses were consistent with the main findings.
Conclusions
SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared-decision making approach to optimally managing AD.
Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory disease that is induced by allergen introduction to the nasal mucosa, which triggers an inflammatory response. The current treatments for AR include allergen avoidance and pharmacotherapy; however, allergen-specific immunotherapy (AIT) is the only treatment that can be employed to modify immunologic responses and to achieve a cure for allergic diseases. The current standard routes of AIT administration are the subcutaneous and sublingual routes. Alternatively, the dermis contains a high density of dermal dendritic cells that act as antigen-presenting cells, so intradermal administration may confer added advantages and increase the efficacy of AIT. Moreover, intradermal immunotherapy (IDIT) may facilitate a reduction in the allergen dosage and a shortening of the treatment duration. The aim of this review was to search and evaluate the current evidence specific to IDIT, including its modified formulations, such as allergoids and peptides. The results of this review reveal conflicting evidence that suggests that the overall benefit of IDIT remains unclear. As such, further clinical trials are needed to establish the clinical utility of IDIT, and to determine the optimal treatment-related protocols.
Introduction
Although clinical trials have shown the efficacy and safety of allergen‐specific immunotherapy (AIT) in the treatment of allergic asthma, there is a need for real‐life studies. We aimed to assess the effectiveness and safety of a microcrystalline tyrosine‐adjuvanted Dermatophagoides pteronyssinus allergoid (Acarovac Plus®) in patients with house dust mite (HDM)‐induced allergic asthma in a real‐life study.
Methods
A subanalysis of a multicenter, prospective, observational, real‐life study. Patients with rhinitis and allergic asthma caused by HDMs were assessed before AIT with Acarovac Plus® and at 6 and 12 months after this treatment. Assessment parameters were percentage of days with asthma symptoms, percentage of days on asthma medication, classification of asthma according to Spanish guidelines for the management of asthma, asthma‐related quality of life (quality of life in adults with asthma questionnaire [QLAAQ]), perception of symptoms (visual analog scale [VAS]), and treatment satisfaction (treatment satisfaction questionnaire for medication [TSQM]). Safety was assessed by the number and severity of adverse reactions.
Results
This subanalysis included 55 patients. Treatment with Acarovac Plus® showed significant differences in the analyzed variables when the baseline visit was compared with the 12‐month visit: reduction of the mean (SD) percentage of days with asthma symptoms (23.9 [9.2] vs. 5.1 [12.8]; p = .002), of the mean [SD] percentage of days on asthma medication (67.6 [42.9] vs. 45.1 [46.8]; p = .002), and of the percentage of patients with persistent asthma (78.2% vs. 38.9%; p = .009). Acarovac Plus® significantly improved asthma‐related quality of life, as shown by a decrease of 1.39 points in QLAAQ score at 12 months (p < .001), and in the subjective perception of symptoms on the VAS (−3.50, p < .0001). Patients showed high treatment satisfaction according to the TSQM, and it was well tolerated. No serious adverse events were reported.
Conclusions
Acarovac Plus® was effective and safe for the treatment of patients with HDM‐induced allergic asthma in a real‐life study.
Allergen-specific immunotherapy (AIT) is presumed to modulate the natural course of allergic disease by inducing immune tolerance. However, conventional AITs, such as subcutaneous immunotherapy and sublingual immunotherapy, require long treatment durations and often provoke local or systemic hypersensitivity reactions. Therefore, only <5% of allergy patients receive AIT as second-line therapy. Novel administration routes, such as intralymphatic, intradermal and epicutaneous immunotherapies, and synthetic recombinant allergen preparations have been evaluated to overcome these limitations. We will review the updated views of diverse AIT methods, and discuss the limitations and opportunities of the AITs for the treatment of allergic diseases in humans.
Background:
The role of salivary-specific IgG4 and IgA in subcutaneous immunotherapy (SCIT) is not well defined. We aimed to investigate the change of IgG4 and IgA in both serum and saliva and their correlations with IgE-blocking-factor (IgE-BF) during SCIT.
Method:
307 Dermatophagoides pteronyssinus (DP) allergic rhinitis and/or asthma patients were recruited for this study. 286 patients received DP-SCIT for 1 year. Twenty-one patients received only symptomatic treatment. DP-, Der p 1-, and Der p 2-specific IgE in serum, specific-IgG4 and Der p 2-specific IgA1 and IgA2 in both serum and saliva were measured at timepoints 0, 4, and 12 months during DP-SCIT. Correlation between salivary and serological IgG4, IgA, and their correlation with DP-specific IgE-BF measured in serum was evaluated.
Results:
During DP-SCIT, the allergen-specific IgG4 in both saliva and serum increased and correlated significantly, the correlation becomes stronger over the treatment time. DP-specific IgE-BF significantly correlated with DP-specific IgG4 in serum (p < 0.0001) at different timepoints and in saliva at 12 months of SCIT (p < 0.01). No change in Der p 2-specific IgA during DP-SCIT was observed, and the IgA in serum did not correlate with IgA in saliva. There was no correlation between DP IgE-BF and Der p 2-specific IgA in serum or saliva. The control group did not exhibit significant changes in any antibody level measured.
Conclusion:
The IgE blocking activity induced by DP-SCIT treatment correlated with specific IgG4 and not IgA. The IgG4 in saliva correlates with serum IgG4 and can be an alternative immunological marker beyond 1 year of SCIT treatment.
Background
Most previous studies used aluminum hydroxide-absorbed allergen extracts in evaluating the potential therapeutic roles of intralymphatic allergen-specific immunotherapy (ILAIT). In this study, we evaluated the therapeutic efficacy and safety of ILAIT with L-tyrosine-adsorbed allergen extracts of Dermatophagoides farinae , D. pteronyssinus , cat, dog, or mixtures thereof, in patients with allergic rhinitis induced by these allergens.
Methods
In this randomized, double-blind, placebo-controlled trial, study subjects received three intralymphatic injections of L-tyrosine-adsorbed allergen extracts (active group) or saline (placebo group) at 4-week intervals.
Results
Although ILAIT reduced daily medication use and skin reactivity to HDM and cat allergens at 4 months after treatment, overall symptom score on a visual analog scale (VAS), sinonasal outcome test-20 (SNOT-20), rhinoconjunctivitis quality of life questionnaire (RQLQ), daily symptom score (dSS), daily medication score (dMS), daily symptom medication score (dSMS), nasal reactivity to HDM allergen, and basophil activity to HDM, cat, and dog allergens at 4 months and 1 year after treatment were similar between the treatment and control groups. Intralymphatic injection was more painful than a venous puncture, and pain at the injection site was the most frequent local adverse event (12.8%); dyspnea and wheezing were the most common systemic adverse events (5.3%).
Conclusions
ILAIT with L-tyrosine-adsorbed allergen extracts does not exhibit profound therapeutic efficacy in allergic rhinitis and can provoke moderate-to-severe systemic reactions and cause pain at the injection site.
Trial registration: clinicaltrials.gov: NCT02665754; date of registration: 28 January 2016
Background
Usually, the number of injections required to achieve the maintenance dose in subcutaneous immunotherapy (SCIT) is relatively small for some of the currently used allergens, but this may still be uncomfortable for patients, thus compromising adherence and compliance.
Objective
The purpose of this study was to evaluate the safety and tolerability of a dose acceleration of a conventional induction schedule using an allergoid extract of grass pollen, birch, hazel, and alder, needed to achieve the ideal maintenance dose.
Methods
In this open-label study, 34 patients with allergic rhinoconjunctivitis, with or without asthma, were treated with SCIT using an allergoid for grass pollen or birch or mix trees with an increase in accelerated induction dose comprising only 3 injections, one per week, compared to a conventional induction pattern in five injections (once a week). Safety determination was assessed by evaluating local and systemic adverse events. Tolerability was evaluated by patients and physicians who performed the treatment.
Results
No treatment-related adverse events were observed in any of the patients undergoing rush SCIT. No local reactions, no systemic reactions of any degree (WAO Grade) have been observed. Tolerability has always been rated as very good by both patients and physician.
Conclusions
The induction phase, needed to achieve the monthly maintenance dose for a pollen extract, can be greatly accelerated, ensuring a tolerability comparable to that of the conventional schedule. (www.actabiomedica.it)
Only few data on safety during high-dose, accelerated escalation schedules during subcutaneous allergen immunotherapy (AIT) are available. The aim of this study was to assess the safety and tolerability of an accelerated dose escalation schedule of AIT in adult patients with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in Group I (1 strength) included 3 injections with 1 strength, B (10,000 TU/mL), whereas the dose escalation scheme for Group II (standard) included 7 injections with 2 strengths, A (1,000 TU/mL) and B (10,000 TU/mL), of an aluminum hydroxide-adsorbed allergoid grass pollen preparation. Overall, 72 of 87 randomized patients (83.7%) reported at least 1 treatment-emergent adverse event (TEAE; 82.2 [Group I] vs. 85.4% [Group II]); 58.8% of all reported TEAEs were assessed as being related to AIT (60.0 vs. 48.8%). The most frequently reported AIT-related TEAEs were swelling (46.7 vs. 34.1%), erythema (28.9 vs. 36.6%), and pruritus (31.1 vs. 17.1%) at the site of the injection. Systemic allergic reactions occurred in 5 (5.8%) patients overall, with more being reported in the 1-strength group (4 [8.9%] vs. 1 [2.4%]). All systemic allergic reactions were classified as World Allergy Organization (WAO) Grade 1 or Grade 2 reactions. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in patients with allergic rhinitis with or without asthma.
Allergen Immunotherapy (AIT) was introduced in clinical practice on an empirical basis more than 100 years ago. Since the first attempts, AIT was administered subcutaneously. Indeed, other routes of administration were proposed and studied, in particular to improve the safety, but only the sublingual route (SLIT) achieved a credibility based on evidence and was then accepted as a viable “alternative” option to the subcutaneous route. SLIT was largely used in clinical trials and clinical practice in this last 30 years. Thus, a large amount of data is available, coming from either controlled trials and postmarketing surveillance studies. It is clear that SLIT is overall effective, but it is also clear that the efficacy is not “class‐related,” as derived from meta‐analyses, but restricted to each specific product. The 30‐year lasting use of SLIT allowed to clarify many clinical aspects, such as efficacy, safety, use in asthma, regimens of administration, and optimal doses. In parallel, the mechanisms of action of AIT were elucidated, and new indications were proposed (eg food allergy, atopic dermatitis). In addition, the introduction of molecular‐based diagnosis, allowed to better refine the prescription of SLIT, based on specific sensitization profiles. The present article will describe the origin and evolution of SLIT for respiratory allergy, taking into account the clinical context that suggested this form of treatment, the recently developed aspects, the future perspectives and unmet needs, This is not, therefore, a systematic review, rather a narrative historical description of the past history, and a look forward to the future opportunities.
Background:
Sublingual immunotherapy (SLIT) has been proven to be effective against house dust mite-induced allergic rhinitis. However, the efficacy in adults with allergic rhinitis has never been reported on SLIT tablets. The current meta-analysis aimed to illustrate the differentiated efficacy of SLIT tablets on allergic rhinitis.
Methods:
Our systematic review and meta-analysis were performed on allergic rhinitis patients and aimed to summarize those randomized controlled studies (RCTs). PubMed, EMBASE, Cochrane library, and MEDLINE were screened for associated articles. We included RCTs on allergic rhinitis patients undergoing SLIT therapy and reporting outcomes on symptom relief and serum-specific IgE levels. The effect of SLIT tablets on the Rhinitis Quality Life Questionnaire Score (RQLQ), Rhinitis Total Symptom Score (RTSS), and serum-specific IgE levels was evaluated using RevMan 5.3.
Results:
Seven studies were included, with 2723 patients identified. All of the studies were RCT. The included seven studies were all conducted on adults. Among the included seven articles, five researches administered patients with SLIT tablets and were eligible for meta-analysis of RTSS, consisting of 1490 patients. Overall, RTSS was significantly reduced in the SLIT tablet group compared with that in the placebo group (standard mean difference = -0.33, 95% confidence interval [-0.54, -0.13], P < 0.01). There was no significant difference in specific IgE levels between SLIT and placebo patients.
Conclusions:
SLIT tablets effectively relieve rhinitis symptoms in adults with allergic rhinitis. Nevertheless, the current evidence may be limited due to sample size and the heterogeneity between studies. Large sample size and multiple center RCTs on the efficacy of different formulations of SLIT drugs are still needed to provide further evidence and a more precise recommendation.
Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology and it may have a disease modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project “EAACI Guidelines on Allergy Immunotherapy”. It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass-tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children. This article is protected by copyright. All rights reserved.
Background:
Allergy immunotherapy (AIT) is the only treatment for allergic rhinitis (AR) and/or allergic asthma (AA) with long-term efficacy. However, there are few real-life data on the progression of AR and/or AA in patients receiving AIT.
Objectives:
To assess the real-world, long-term efficacy of grass-pollen sublingual immunotherapy (SLIT) tablets in AR and their impact on asthma onset and progression.
Methods:
In a retrospective analysis of a German longitudinal prescription database, AR patients treated with grass pollen SLIT tablets were compared with a control group not having received AIT. Multiple regression was used to compare changes over time in rescue symptomatic AR medication use after treatment cessation, asthma medication use, and the time to asthma onset in the two groups.
Results:
After applying all selection criteria, 2851 SLIT and 71275 Control patients were selected for the study.After treatment cessation, AR medication use was 18.8 percentage points lower (after adjustment for covariates, and relative to the pre-treatment period) in SLIT tablet group than in the non AIT group (p<0.001). Asthma onset was less frequent in SLIT tablet group than in non AIT group (odds ratio: 0.696, p=0.002), and time to asthma was significantly longer (hazard ratio: 0.523; p=0.003). After SLIT cessation, asthma medication use fell by an additional 16.7 percentage points (relative to the pre-treatment period) in the SLIT tablet group vs. the non AIT group (p=0.004).
Conclusions:
Real-world treatment of AR patients with grass pollen SLIT tablets was associated with slower AR progression, less frequent asthma onset and slower asthma progression This article is protected by copyright. All rights reserved.
Background:
To inform the development of the European Academy of Allergy and Clinical Immunonology's (EAACI) Guidelines on Allergen Immunotherapy (AIT) for allergic asthma, we assessed the evidence on the effectiveness, cost-effectiveness and safety of AIT.
Methods:
We performed a systematic review, which involved searching nine databases. Studies were screened against pre-defined eligibility criteria and critically appraised using established instruments. Data were synthesized using random-effects meta-analyses.
Results:
98 studies satisfied the inclusion criteria. Short-term symptom scores were reduced with a standardized mean difference (SMD) of -1.11 (95%CI -1.66, -0.56). This was robust to a pre-specified sensitivity analyses, but there was evidence suggestive of publication bias. Short-term medication scores were reduced SMD -1.21 (95%CI -1.87, -0.54), again with evidence of potential publication bias. There was no reduction in short-term combined medication and symptom scores SMD 0.17 (95%CI -0.23, 0.58), but one study showed a beneficial long-term effect. For secondary outcomes subcutaneous immunotherapy (SCIT) improved quality of life and decreased allergen specific airways hyperreactivity (AHR) but this was not the case for sub-lingual immunotherapy (SLIT). There were no consistent effects on asthma control, exacerbations, lung function, and non-specific AHR. AIT resulted in a modest increased risk of adverse events (AEs). Although relatively uncommon, systemic AEs were more frequent with SCIT; however no fatalities were reported. The limited evidence on cost-effectiveness was mainly available for sublingual immunotherapy (SLIT) and this suggested that SLIT is likely to be cost-effective.
Conclusions:
AIT can achieve substantial reductions in short-term symptom and medication scores in allergic asthma. It was however associated with a modest increased risk of systemic and local AEs. More data are needed in relation to secondary outcomes, longer-term effectiveness and cost-effectiveness. This article is protected by copyright. All rights reserved.
Background
Allergen immunotherapy (AIT) is currently the only immune-modifying treatment for allergic disease. The clinical efficacy of AIT for the treatment of allergic rhinitis and bronchial asthma is well documented. However, many factors including inconvenience, cost, side effects, and adherence influence the initiation and persistence of AIT, and patients lack knowledge and have misconceptions about the treatment.
Objective
We evaluated the knowledge, attitude, and satisfaction of patients who received AIT.
Methods
We conducted a retrospective analysis of medical records of 167 patients who received AIT, and compared the clinical characteristics between conventional immunotherapy (CIT) and rush immunotherapy (RIT). Ninety-nine patients completed a questionnaire survey.
Results
Of the total 167 patients, 65.9% (n=110) were treated with CIT and 34.1% (n=57) with RIT. More than half of the patients (68.7%) initiated AIT according to their physician’s recommendation. Frequent hospital visits were the main barrier for persistence of AIT. RIT patients were younger and started AIT earlier than CIT patients. The majority (77%) of patients who received AIT were satisfied, with no significant difference between CIT and RIT groups. RIT and fewer allergens used in AIT were related with preference for AIT to pharmacotherapy. The longer duration of AIT was associated with higher treatment satisfaction.
Conclusion
A majority of patients initiated AIT by the physician’s recommendation and were satisfied with treatment regardless of CIT or RIT schedule. Adequate patient education and a strict patient–physician relationship in early AIT period could improve the effectiveness and compliance of AIT.
Background: Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. Objective: We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis.
Adherence to allergen immunotherapy is important for its effectiveness. There is currently limited data available on allergen immunotherapy adherence outside of clinical trials i.e. in real-life clinical practice. As part of a European Academy of Allergy and Clinical Immunology Immunotherapy Interest group initiative, we endeavoured to design a survey in order to prospectively evaluate adherence to subcutaneous and sublingual immunotherapy across different European countries.
The inclusion criteria for this prospective, multi-country survey were set as: adults, starting clinically indicated allergen immunotherapy for respiratory allergic disorders or Hymenoptera venom allergy. An online survey was designed in order to enrol participants and assess adherence to immunotherapy. Eight countries (Czech Republic, Georgia, Germany, Greece, Italy, Poland, Portugal, Spain) were selected to reflect different parts of Europe and differences in allergens and routes of immunotherapy administration. Each country has an allocated National co-ordinator that has identified local Allergy departments willing to enrol participants in this survey. Each participant will be followed up for a total of three years. In order to assess adherence, a 4-monthly follow-up form detailing any missed doses and reasons will be completed online. In case of a participant discontinuing treatment, reasons for this will be recorded.
The use of online survey software has enabled us to make this survey a reality and reach clinicians in different countries. Forty-five centres have enrolled a total of over 1,350 participants. It is hoped that this prospective real life survey will enable us to gain a better understanding of reasons that affect adherence to subcutaneous and sublingual immunotherapy and assist in developing ways to improve this.
Background:
Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and persistence are crucial to achieving the desired clinical effects.
Objective:
Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation.
Methods:
We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate.
Results:
Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent.
Conclusion:
Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance.
Objective: Sublingual immunotherapy (SLIT) has emerged as a potentially safe and convenient option for allergen immunotherapy for patients with inhalant allergy. Larger studies on the overall side effects and severe reactions anaphylaxis are still lacking. Study Design: Systematic review and meta-analysis. Setting: Author’s review was completed in the University of Texas Medical Branch. Methods: A systematic review and meta-analysis of prospective clinical trials focusing on SLIT safety published from January 1, 2001, to December 31, 2021, was conducted. Results: Twenty-six studies were included with analysis of 7827 patients, representing over 2.7 million SLIT doses. All studies focused on single-antigen immunotherapy. The mean duration of treatment was 11.54 months. Local side effects were present in 40.83% of patients [95% confidence interval (CI) 24.78-57.96]. Systemic side effects were encountered in 1.09% of SLIT patients (95% CI 0.57-1.78). Anaphylaxis was reported in 0.13% of patients (95% CI 0.06-0.22). Discontinuation rates due to side effects were low, at 4.32% of patients (95% CI 3.28-5.49). Conclusion: This meta-analysis shows that single-antigen SLIT is well-tolerated, with overall low rates of systemic side effects including anaphylaxis. Although there is a high rate of minor local side effect, the treatment attrition during the first year is low. With growing allergy burden worldwide, SLIT is a convenient and economically feasible option for immunotherapy. Further work is needed to evaluate long-term safety and efficacy of single as well as multi-antigen SLIT, including quality of life assessments.
Allergen immunotherapy is a form of therapeutic vaccination for established IgE-mediated hypersensitivity to common allergen sources such as pollens, house dust mites and the venom of stinging insects. The classical protocol, introduced in 1911, involves repeated subcutaneous injection of increasing amounts of allergen extract, followed by maintenance injections over a period of 3 years, achieving a form of allergen-specific tolerance that provides clinical benefit for years after its discontinuation. More recently, administration through the sublingual route has emerged as an effective, safe alternative. Oral immunotherapy for peanut allergy induces effective 'desensitization' but not long-term tolerance. Research and clinical trials over the past few decades have elucidated the mechanisms underlying immunotherapy-induced tolerance, involving a reduction of allergen-specific T helper 2 (TH2) cells, an induction of regulatory T and B cells, and production of IgG and IgA 'blocking' antibodies. To better harness these mechanisms, novel strategies are being explored to achieve safer, effective, more convenient regimens and more durable long-term tolerance; these include alternative routes for current immunotherapy approaches, novel adjuvants, use of recombinant allergens (including hypoallergenic variants) and combination of allergens with immune modifiers or monoclonal antibodies targeting the TH2 cell pathway.
Background:
Given that subcutaneous immunotherapy (SCIT) adherence in the literature is often studied in closely monitored trials, few studies report real-world SCIT adherence. The purpose of this review is to assess SCIT adherence in real-world settings.
Methods:
A literature search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus for real-world studies examining SCIT adherence was performed. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up after initiating SCIT, and "adherence" defined as persistence in accordance with prescribed SCIT dose, dosing schedule, and duration. Article quality was first assessed using a modified Newcastle-Ottawa scale and then converted to Agency for Healthcare Research and Quality standards (good, fair, and poor).
Results:
The search yielded 1596 nonduplicate abstracts, from which 17 articles (n = 263,221 patients) met inclusion criteria. Fourteen (82%) studies reported persistence rates, ranging from 16.0% to 93.7%. Seven (41%) studies reported adherence rates, ranging from 15.1% to 99%. Five (29%) studies (n = 416 patients) collected original data on reasons for discontinuing SCIT, of which inconvenience was most cited. All studies were Oxford level of evidence 2b and of good (n = 10) to fair (n = 7) quality.
Conclusion:
Real-world SCIT persistence and adherence rates are poor, with the majority of included studies reporting rates <80%; however, they range widely, explained in part by inter-study differences in measuring and reporting adherence-related findings. Future studies on SCIT adherence may benefit from following concordant definitions of persistence and adherence in addition to standardized reporting metrics. This article is protected by copyright. All rights reserved.
Accelerated allergy shot schedules for inhalant and venom allergens provide individuals with allergy symptom relief but in a shorter time frame than conventional therapy. Accelerated immunotherapy (IT) protocols allow patients to reach therapeutic doses in a shorter time frame while improving adherence and reducing direct costs (e.g., fewer office visits and medications) and indirect costs (e.g., less travel time, missed work or school). Rush IT and cluster IT are believed to work through mechanisms similar to conventional subcutaneous IT (SCIT). The risk for severe systemic reactions during accelerated IT is low when appropriately administered; however, life-threatening and fatal reactions do occur. To reduce the incidence of systemic allergic reactions during cluster and rush IT protocols, premedication is recommended. It is important to exclude individuals at high risk such as those with poorly controlled asthma or those who are on β-blockers to mitigate the risk for developing systemic allergic reactions. However, accelerated SCIT regimens offer increased convenience, faster improvement in allergy symptoms, and the potential to reduce health-care costs while providing equivalent safety outcomes compared with conventional IT protocols.
Background: Allergen immunotherapy (AIT)-associated adverse events are a major concern for safety and efficacy of AIT. Presently, there is no consensus to whether antihistamine premedication could improve such conditions.
Objective: To identify the superiority of antihistamine pretreatment in AIT.
Methods: A comprehensive literature search for randomized controlled trials (RCTs) reporting the effects of antihistamine premedication on safety and efficacy of AIT was performed in MEDLINE, Embase and Cochrane Library databases. Safety was assessed according to the number of patients reporting systemic adverse reactions (SARs; the primary outcome), efficacy according to the number of patients achieving target maintenance dose (TMD) and sustained unresponsiveness (SU) to allergen. Results: Eleven RCTs (including 609 patients) satisfied the inclusion criteria for the meta-analysis. All premedication protocols were temporary. Pooled analysis demonstrated that compared to control patients, significantly fewer antihistaminepretreated patients reported total and moderate-to-severe SARs (OR= 0.36; 95%CI,
0.23 to 0.56, P<0.05; and OR= 0.20; 95%CI, 0.06 to 0.74, P<0.05; respectively), as well as total and moderate-to-severe SAR episodes (OR= 0.42; 95%CI: 0.34 to 0.53, P<0.05; and OR= 0.09; 95%CI: 0.01 to 0.50, P<0.05; respectively). Similarly, antihistamine pretreatment significantly increased the number of patients achieving TMD (OR= 2.94; 95%CI: 1.72 to 5.03, P<0.05), but not SU (OR= 1.65; 95%CI: 0.77 to 3.54, P=0.2), compared with the control group. Subgroup analysis according to different allergens and dose escalating approaches also displayed superiority of antihistamine pretreatment over control.
Conclusion: Antihistamine premedication can significantly improve safety and efficacy of AIT by reducing frequency and severity of SAR and increasing TMD.
Background
Subcutaneous allergen immunotherapy (SCIT) is highly effective but risks exist.
Objective
Identify practices that influence systemic allergic reactions (SRs) to SCIT, and SCIT-associated infections.
Methods
ACAAI/AAAAI members completed an annual survey of SCIT-related SRs of varying severity (2008-2018). Injection-related infections were queried (2014-2018). Strategies to enforce post-injection waiting times, and to reduce risks from asthma/severe asthma were queried (2016-2018).
Results
Data were gathered on 64.5 million injection visits. Ten confirmed fatalities occurred since 2008, including 3 new fatalities since 2017. One fatal reaction occurred per 7.2 million injection visits (2008-2018). No infections occurred. Practices that tracked the time after injections, and required checking out with office personnel, had significantly lower total (p<0.0001), Grade 3 (severe) (p<0.0008) and Grade 4 (very severe) SRs (p<0.0001). Having more asthmatics on SCIT was associated with more Grade 3 SRs (p<0.02). Not prescribing SCIT in uncontrolled asthmatics was associated with fewer Grade 3 SRs (p=0.02). Having more severe asthmatics on SCIT was associated with more total, Grade 1, and Grade 2 SRs (p<0.0001); 50% of Grade 3 and 4 SRs occurred in severe asthmatics.
Conclusion
SCIT- related fatalities have declined since 2008, with a slight increase in recent years. SCIT is not associated with an increased risk of infections. Tracking the time after injections and checking out with office staff confers significantly lower risks of severe SRs. Asthma, and especially severe asthma, are major risk factors for severe and fatal SRs. Strategies that reduce risks for asthmatics, such as not prescribing SCIT to uncontrolled asthmatics, may lower risks.
Objective:
Sublingual immunotherapy (SLIT) is administered via tablets (SLIT-T) or liquid drops (SLIT-D). In North America, currently four SLIT-T formulations are FDA approved for allergy immunotherapy and SLIT-D are an off-label use of subcutaneous immunotherapy (SCIT) extracts. The purpose of this review is to compare and contrast aspects of SLIT-T and SLIT-D including physical characteristics, mechanism of action, dosing, efficacy, safety, adherence, and cost.
Data sources:
PubMed literature review (no limits), product prescribing information, and manufacturer websites.
Study selections:
Publications related to physical characteristics, mechanism of action, dosing, efficacy, safety, and adherence.
Results:
Published evidence indicates that tablet and drop formulations differ in regard to physical characteristics, dosing, and strength of evidence for efficacy. It is currently unknown if there are any differences in absorption and mechanism of action between the two formulations. Optimal dosing, efficacy, and safety have been established for SLIT-T. In contrast, in North America there is little support for efficacy of SLIT-D from randomized DBPC trials and dose ranges have not been appropriately evaluated. SLIT-T treat a single allergen whereas in the United States SLIT-D often contain multiple allergens to treat polysensitization. The safety profile of SLIT-T and SLIT-D appears similar, and both formulations are considered safer than SCIT.
Conclusion:
Professional guidelines should make a clear distinction between SLIT-T and SLIT-D in their recommendations to minimize confusion with the umbrella term of SLIT.
Purpose of review:
We evaluated the time-course of clinical and immunologic changes that occur during and after cessation of sublingual and subcutaneous allergen immunotherapy for inhalant allergies.
Recent findings:
Increases in production of inhibitory cytokines, such as IL-10 and allergen-specific IgE and IgG4 antibodies are induced within weeks of starting immunotherapy for both seasonal and perennial allergens. In general, 2-4 months' immunotherapy is needed for onset of efficacy whereas maximal clinical effect is achieved within 1-2 years of treatment. Therefore, assuming optimal patient selection, good compliance and at least moderate allergen exposure, if immunotherapy is ineffective at 2 years, it is reasonable to discontinue the treatment. For long-term clinical efficacy, at least 3 years of either subcutaneous or sublingual immunotherapy is required and this results in clinical and immunologic tolerance -- persistence of clinical benefits and suppression of type 2 immunity for years after discontinuation of treatment.
Summary:
Both sublingual and subcutaneous immunotherapy are effective and well tolerated for respiratory allergy. Clinical and immunological changes occur at early stages of treatment. Long-term evaluations support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance.
Allergen immunotherapy (AIT) is thought to be clinically effective and safe in treating allergic rhinitis, asthma, and stinging insect allergy in Europe and North America. However, there are intercontinental differences in AIT therapeutic products in terms of their application and regulation. In North America unmodified standardized and nonstandardized aqueous aeroallergen extracts are approved and used almost exclusively for subcutaneous immunotherapy, whereas more product options are available in Europe, including adsorbed allergens, chemically modified allergens, or both. Both liquid extracts and tablets are approved for sublingual immunotherapy in Europe. Nevertheless, within the European Union, there are major differences in AIT products approved and used in individual countries. There are major differences in the clinical approach to subcutaneous immunotherapy in polysensitized patients; in the United States mixed extracts containing multiple aeroallergens are used, whereas European allergists preferably administer separate injections of single allergen sources or homologous groups deemed to be clinically relevant. Moreover, the regulatory approach differs between the European Union and United States. In contrast to the United States, where common allergen standards exist based on biologic activity, no common standards exist in Europe. In terms of development of new investigational products, the United States has followed the European example for phase II and III studies; no formal US Food and Drug Administration guidance has been issued.
Background:
Studies on real-life adherence to subcutaneous allergen immunotherapy (SCIT) for respiratory allergy are scarce. The aim of this study was to evaluate adherence to SCIT.
Methods:
The patients prescribed SCIT for allergic rhinitis and/or asthma in 2009-2011 were contacted in 2014 and asked whether they completed at least the 3 years of SCIT and/or whether they suspended the treatment for at least 2 months. The Total Symptom Score-6, visual analog scale (VAS), asthma control test (ACT), medication scores, quality of life (QoL) scores, and immunotherapy satisfaction scores with VAS obtained before the initiation of SCIT in the first year and at the end of SCIT were compared.
Results:
A total of 204 patients (136 female [66.7%]; mean age, 38.83 ± 12.02 years) were included; 73% (149/204) were both compliant and persistent; 14% (29/204) were only persistent; and, overall, 87.3% (178/204) were considered adherent. Adherence was more frequent in female patients (95% CI, 62.3-76.3%; p = 0.018). Medication, symptom, ACT, and QoL scores in the first year and at the end of the treatment were significantly lower than the initial scores, and the immunotherapy satisfaction scores at the end of treatment were higher than the scores in the first year in the patients who were adherent (p < 0.001 for each score).
Conclusion:
The adherence rate to SCIT in our study was relatively high, in contrast to previous real-life data. Results of our study indicated that a close relationship between allergists and their patients during SCIT and the follow-up period in the same center improved the outcome of SCIT.
Background:
Given the choice of standard, cluster, and rush build-up for aeroallergen immunotherapy, standard-build immunotherapy has generally been preferred because of a perceived high rate of systemic reactions (SRs) associated with cluster and rush immunotherapy.
Objective:
To characterize the incidence of SRs during standard, cluster, and rush build-up immunotherapy in an allergy practice during a 5-year period.
Methods:
A retrospective review was conducted among patients receiving standard-build, 8- to 10-step cluster, or 2-day rush immunotherapy from January 1, 2010, through December 31, 2014, at Family Allergy & Asthma clinics in Louisville, Kentucky. Investigators excluded reactions that occurred during skin prick testing, venom immunotherapy, and not-true SRs, and identified the build-up method, age, sex, date of reaction, vial concentration, and presence of asthma. Per-shot and per-patient incidence of SRs was computed from these data.
Results:
During our review period, 2,549,643 injections were administered to 11,982 patients. Per-shot incidence of SR was 0.01%, 0.06%, and 0.33% for standard, cluster, and rush immunotherapy, respectively; per-patient incidence of SR was 2.84%, 2.52%, and 11.86% for standard, cluster, and rush immunotherapy, respectively. A total of 42% of SRs were grade 1, 43% were grade 2, 12% were grade 3, and 3% were grade 4. No fatalities were reported. A total of 70% of total SRs, 75% of cluster SR, and 55% of rush SR occurred in females, with an emergent peak in SR from May to October.
Conclusion:
Compared with previously published rates, we observed a decrease in the incidence of SR for standard, cluster, and rush immunotherapy, with peak seasonality from May to October and a female predominance.
BACKGROUND: Allergy immunotherapy (AIT) is the only available treatment that alters the natural course of allergies and has possible disease-modifying effects. AIT is administered primarily via subcutaneous injection delivered in a physician's office. Few studies have been conducted in the United States or Canada to evaluate the costs of subcutaneous immunotherapy (SCIT). OBJECTIVES: To (a) describe SCIT administration processes, resources, and costs and (b) characterize the patient population receiving SCIT. METHODS: A multisite, prospective, observational time and motion study was conducted. Injection and wait times were collected by a third-party observer on 1 visit for each patient. Extract preparation processes were also observed. Site staff reported on treatment protocols, administrative time, supplies, and patient medical history. Patients responded to questionnaires on demographics, reasons for treatment, medication use, productivity, and travel time. Costs were estimated by applying unit costs to the time observations and the patient- and staff-reported data. RESULTS: A total of 670 SCIT patients were enrolled at 6 sites in the United States and 6 sites in Canada. Average age in the United States was 41 years (SD = 18) and 44 years (15) in Canada, with 10% of the patients aged ≥ 65 years. Annual incomes were over 30 for Canadian patients per visit and $32 per visit for U.S. patients, half accounted for by the cost of the extract. Preand postinjection administrative tasks were the second largest driver of direct costs. Total injection visit-related time for patients, including roundtrip travel time, averaged about 80 minutes per visit in the United States and in Canada. CONCLUSIONS: Analyses revealed substantial variation in SCIT regimens among sites, but the sites had commonalities in the injection process components. SCIT requires patient commitment to a long-term treatment regimen involving numerous clinic visits and resources for administration.
Background
Immunotherapy has shown to be an effective treatment for the management of some IgE-mediated allergies. However, due to its long duration, a high number of patients withdraw from it before completion.
Objective
Explore if allowing patients to select the route of immunotherapy, educational sessions and strict follow-up could improve treatment compliance.
Methods
Patients consulting allergy service were divided into two groups; if they chose the route of administration of immunotherapy, they were selected for the active group; if their physician decided, they were selected for the control group. All patients had to attend the allergy service monthly for control. Before the first application of immunotherapy, all patients received an educative session about the benefits and risks of the treatment. Patients in the active group received an additional session about subcutaneous and sublingual routes and they chose the most appropriate according to their personal characteristics.
Results
A total of 204 patients were in the active group and 103 were included in the control group. At six months, a total of 46 patients withdrew from immunotherapy during follow-up, 24 (11%) in the active group and 22 (21%) in the control group (p = 0.02). In the active group we observed no statistically significant difference in adherence between those who preferred subcutaneous or sublingual immunotherapy; however in the control group, the drop out of sublingual immunotherapy was significantly higher than those who received subcutaneous (p = 0.05).
Conclusion
Educational sessions, strict follow-up and considering personal preferences of patients could improve adherence to allergen immunotherapy.
Objective:
To define the incidence of and clinical practices associated with subcutaneous immunotherapy (SCIT)-related systemic reactions (SRs).
Methods:
From 2008-2011, American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma & Immunology members completed an annual survey of SCIT-related SRs of varying severity (with grade 1 indicating mild; grade 2, moderate; and grade 3, severe anaphylaxis). From 2010-2011 (year 3) data were collected regarding SCIT-related procedures, including screening of patients with asthma, dose adjustment during peak pollen seasons, build-up regimens (conventional, cluster, or rush), and premedication.
Results:
No fatal reactions were directly or indirectly reported from 2008-2011. The SR rates were similar for all 3 years (0.1% of injection visits; 83% of practices), as were severity grades. On average, for all 3 years, there were 7.1 grade 1, 2.6 grade 2, and 0.4 grade 3 SRs per 10,000 injection visits. Screening for worsening asthma symptoms was highly prevalent (86% always screened). Practices that always reduced doses during peak pollen season were significantly less likely to report grade 2 or 3 SRs (44% vs 65%; P = .04). Cluster and rush build-up were associated with significantly more SRs (P < .001). Practices that premedicated were significantly more likely to report grade 2 and 3 SRs (P < .01).
Conclusion:
Fatal reactions to SCIT appear to be declining, possibly related to almost universal screening of asthmatic patients. Adjusting doses during the pollen season may be associated with decreased risk for severe SRs. Cluster and rush immunotherapy were associated with increased risk for SRs. Premedication by practices reporting SRs likely reflects past experience with SRs.
The term compliance simply indicates how much doses of the prescribed medication are taken, whereas the term adherence implies also an agreement between patient and physician about the therapeutic plan, and it is therefore preferred. Adherence is a main problem in all long-term treatments. Thus, it represents a problem also in the case of rhinitis, expecially concerning specific immunotherapy that must be assumed continuously for several years. Many factors can affect the adherence, depending on patient, on treatment itself and on the healthcare context, and all those factors usually interact. The adherence measured in controlled trials is usually good, but this does not reflect what happens in real life, where adherence should be preferably measured. There are few data on the adherence in real life for pharmacological treatments of allergic rhinitis (e.g. nasal steroids or antihistamines), whereas more data are available for specific immunotherapy. In this latter case, in real life, adherence seems to be far from optimal, for both sublingual and subcutaneous immunotherapy, although the recent studies agree on the fact that some interventions (i.e. patients' education, strict follow-up, regular contacts) could effectively improve the adherence. In this article, the literature concerning the adherence to pharmacological treatments and immunotherapy in allergic rhinitis was searched and reviewed.
For the risk assessment, all adverse drug reactions (ADR) to diagnostic and therapeutic allergen extracts in Germany in the time period from 1991 to 2000 were analyzed. Only ADR that were categorized as “serious” according to international definitions and which had at least a possible causal relationship with the usage of diagnostic and therapeutic allergen extracts, were included in the analysis. 12 live-threatening reactions after application of diagnostic allergen extracts, 555 after subcutaneous injection and 3 after oral or sublingual application of therapeutic allergen preparations were reported. Three incidences with fatal outcome were registered. Serious ADR after conventional immunotherapy were analyzed seperately for two time periods, 1991 to 1995 and 1996 to 2000, respectively. The comparison of the two time periods showed a reduction of approximately 25% of registered serious ADRs. Significant differences in regard to evaluated risk factors, with the exception of asthma, were not observed. Approximate 37% of 555 serious systemic reactions were avoidable. Physicians have an important role to minimise the risk of serious ADRs. For the assessment of risk-benefit-ratio of the application of diagnostic and therapeutic allergen extracts, the incidences of serious, but non-fatal ADRs as reported in published studies and periodic safety reports of extract manufacturers, were used. This analysis indicated that the benefits of allergy diagnosis and immunotherapy outweighs the risk of application of diagnostic and therapeutic allergen extracts.
Sublingual immunotherapy (SLIT) has become established in Europe, and its efficacy is being evaluated in the United States. The doses used for SLIT in Europe today are difficult to evaluate, because each manufacturer expresses the potency of its extracts differently.
To compare in vitro European SLIT maintenance solutions against US licensed standardized allergenic extract concentrates and to determine the monthly SLIT doses delivered expressed in bioequivalent allergy units ([B]AU).
We studied Dermatophagoides pteronyssinus, timothy grass pollen, cat (hair) and short ragweed pollen allergen extracts. The SLIT maintenance solutions of 4 leading European manufacturers and standardized concentrate extracts of 3 US manufacturers were analyzed with the following assays: protein content, relative potency (immunoglobulin E [IgE]-binding enzyme-linked immunosorbent assay [ELISA] inhibition) and major allergen content. The relative monthly allergen dose in (B)AU was calculated for each recommended SLIT schedule.
Relative potency was approximately 10 times higher for US concentrate standardized extracts-which are meant to be diluted-than for European SLIT maintenance solutions of D pteronyssinus and timothy grass pollen. For cat (hair) and short ragweed pollen, the difference was less. Measurements of relative potency and major allergen content correlated well. In our assays, European mite extracts contain a very low quantity of Der p 2 compared with US mites.
Recommended SLIT doses in Europe vary widely among the manufacturers, but are consistently lower (Eur1) or higher (Eur4) over all four allergens tested. SLIT efficacy probably depends on additional factors apart from the exact dose. SLIT dose finding studies should be done for each product.
Different vaccines containing intact allergens or chemically modified allergoids as active ingredients are commercially available for specific immunotherapy. Allergoids are claimed to have decreased allergenicity without loss of immunogenicity and this is stated to allow administration of high allergoid doses. We compared the allergenicity and immunogenicity of four commercially available chemically modified grass pollen allergoid products with three commercially available intact grass pollen allergen vaccines. The allergenicity was investigated with immunoglobulin (Ig)E-inhibition and basophil activation assays. Human T cell proliferation and specific IgG-titres following mouse immunizations were used to address immunogenicity. Furthermore, intact allergen vaccines with different contents of active ingredients were selected to study the influence of the allergen dose. In general, a lower allergenicity for allergen vaccines was clearly linked to a reduced immunogenicity. Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies. Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids. In addition, the linkage between allergenicity, immunogenicity and dose found for intact allergen vaccines and the immunogen as well as allergenic immune responses observed for allergoids suggest that the modified allergen vaccines do not contain high doses of immunologically active ingredients.
Subcutaneous allergen-specific immunotherapy is an effective treatment of IgE-mediated allergies, but it requires repeated allergen injections with a risk of systemic allergic reactions. Transcutaneous immunotherapy may improve patient compliance and safety.
To assess the safety and efficacy of epicutaneous allergen immunotherapy.
This monocentric, placebo-controlled, double-blind trial was conducted from March 2006 to December 2007 at the University Hospital Zurich. Thirty-seven adult patients with positive skin prick and nasal provocation tests to grass pollen were randomized to receive patches containing either allergen (n = 21) or placebo (n = 16). Treatment took place before and during the pollen season 2006, and follow-up visits took place before (n = 26) and after the pollen season 2007 (n = 30). The primary outcome measures were nasal provocation tests.
Allergen-treated patients showed significantly decreased scores in nasal provocation tests in the first (P < .001) and second year (P = .003) after treatment. In contrast, placebo-treated patients had decreased scores in the first treatment year, 2006 (P = .03), but the effect diminished in the second year (P = .53). Although improvement of nasal provocation test scores was not significantly better in the verum versus placebo group, the overall treatment success was rated significantly higher by the allergen-treated group than by the placebo group (2006, P = .02; 2007, P = .005). No severe adverse events were observed. Occurrence of eczema after allergen patch applications proved stimulation of specific T-cell responses, but was noted as an adverse effect of the treatment.
Epicutaneous allergen immunotherapy is a promising strategy to treat allergies and merits further investigation.
In 1969 and 1970, groups of patients with ragweed hay fever never before treated were started on preseasonal course of immunization with an alum precipitate of aqueous ragweed extract. A comparison between these two groups of patients and a similar group of patients treated with unprecipitated aqueous extract in 1968 shows that treatment with alum precipitate was safely initiated with fever injections even though a higher dose was administered. The larger cumulative dose appeared to give better IgG antibody responses and greater relief of symptoms. A repeat preseasonal course the next year again required fewer injections of the alum-precipitated extract than a repeat course of aqueous extract.