Subcutaneous Injection Immunotherapy Research Articles

Recombinant allergen-based monitoring of antibody responses during injection grass pollen immunotherapy and after 5 years of discontinuation

Subcutaneous injection immunotherapy (SCIT) is considered as antigen-specific and disease-modifying treatment with long-lasting effect. We used a panel of recombinant grass pollen allergens for analyzing allergen-specific IgE, IgG(1) -IgG(4) , IgM, IgA, and light-chain (kappa, lambda) responses in grass pollen-allergic patients who had received one course of injection immunotherapy (SCIT) with an aluminum hydroxide-adsorbed grass pollen extract or only anti-inflammatory treatment. Serum samples were analyzed before and after 5 months of treatment as well as after 5 years. After 5 months of SCIT but not of anti-inflammatory treatment, IgG(1) > IgG(4) > IgG(2) > IgA antibody responses using both kappa and lambda light chains specific for major grass pollen allergens (Phl p 1, Phl p 5, Phl p 6, Phl p 2) increased significantly, whereas specific IgM or IgG(3) levels were unaltered. Allergen-dependent basophil degranulation was only inhibited with SCIT sera containing therapy-induced allergen-specific IgG antibodies. Likewise, decreases in Phl p 1- and Phl p 5-specific IgE levels and significant (P<0.001) reduction in symptom and medication scores were found only in the SCIT group but not in the group of patients receiving anti-inflammatory treatment. After 5 years, allergen-specific IgG antibody levels in the SCIT group had returned to baseline levels and there was no significant difference regarding symptoms between the SCIT and non-SCIT groups. The results from our observational study demonstrate that only SCIT but not anti-inflammatory treatment induces allergen-specific IgG and reduces boosts of allergen-specific IgE production but that one SCIT course was not sufficient to achieve long-term immunological and clinical effects.

Allergen Immunotherapy: A Centenary Celebration

In 1911 and long before the availability of antiallergic drugs, Leonard Noon demonstrated that prophylactic subcutaneous inoculation with a grass pollen extract was effective in suppressing immediate conjunctival sensitivity to grass pollen.1 Noon’s coworker, John Freeman, continued to practice immunotherapy and in 1930 published the first rush immunotherapy protocol.2 William Frankland, a colleague of Freeman, performed the first controlled clinical trial of grass pollen immunotherapy in 1954.3 He used a whole grass pollen extract that was compared with its partially purified proteins, the corresponding ultrafiltrate that contained no protein and a phenol-containing diluent. Both the whole extract and the purified grass pollen proteins were effective compared with the ultrafiltrate and the diluent control alone (Fig. 1). Frankland’s study established a firm scientific foundation for the practice of allergen immunotherapy. Noon, Freeman, and Frankland were all physicians at St. Mary’s Hospital, Paddington, now affiliated to Imperial College London, United Kingdom. Frankland in his 99th year continues to practice and play a major role in the allergy community; much admired and respected by his colleagues, he represents our centenary link with the origins of the practice of immunotherapy (Fig. 2). Major advances in allergen immunotherapy have resulted from parallel studies performed in the United States. Lowell and Franklin in 1964 were the first to clearly demonstrate that a single allergen (ragweed) in a multiallergen mixture was effective in reducing seasonal allergic symptoms.4 Philip Norman and Larry Lichtenstein in 1978 convincingly demonstrated the allergen-specificity of ragweed immunotherapy in patients with dual sensitivity to ragweed and grass pollen.5 Johnstone first highlighted the possibility that immunotherapy in children might confer protection against development of asthma,6 a concept supported by the more recent Preventive Allergy Treatment (PAT) study that identified a 2–3 fold risk reduction for developing asthma after 3 years treatment in children with seasonal pollinosis, protection that persisted for a further 7 years after discontinuation of immunotherapy.7 Hunt and colleagues8 demonstrated the efficacy of purified venom over whole insect body extract and placebo in patients with anaphylaxis to the stings of hymenoptera. Studies9 have confirmed the dose-dependency of allergen immunotherapy whereas the long-term benefits of allergen immunotherapy, with persistence of efficacy for several years after discontinuation10 have been illustrated for both venom11 and grass pollen immunotherapy, the latter both for subcutaneous and sublingual routes of therapy.12 Our increasing knowledge of the mechanisms of immunotherapy has informed both novel approaches and the development of putative biomarkers that might predict the clinical response to immunotherapy. Prausnitz and Kustner13 published in 1921 that a serum factor (‘reagin’) could transfer immediate allergen sensitivity as shown by skin testing was followed Robert Cooke’s observation in 1935 that serum obtained after pollen immunotherapy could confer ‘immunity and hypersensitivity.’14 These seminal observations long preceded the discovery of IgE antibody as reagin by the Ishizakas,15 Johansson and Bennich,16 and the concept of IgG ‘blocking antibodies.’17 The suppressive effect of ragweed immunotherapy on nasal eosinophils as a local marker of allergic inflammation was shown by Creticos in 1984,18 whereas Passalacqua and Canonica similarly demonstrated decreased local eosinophilia and adhesion molecule expression during mite sublingual immunotherapy.19 Warner in 197820 and Rak21 in 1991 observed decreases in allergeninduced late asthmatic responses and associated bronchial inflammation, respectively, in children and adults. A link between altered T-cell responses and immunotherapy was first shown by Rocklin22 whereas the critical role of regulatory T cells and IL-10 was highlighted by Akdis and colleagues.23 The concept of immune deviation of allergenspecific TH2 responses in favor of TH1 responses in both the periphery and in target organs has developed in parallel.24–26 From the Royal Brompton National Heart & Lung Institute, London; and National Jewish Health, Denver, CO. Correspondence to: Stephen R. Durham, MA, MD, FRCP, Royal Brompton Hospital and Imperial College, Dovehouse Street, London SW3 6LY United Kingdom. Telephone: 442073518024. Fax: 442073497780. E-mail: s.durham@ imperial.ac.uk. Copyright © 2011 by World Allergy Organization FIGURE 1. Table II shows the results of the first immunotherapy controlled trial, as published in: Frankland AW, Augustin R. Prophylaxis of summer hay-fever and asthma: a controlled trial comparing crude grass-pollen extracts with the isolated main protein component, The Lancet, May 24, 1954.

How Should Allergists Deal With Local Reactions to Allergen Immunotherapy?

Despite the well-known benefits of subcutaneous immunotherapy (SCIT), adverse reactions include both local reactions (LRs) and systemic reactions. An LR is a well-known adverse event associated with SCIT injections and is defined as any swelling located at or near the injection site following allergen injection. Concerns that LRs might predict systemic reactions have historically motivated allergists to dose adjust for LRs. More recent data have dispelled this notion, although many allergists continue to dose adjust for other reasons. This article discusses the historical response to LRs and dose adjustments and reviews the most recent literature addressing LRs to SCIT. Treatment options, although they are either unproven or not studied, are offered as an alternative to routine dose adjustments for LRs. Education remains the foundation of physician-patient communication concerning LRs.

Assessing the safety of subcutaneous immunotherapy dose adjustments

Subcutaneous immunotherapy injections are often dose adjusted owing to late injections, for newly mixed vials after refills, or after systemic reactions (SRs) to reduce the subsequent SR risk. This practice is not strongly evidence based. To analyze the safety of the Wilford Hall Medical Center dose-adjustment schedule. A retrospective cohort analysis of a standardized dose-adjustment schedule across 4 years and covering 12,895 injections was performed to analyze the SR rate immediately after dose adjustments for late reactions (1 dose for each week late starting after 2 weeks), for newly mixed vials (a 50% dose reduction), or after a SR (a 10-fold dilution). Male patients (odds ratio [OR], 1.15; P <. 005), pediatric patients (OR, 1.19; P <. 01), and maintenance stage injections (OR, 2.14; P <.001) required more dose adjustments for late injections. Maintenance stage injections also experienced more dose adjustments for newly mixed vials (OR, 10.78; P <. 001). Pediatric patients (OR, 2.15; P <. 002) and buildup stage injections (OR, 2.38; P <. 005) were associated with an increased SR frequency and, as a result, required more post-SR dose adjustments. In each scenario, following the dose-adjustment schedule included in this article did not cause an increase in subsequent SRs. Multiple unique characteristics were found to be associated with the requirement for subcutaneous immunotherapy dose adjustment, and this sample dose-adjustment protocol was not associated with an increased risk of a subsequent SR. The safety of this proposed dose-adjustment protocol should be confirmed in future prospective studies.

Surveillance of systemic reactions to subcutaneous immunotherapy injections: year 1 outcomes of the ACAAI and AAAAI Collaborative Study

Although systemic reactions (SRs) to subcutaneous immunotherapy (SCIT) injections are not uncommon, life-threatening and fatal reactions are rare. The annual incidence of injection-related SRs of varying severity is not well-defined. To determine the annual frequencies of SCIT reactions in North America via a longitudinal surveillance program initiated among practicing allergists in 2008. Physicians were asked to complete a Web-based survey reporting numbers of injections administered, injection- and skin test-related fatal reactions, and all nonfatal SRs in their clinical practices during the previous 12 months. The SR events were classified as mild (grade 1: cutaneous or upper respiratory symptoms), moderate (grade 2: asthma with reduced lung function), or severe (grade 3: life-threatening airway compromise or hypotension). In the initial year of the program, 806 physicians responded, representing 1,922 SCIT prescribers. No fatal reactions to SCIT injections were identified during the first 12 months, although 6 SCIT fatal reactions were reported retrospectively between 2001 and 2007. Eighty-two percent of practices reported 8,502 SRs to SCIT (10.2 SRs per 10,000 = 0.1% of injection visits). Most were grade 1 (74%) or grade 2 (23%) SRs. However, 3% (n = 265) were grade 3 anaphylactic events (3 severe reactions for every 100,000 injection visits). We demonstrated the feasibility of annual surveillance of SRs associated with SCIT injections. This surveillance study will continue to monitor SCIT adverse events in parallel with vigorous efforts instituted by members of professional organizations aimed at reducing the risk of severe reactions.

Willingness to pay for allergy-vaccination among Danish patients with respiratory allergy

The aim of this study was to elicit willingness to pay (WTP) for allergen-specific subcutaneous injection immunotherapy (SCIT) in a cohort of respondents suffering from allergic-rhinoconjunctivitis (a-RC)/asthma, and to investigate how patients self-select to SCIT according to need. A random sample of the general population was screened for a-RC/asthma and asked if they were willing to consider SCIT. They were asked to state their WTP for SCIT by way of a discrete choice question (DC-q), an open-ended WTP question (o-WTP-q), and questions relating to their sociodemographic background and the severity of their a-RC/asthma. The characteristics of respondents demanding SCIT were compared with the characteristics of respondents who have actually received SCIT to establish possible barriers to demand. Our results suggest that respondents do well in self-selecting themselves to SCIT on the basis of need according to disease burden measured in terms of a-RC classification, number of contacts with a general practitioner, number of sick days, and potential quality-adjusted life-year loss. Mean WTP for SCIT was estimated at 655 euros (median, 267 euros) (o-WTP-q) and 903 euros (95 percent confidence limit, 348-1,459) (DC-q). Characteristics of respondents, who consider SCIT and are willing to pay for SCIT, suggest that allergy sufferers select themselves appropriately according to need and not according to other characteristics, such as income or education. There is a significant discrepancy between those who hypothetically consider SCIT and those demanding SCIT in real life. This study suggests that there are barriers to entry related to age and education, but not to income.

Analysis of the Antibody Responses Induced by Subcutaneous Injection Immunotherapy with Birch and Fagales Pollen Extracts Adsorbed onto Aluminum Hydroxide

Background: Allergen-specific subcutaneous immunotherapy (SCIT) is an antigen-specific therapy of IgE-mediated allergies. In the present study, we analyze the epitope specificities of antibody responses induced by SCIT with allergen extracts from pollen of trees belonging to the order Fagales (birch, alder, hazel) adsorbed onto aluminum hydroxide. Methods: The IgE, IgG1–4 and IgA responses to defined recombinant allergens (birch pollen: Bet v 1; alder pollen: Aln g 1; hazel pollen: Cor a 1; apple: Mal d 1) as well as to Bet v 1-derived recombinant fragments and synthetic peptides were analyzed in sera from patients who had undergone SCIT for different periods of time. Results: Long-term SCIT (>1 year; cumulative dose >1,000,000 SQ units) induced more pronounced IgG1, IgG2 and IgG4 responses to Bet v 1 and Bet v 1-related allergens according to the degree of sequence homology (Bet v 1>Aln g 1>Cor a 1>Mal d 1) than short-term SCIT (<1 year; cumulative dose <1,000,000 SQ units). In contrast to patients treated for <1 year, patients treated for >1 year mounted distinct IgG1, IgG2 and IgG4 responses against sequential Bet v 1 epitopes. No relevant allergen-specific IgA or IgG3 responses were induced by short- or long-term SCIT. Using a competitive ELISA assay, it could be shown that serum IgG from patients undergoing long-term SCIT inhibited IgE reactivity to Bet v 1 better than IgG from patients undergoing short-term SCIT. Conclusion: SCIT with allergen extracts adsorbed onto aluminum hydroxide induces IgG responses against new epitopes that block IgE binding and cross-react with structurally related allergens depending, among other factors, on duration of treatment and cumulative injected dose.

Sublingual Immunotherapy: A Novel, Albeit Not so New, Immunotherapy Treatment Modality

Specific allergy immunotherapy traditionally has been thought of as subcutaneous injection immunotherapy (SCIT). There also are noninjection routes for the administration of immunotherapy. The best-known and studied of these noninjection routes is the sublingual route, usually known as sublingual immunotherapy (SLIT). SLIT has been in use for many decades; however, to this date, it is not well known to the majority of allergy practitioners in this country. The purpose of this study is to help change this perception so that SLIT eventually can be considered one more tool in the allergist's armamentarium. A literature review was performed. It included articles from the early American clinicians and present publications that are mostly of European origin. It will become clear to the reader that the key features of SLIT are its efficacy, great safety, and simplicity of administration. SLIT is a safe treatment modality that should be considered as a useful additional tool in the therapeutic armamentarium.

Efficacy Comparison of Multiple-Antigen Subcutaneous Injection Immunotherapy and Multiple-Antigen Sublingual Immunotherapy

We performed an observational study to determine whether allergen-specific sublingual immunotherapy (SLIT) is as effective as allergen-specific subcutaneous injection immunotherapy (SCIT). Our study population was comprised of 66 patients who had been taking SLIT. Of this group, 36 patients had switched to SLIT after having been treated with SCIT (group I), while the remaining 30 patients had received SLIT only (group II). A questionnaire was used to evaluate the results of treatment. In group I, 33 patients (92%) gave SLIT a favorable rating; 27 of these patients (75%) said it was just as effective as SCIT and 6 (17%) said it was actually superior(the remaining 3 patients [8%] said that SCIT was better). In group II, 27 of 30 patients (90%) said they had attained symptom relief with SLIT; 21 (70%) said that the relief had been very significant. Overall, 60 of the 66 patients (91%) expressed various degrees of satisfaction with SLIT We believe that our SLIT protocol, which is based on established guidelines for SCIT administration, is an effective, safe, well-tolerated, and easy-to-use regimen. Future prospective studies of larger groups are clearly indicated.

Allergen-specific immunotherapy with recombinant grass pollen allergens

Allergen-specific immunotherapy uses aqueous extracts of natural source materials as a basis for preparations to down regulate the allergic response. Recombinant DNA technology has enabled the cloning of many allergens, thus facilitating investigations aimed at improving efficacy and safety of immunotherapy. To determine the effectiveness of a mixture of 5 recombinant grass pollen allergens in reducing symptoms and need for symptomatic medication in patients allergic to grass pollen. A randomized, double-blind, placebo-controlled study of subcutaneous injection immunotherapy was performed in subjects with allergic rhinoconjunctivitis, with or without asthma. Primary endpoint was a symptom medication score compiled from separate symptom and medication scores. Secondary endpoints included a rhinitis quality of life questionnaire, conjunctival provocation, and specific antibody responses. The symptom medication score showed significant improvements in subjects receiving recombinant allergens as opposed to placebo, with reductions in both symptoms and medication usage. The rhinitis quality of life questionnaire revealed clinically relevant significant improvements in overall assessment and in 5 of 7 separate domains, and conjunctival provocation showed a clear trend in favor of active treatment. All treated subjects developed strong allergen-specific IgG(1) and IgG(4) antibody responses. Some patients were not sensitized to Ph l p 5 but nevertheless developed strong IgG antibody responses to that allergen. A recombinant allergen vaccine can be a effective and safe treatment to ameliorate symptoms of allergic rhinitis. The clinical benefit is associated with modification of the specific immune response with promotion of IgG(4) and reduction of IgE antibodies consistent with the induction of IL-10-producing regulatory T cells.