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Background: Conjugating immunostimulatory sequences of DNA to specific allergens offers a new approach to allergen immunotherapy that reduces acute allergic responses.Methods: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of a vaccine consisting of Amb a 1, a ragweed-pollen antigen, conjugated to a phosphorothioate oligodeoxyribonucleotide immunostimulatory sequence of DNA (AIC) in 25 adults who were allergic to ragweed. Patients received six weekly injections of the AIC or placebo vaccine before the first ragweed season and were monitored during the next two ragweed seasons.Results: There was no pattern of vaccine-associated systemic reactions or clinically significant laboratory abnormalities. AIC did not alter the primary end point, the vascular permeability response (measured by the albumin level in nasal-lavage fluid) to nasal provocation. During the first ragweed season, the AIC group had better peak-season rhinitis scores on the visual-analogue scale (P=0.006), peak-season daily nasal symptom diary scores (P=0.02), and midseason overall quality-of-life scores (P=0.05) than the placebo group. AIC induced a transient increase in Amb a 1-specific IgG antibody but suppressed the seasonal increase in Amb a 1-specific IgE antibody. A reduction in the number of interleukin-4-positive basophils in AIC-treated patients correlated with lower rhinitis visual-analogue scores (r=0.49, P=0.03). Clinical benefits of AIC were again observed in the subsequent ragweed season, with improvements over placebo in peak-season rhinitis visual-analogue scores (P=0.02) and peak-season daily nasal symptom diary scores (P=0.02). The seasonal specific IgE antibody response was again suppressed, with no significant change in IgE antibody titer during the ragweed season (P=0.19).Conclusions: In this pilot study, a 6-week regimen of the AIC vaccine appeared to offer long-term clinical efficacy in the treatment of ragweed allergic rhinitis. (ClinicalTrials.gov number, NCT00346086 [ClinicalTrials.gov] .). [ABSTRACT FROM AUTHOR]

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Subcutaneous immunotherapy is recognized as a cornerstone in the management of allergic respiratory disease in patients who are properly characterized with allergy and with allergic rhinoconjunctivis and/or well-controlled asthma, and who are willing to adhere to the rigorous treatment program. A key tenet is that it affords the opportunity to effect long-term clinical remission through its disease-modifying properties. Furthermore, it has the potential to prevent the progression of allergic rhinitis to asthma, prevent new allergen sensitivities, and improve a patient's quality of life.

Purpose of Review: Sublingual tablet immunotherapy has been demonstrated to be effective for allergies induced by exposure to grass, ragweed, specific trees (Japanese Cedar; birch homologous tree mix), and house dust mites (HDM). This review provides both an overview of the evidence-based clinical studies that address the use of the HDM SLIT-tablet for the treatment of HDM-induced allergic rhinitis/conjunctivitis and its appropriate use in carefully selected asthmatic patients and provides the clinician with practical management considerations., Recent Findings: Solid evidence-based clinical studies have shown that the HDM SLIT-tablet is both well tolerated in patients with mild-to-moderate asthma and has demonstrated a meaningful improvement in exacerbations, need for rescue medication, quality of life, and asthma control., Summary: The HDM SLIT-tablet provides the allergy specialist with a well-tolerated treatment that has established superior safety to subcutaneous injection therapy, which can be administered easily as a sublingual dissolvable tablet, and which provides the opportunity to address one of the more difficult aspects in the management of an inducer of perennial allergic disease - that of persistent airway inflammation and allergic asthma., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with type 1-mediated allergic diseases such as allergic rhinitis/rhinoconjunctivitis with/without allergic asthma. Although many innovations have been developed since the first clinical report of Noon et al in 1911, the improvement of clinical efficacy and tolerability of this treatment is still an important unmet need. Hence, much progress has been made in the characterization of the cell types, cytokines, and intracellular signaling events involved in the development, maintenance, and regulation of allergic reactions, and also in the understanding of the mechanisms of tolerance induction in AIT. This comprehensive review aims to summarize the current innovative approaches in AIT, but also gives an outlook on promising candidates of the future. On the basis of an extensive literature review, integrating a clinical point of view, this article focuses on recent and future innovations regarding biologicals, allergen-derived peptides, recombinant allergens, "Toll"-like receptor agonists and other adjuvants, and novel application routes being developed for future AIT., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Allergen immunotherapy (AIT) is the only treatment option available for allergic patients with disease-modifying intention. Both efficacy and safety has been demonstrated for multiple trials in children, adolescents and adults. Though regulatory requirements for marketing authorization have been clearly outlined and an increasing number of high quality trials has been initiated, multiple concepts and details in study design may be further elaborated, harmonized and improved. An international group of experts in the field of AIT has thoroughly reviewed and discussed current concepts and provided an outlook on further improvement especially in the age group of children and adolescents. Emphasis of the group's discussion as a basis for this article was put on (i) the regulatory background of marketing authorization of AIT products including the 'Pediatric Investigational Plan', (ii) patient reported outcomes and endpoints in AIT trials, (iii) considerations regarding the 'minimal clinically important difference', (iv) the role of placebo effects in AIT clinical trials and clinical routine and (v) the potential of mobile Health for future development of AIT. Current concepts in AIT have been optimized throughout the recent decades, but there remains room for improvement e.g., in the topics outlined in this article., Competing Interests: Competing interestsDr. Pfaar reports grants and personal fees from ALK-Abelló, grants and personal fees from Allergopharma, grants and personal fees from Stallergenes Greer, grants and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants and personal fees from Bencard Allergie GmbH/Allergy Therapeutics, grants and personal fees from Lofarma, grants from Biomay, grants from Circassia, grants and personal fees from ASIT Biotech Tools S.A., grants and personal fees from Laboratorios LETI/LETI Pharma, personal fees from MEDA Pharma/MYLAN, grants and personal fees from Anergis S.A., personal fees from Mobile Chamber Experts (a GA2LEN Partner), personal fees from Indoor Biotechnologies, grants from Glaxo Smith Kline, personal fees from Astellas Pharma Global, personal fees from EUFOREA, personal fees from ROXALL, personal fees from NOVARTIS, personal fees from SANOFI AVENTIS, outside the submitted work. Dr. Gerth van Wijk reports personal fees from ALK Abello, personal fees from Allergopharma, personal fees from Circassia, outside the submitted work. Dr. Klimek reports grants and personal fees from ALK Abelló, Denmark, personal fees from MEDA, Sweden, grants and personal fees from Novartis, Switzerland, grants and personal fees from Allergopharma, Germany, grants and personal fees from Bionorica, Germany, personal fees from Boehringer Ingelheim, Germany, grants and personal fees from GSK, Great Britain, grants and personal fees from Lofarma, Italy, grants from Biomay, Austria, grants from HAL, Netherlands, grants from LETI, Spain, grants from Roxall, Germany, grants from Bencard, Great Britain, outside the submitted work. Dr. Bousquet reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi-Aventis, Takeda, Teva, Uriach, other from KYomed-Innov, outside the submitted work. Dr. Creticos reports grants and personal fees from Stallergenes-Greer, personal fees from Circassia, personal fees from ASIT, personal fees from Allergy Therapeutics, personal fees from UpToDate, personal fees from Cliantha, personal fees from Biomay, grants from ALK, outside the submitted work., (© The Author(s) 2020.)

The Agency for Healthcare Research and Quality and the National Institute of Allergy and Infectious Diseases organized a workshop to develop trial concepts that could improve the use and effectiveness of aeroallergen immunotherapy (AAIT). Expert groups were formed to accomplish the following tasks: (1) propose a study design to compare the effectiveness and safety of subcutaneous versus sublingual AAIT; (2) propose a study design to compare the effectiveness and safety of AAIT by using 1 or a few allergens versus all or most allergens to which a patient is sensitized; (3) propose a study design to determine whether AAIT can alter the progression of childhood allergic airways disease; and (4) propose a study design to determine the optimal dose and duration of AAIT to achieve maximal effectiveness with acceptable safety. Study designs were presented by the workgroups, extensively discussed at the workshop, and revised for this report. The proposed trials would be of long duration and require large highly characterized patient populations. Scientific caveats and feasibility matters are discussed. These concepts are intended to help the development of clinical trials that can address some of the major questions related to the practice of AAIT for the management and prevention of allergic airways disease., (Published by Elsevier Inc.)

Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both efficacious and safe for the treatment of respiratory allergies such as allergic rhinoconjunctivitis or allergic asthma. Based on the clinical documentation of SLIT ragweed tablets, they have gained marketing authorization in the USA by the US FDA in 2014 for adult patients. Following clinical data from (pivotal) multicenter Phase II and III trials as performed in the USA and Canada and real life experience after registration in 2014, SLIT ragweed tablets can be recommended as efficacious and safe treatment option with disease modifying potential when adequately indicated and performed. Therefore, several practical issues should be considered for treating ragweed allergic patients with these tablets. This second part of a thorough review on ragweed SLIT tablets addresses important clinical questions which should be taken into account by the subscribing practitioner before initiation and during the treatment.

Sublingual tablet immunotherapy provides an attractive alternative approach to allergen immunotherapy, as the allergen is administered as a rapidly dissolving sublingual tablet. Part I of this two-part series on the ragweed sublingual tablet describes the dose-ranging clinical work, the safety studies and the clinical outcomes from the pivotal trials which provide clear evidence for statistically significant and clinically meaningful benefit in the treatment of patients suffering from ragweed-induced seasonal allergic rhinitis-conjunctivitis with or without milder asthma. The robust results observed in the clinical trials performed with the ragweed sublingual tablet are defined by the quality of their study design, their use of a standardized allergen extract, their consistent reproducibility in demonstrating therapeutic efficacy and their properly quantified and graded safety data.

Background: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR)., Methods: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus., Results: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR., Conclusion: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding., (© 2018 ARS-AAOA, LLC.)

Background: It is unclear whether allergen immunotherapy (AIT) can be safely initiated during the pollen season (coseasonal initiation [CSI]) because of a potential increased risk of systemic allergic reactions., Objective: To systematically review publications reporting the safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) CSI to validate or invalidate the perception of increased safety risk., Methods: PubMed, EMBASE, Ovid, Literatura Latino Americana em Ciências da Saúde (LILACS), and Cochrane Library databases were searched without limits for studies of any design reporting SCIT or SLIT CSI for pollen allergen. Congress abstracts were included., Results: Nineteen eligible studies were identified: 8 SCIT (n = 947 subjects total; n = 340 double-blind placebo-controlled [DBPC]) and 11 SLIT (n = 2668 subjects total; n = 565 DBPC). Study characteristics and safety reporting were heterogeneous. No epinephrine administrations were reported. Discontinuation frequencies were 6% or less and 10% or less with SCIT and SLIT CSI, respectively. In SCIT studies, systemic allergic reaction frequency was 0% to 7% with "up to peak season" or CSI, 0% to 6% with "after peak season" or out-of-season initiation, and 0% to 7% with placebo. In SCIT studies, serious treatment-related adverse event (AE) frequency with CSI ranged from 0% to 2%; few severe AEs were reported. In SLIT studies, systemic allergic reaction frequency ranged from 0% to 4% with CSI, 0% with out-of-season initiation, and 0% to 2% with placebo. Overall, 2 serious treatment-related AEs with SLIT CSI were reported. Severe AE frequency in SLIT studies ranged from 0% to 8% with CSI, 0% to 12% with out-of-season initiation, and 0% to 8% with placebo., Conclusions: No increase in AEs of concern was observed with SCIT or SLIT CSI; however, additional data with standardized regimens and doses are needed., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking., Objective: We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR)., Methods: Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 μg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs., Results: In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials., Conclusions: Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional benefit of long-term efficacy., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

There is a need for newer therapeutic agents that improve the safety of allergen immunotherapy, provide ease of delivery to patients that fosters compliance and allows access to a greater proportion of the allergic population who could benefit from this disease-modifying treatment, and achieve an acceptable therapeutic benefit for patients committing to the treatment. The advances in sublingual allergen immunotherapy are encouraging, as this offers patients a noninjectable form of treatment of inhalant allergies. The continued research and development of the novel therapeutic constructs discussed in this article holds the promise of accomplishing the aforementioned goals in the future., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Synthetic peptide immuno-regulatory epitopes (SPIRE) represent a new class of therapeutics for allergen immunotherapy that offer the potential to suppress the IgE-mediated allergic disease process through induction of T-cell tolerance. These synthetic T-cell-tolerizing peptides have been designed to induce immunologic tolerance via binding to MHC class II molecules on antigen presenting cells, with subsequent upregulation of regulatory T-cells.

Background: The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment., Methods: The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression., Results: The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2)  = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season., Conclusions: In seasonal allergy trials with grass SLIT-tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results., (© 2014 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: Sublingual immunotherapy with liquid extracts provides an appealing alternative to subcutaneous immunotherapy for the treatment of allergic rhinoconjunctivitis (ARC), but a lack of robust evidence has deterred its use in North America., Objective: To determine the efficacy and tolerability of standardized glycerinated short ragweed sublingual allergen immunotherapy liquid (RW-SAIL) extract in subjects with ragweed-related ARC., Methods: This phase 3, randomized, placebo-controlled trial was conducted in North America. Subjects (age range, 18-55 years) with or without asthma were selected based on ARC symptom severity and erythema skin prick reaction to short ragweed. Subjects self-administered the maximum tolerated dose of RW-SAIL (n = 218) or placebo (n = 211) daily beginning approximately 8 to 16 weeks before and through the end of the ragweed pollen season. The primary end point was subject-assessed total combined daily rhinoconjunctivitis symptom and medication scores (TCS)., Results: During the entire season, there was a 43% decrease in TCS in subjects treated with RW-SAIL compared with placebo. Similar decreases were observed in TCS between the 2 groups during peak season (42%) and in daily symptom scores during the entire (42%) and peak (41%) seasons. The occurrence of adverse events was similar between the treatment groups; most were mild in severity. Treatment-related oromucosal local application site reactions occurred early and were transient and self-limited. No anaphylaxis occurred., Conclusions: This is the first successful North American confirmatory phase 3 clinical trial to demonstrate the safety and efficacy of a sublingual standardized ragweed allergen immunotherapy liquid extract for the treatment of ARC., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Introduction: Allergic rhinoconjunctivitis is an increasingly common source of morbidity with sensitivity to cats accounting for 10-15% of the disease burden. Allergy to cats is a major risk factor for the development of asthma., Areas Covered: Within the present manuscript, the current data on a novel therapeutic approach to treat cat allergy is reviewed. Cat Peptide Antigen Desensitisation (Cat-PAD) is a mixture of seven small peptides developed for the treatment of cat allergy. It is designed to induce immunological tolerance via binding to MHC class II on antigen presenting cells and interacting with regulatory T cells without triggering the cross-linking of IgE on mast cells and basophils. The peptide sequences are derived from the major cat allergen Fel d 1. The peptides have been selected to ensure a similar T cell response to that generated to whole cat dander in ex-vivo PBMC derived from cat allergic individuals. The size of the peptides is insufficient to induce cross-linking of IgE. Clinical data from a series of studies shows that Cat-PAD is able to significantly reduce allergic rhinoconjunctivitis symptoms after a short course of four injections over 12 weeks, and that the treatment effect is persistent lasting 2 years after the start of treatment., Expert Opinion: Taken together Cat-PAD is a novel, well tolerated and promising therapeutic approach to treat cat allergic patients. Data from the current international Phase III study will unravel whether the concept is also efficient and tolerable under daily life circumstances.

Background: In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration., Objectives: This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy., Methods: Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration., Results: During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (-0.76; P = .22), 19% (-1.58; P = .01), and 24% (-2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (-0.88; P = .09), 18% (-1.28; P = .01), and 27% (-1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred., Conclusions: In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Previous trials have demonstrated the efficacy, safety, and optimal dosage of the 5-grass pollen sublingual tablet for adults and children with grass pollen-induced allergic rhinoconjunctivitis., Objectives: We sought to evaluate the efficacy and safety of 300 index of reactivity (IR) 5-grass pollen sublingual tablet in US adults., Methods: Adults with grass pollen allergy and Rhinoconjunctivitis Total Symptom Scores of 12 or greater (scale, 0-18) during the previous grass pollen season were randomized in a double-blind, placebo-controlled study to receive 300IR 5-grass pollen sublingual tablet or placebo starting 4 months before and continuing through the pollen season. The primary efficacy end point was the daily Combined Score (CS; scale, 0-3), which integrates symptoms and rescue medication use., Results: Four hundred seventy-three participants were randomized. The mean daily CS over the pollen period was significantly lower in the active treatment group versus the placebo group (least-squares mean difference: -0.13; 95% CI, -0.19 to -0.06; P = .0003; relative reduction: 28.2%; 95% CI, 13.0% to 43.4%). In placebo-treated participants, the daily CS least-squares mean was 0.32 in the subgroup with baseline timothy grass-specific serum IgE of less than 0.1 kU/L (n = 23) and 0.46 in those with baseline timothy grass-specific serum IgE of 0.1 kU/L or greater (n = 204). The most frequent reported adverse events were oral pruritus, throat irritation, and nasopharyngitis. There were no reports of anaphylaxis, and no actively treated participant received epinephrine., Conclusion: In US adults with grass pollen-induced allergic rhinoconjunctivitis, preseasonal and coseasonal treatment with 300IR 5-grass pollen sublingual tablet demonstrated clinically meaningful efficacy, especially in study subjects with measurable timothy grass-specific serum IgE. Use of 300IR 5-grass pollen sublingual tablet was safe and well tolerated. A requirement for a measurable level of allergen-specific serum IgE should be considered in future studies in this field., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Despite its success, conventional immunotherapy is saddled with a number of encumbrances. An allergenic vaccine that could reduce allergenicity, maintain immunogenicity, and be given in a few doses would have important therapeutic implications, as millions of patients with poorly controlled allergic rhinitis and asthma would be candidates for such a form of immunomodulation. This article addresses a specific adjuvant approach to immunotherapy in which highly active immunostimulatory phosphorothioate oligodeoxyribonucleotide moieties are linked to the principal allergenic moiety of a relevant aeroallergen.

Background: Innate immune responses play a critical role in determining the course of acquired immunity, including that associated with allergic disease. Type I interferons, which are generated early in these reactions, are important soluble factors that prime for TH1-like activity., Objective: Because human basophils secrete IL-4 and IL-13 in response to both IgE-dependent and IgE-independent stimuli, we tested whether IFN-alpha, a major type I IFN, affects the production of these TH2 cytokines and/or mediator release from these cells., Methods: Basophils isolated from blood were treated with IFN-alpha in the presence and absence of IL-3 priming before stimulating through the IgE receptor to release histamine, leukotriene C4, and IL-4. Effects of IFN-alpha on IL-3-mediated IL-13 secretion and basophil survival were also tested. IFN-alpha receptor expression was determined by RT-PCR., Results: IFN-alpha specifically inhibited the effects IL-3 has on basophil cytokine secretion. Enhanced secretion of IL-4 resulting from IL-3 priming was significantly inhibited in cells concurrently cultured with IFN-alpha. This effect was specific for cytokine generation, because histamine and leukotriene C4 were unaffected. Furthermore, IFN-alpha blocked IL-13 secretion directly induced by IL-3. Although IFN-beta also possessed some inhibitory activity, IFN-gamma (a type II IFN) had no effect on basophil cytokine secretion. Basophils constitutively expressed mRNA for the type I IFN receptor, and IFN-alpha did not affect basophil viability with regard to inhibition of cytokine secretion., Conclusions: These results support the belief that early innate immune responses resulting in IFN-alpha production negatively regulate allergic responses by also inhibiting priming of basophil cytokine release.

Allergen immunotherapy was first introduced in the early part of the twentieth century. It is widely practiced despite having specific limitations. Considerable effort has been devoted to developing new modified allergens that, compared with conventional allergen immunotherapy, improve efficacy, decrease the time required to achieve effect, reduce inconvenience, and enhance safety. Increased understanding of allergic respiratory inflammation has led to the development of therapeutic modalities that potentially arrest the disease process in asthma or allergic rhinitis. This paper addresses an adjuvant approach in which highly active immunostimulatory phosphorothioate oligodeoxyribonucleotide sequence (i.e. immunostimulatory DNA) are conjugated to the principal allergenic moiety of a relevant aeroallergen. We have recently completed the first human safety studies in patients with allergic rhinitis with Amb a 1-immuno-stimulatory oligonucleotide conjugate (AIC) --a novel therapeutic vaccine comprised of Amb a 1, the principal allergenic protein of ragweed, conjugated specific immunostimulatory oligonucleotides (ISS). The results demonstrate that AIC was several hundred-fold less reactive than a standardized ragweed extract when evaluated by quantitative intradermal skin titration methodology. Furthermore, AIC reduced histamine release from basophils to a similar degree. The DNA vaccine induced IgG antibody production in treated patients. AIC compared with standardized aqueous ragwood exhibited fewer local reactions on skin testing, a finding that suggests that AIC offers the potential for an improved safety profile for immunotherapy. Additional trials to further evaluate the safety, immunologic effect, and therapeutic efficacy of AIC for ragwood-induced allergic rhinitis and asthma are ongoing.

Inhaled corticosteroids (ICSs) are recognized as the cornerstone of asthma therapy. They are considered to be the most effective anti-inflammatory medication currently available for the treatment of persistent asthma, regardless of its severity. Leukotriene receptor antagonists (LTRAs) are also used as initial maintenance therapy in patients whose asthma is uncontrolled by bronchodilators alone. There are now sufficient data available to allow a comparison of the relative effectiveness and cost-effectiveness of LTRAs and ICSs as initial maintenance therapy. The consensus from the studies reviewed in this article demonstrates that ICSs are more effective than LTRAs as initial maintenance therapy. In particular, studies on fluticasone propionate have shown that it was more effective than LTRAs in clinical outcomes: producing greater improvements in lung function and asthma control; as measured by either forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF); by a greater reduction in daytime and night-time asthma symptoms; and short-acting beta2-agonist use. This superiority was also seen when patients were switched from an LTRA to fluticasone propionate. Similar findings have been demonstrated with beclomethasone dipropionate (BDP), showing that, in adults, this inhaled steroid also had a greater effect on pulmonary function and symptom scores than did LTRAs. Quality of life assessments showed that fluticasone propionate achieved improvements that were deemed to be clinically meaningful; these changes were significantly greater than those achieved with LTRAs. However, questionnaire-based patient preference studies comparing BDP with LTRAs showed that children and adolescents generally preferred an LTRA to BDP. A number of comparative analyses showed that inhaled fluticasone propionate is more cost-effective than either montelukast or zafirlukast; these analyses used cost per symptom-free day and cost per successfully treated patient as outcome measures, from the perspective of a third-party payer. In general, these results were supported by resource utilisation studies in real-world settings. Asthma treatment guidelines (e.g. GINA, 2002) recommend combination therapy with ICSs and a long-acting beta2-agonist as initial maintenance therapy if the disease is of sufficient severity. Studies that assessed the effectiveness, cost-effectiveness, and quality of life achieved with a salmeterol fluticasone propionate combination as initial maintenance therapy also showed it to be superior to LTRAs. In conclusion, in terms of efficacy and quality of life, fluticasone propionate is more effective than LTRAs as initial maintenance therapy and is associated with significantly lower healthcare costs and less frequent use of healthcare resources than LTRAs. There is also evidence to suggest that initial maintenance therapy with the combination of an inhaled steroid plus a long-acting beta-agonist bronchodilator may be a more effective option for the management of persistent asthma than treatment with a single-controller agent alone (ICS or LTRA).

Background: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation., Objective: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations., Methods: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV(1) was measured after each methacholine dose until a 20 % decrease in FEV(1) (PD(20)) was achieved., Results: Mean PD(20) values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD(20) values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 microg) of albuterol MDI were within the sensitive region of the dose- response curve. The mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was 119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage coefficient of variation of 69.0 %., Conclusions: The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products.

Background: Recent studies have demonstrated that bacterially derived immunostimulatory sequences (ISSs) of DNA can activate the mammalian innate immune system and promote the development of T(H)1 cells. Promotion of T(H)1 immunity by means of immunotherapy in allergic patients has led to the alleviation of symptoms that result from allergen-specific T(H)2 responses., Objective: Our purpose was to investigate whether the T(H)1-enhancing properties of ISSs could be used to alter the T(H)2-dominated immune response of allergic PBMCs in vitro., Methods: Ragweed protein-linked ISS (PLI) was generated from a specific, highly active 22-base ISS and Amb a 1, the immunodominant allergen in ragweed pollen, to combine the T(H)1-enhancing properties of ISSs with allergen selectivity, and its activity was investigated in PBMC cultures from subjects with ragweed allergy., Results: PLI was markedly successful at reversing the dominant allergen-induced T(H)2 profile while greatly enhancing IFN-gamma production. Delivering ISSs in a linked form proved to be much more effective at modulating the resulting cytokine profile than delivering free ISSs in a mixture with unlinked Amb a 1. PLI also demonstrated cytokine-modulating properties, even when used to stimulate cells that had already been primed for 6 days with Amb a 1. The antigen specificity of the action of PLI was confirmed by the observations that PLI enhances Amb a 1--specific T-cell proliferation., Conclusion: These data indicate that delivery of ISSs within an antigen-specific context exhibits potent cytokine-modulating activity and, combined with its reduced allergenicity, makes this molecule a strong candidate for use in improved immunotherapy applications.

Background: Immunotherapy (IT) has undergone rigorous trials to evaluate its therapeutic benefit in the treatment of allergic respiratory disease. The tools of molecular biology have provided a framework with which to begin to understand the mechanistic effects of IT on the underlying inflammatory component of allergic respiratory disease., Results: The clinical relevance of these observations belies our understanding of allergic inflammation as the subsoil for the development of abnormal airway physiology, heightened bronchial reactivity, and the development of chronic asthmatic symptomatology., Conclusions: IT provides the potential to downregulate this inflammatory cascade, reduce IgE antibody production, and attenuate symptoms. Conceptually, early intervention of allergic disease holds the most promise as a therapeutic intervention capable of arresting the progression of the disease, altering the severity of the disease, and/or preventing the development of the respiratory disease process.

Asthma is a chronic inflammatory disorder of the airways with a spectrum of presentations--from intermittent but mild symptoms to persistent symptoms with chronicity. The key to successful management of the disease process is not only to treat the acute symptoms of wheezing, breathlessness, chest tightness, and cough but also to suppress the underlying inflammatory component. Management requires an integrated approach that incorporates patient education, control of environmental triggers, the judicious use of an appropriate agent to suppress underlying inflammation, addition of adjunctive therapy to optimize primary control, and the supplemental use of a bronchodilator to control breakthrough symptoms. Inhaled corticosteroids are the most effective agents for primary control of patients with persistent asthma. The nonsteroidal antiinflammatory agents cromolyn and nedocromil are alternative choices for primary control. Adjunctive or secondary controllers include maintenance bronchodilators such as salmeterol and long-acting theophylline as well as leukotriene modifiers. Concurrent therapy with an inhaled corticosteroid and a long-acting beta agonist has been shown to provide better asthma control than therapy with either an inhaled corticosteroid plus a leukotriene modifier, an inhaled corticosteroid plus theophylline, or higher doses of an inhaled corticosteroid alone.

Background: Allergen immunotherapy is inconvenient and associated with the risk of anaphylaxis. Efforts to improve the safety of immunotherapy by means of chemical modification of allergens have not been successful because it greatly reduced their antigenicity. Recently, immunostimulatory DNA sequences (ISS or CpG motifs) have been shown to act as strong T(H)1 response-inducing adjuvants., Objective: We sought to determine whether conjugation of ISS to the major short ragweed allergen Amb a 1 results in enhanced immunotherapeutic potential in mice and decreased allergenicity in human subjects., Methods: A 22-mer ISS oligodeoxynucleotide (ISS-ODN) was coupled to Amb a 1 and used for immunization of mice, rabbits, and monkeys., Results: In mice the Amb a 1-ISS conjugate induced a T(H)1 response (IFN-gamma secretion), whereas Amb a 1 induced a T(H)2 response (IL-5 secretion). The T(H)1 response was not observed with an Amb a 1-non-ISS conjugate. Coinjection of Amb a 1 with ISS-ODN was much less effective in inducing a T(H)1 response. In mice primed for a T(H)2 response, injection with Amb a 1-ISS conjugate induced a de novo T(H)1 response and suppressed IgE antibody formation after challenge with Amb a 1. Amb a 1-ISS conjugate induced high-titer anti-Amb a 1 IgG antibodies in rabbits and cynomolgus monkeys, whereas Amb a 1 alone or Amb a 1 coinjected with ISS-ODN did not induce a detectable response. Amb a 1-ISS conjugate was less allergenic than Amb a 1 alone, as shown by a 30-fold lower histamine release from human basophils of patients with ragweed allergy, whereas mixing ISS-ODN with Amb a 1 did not reduce histamine release., Conclusion: Amb a 1-ISS conjugate has an enhanced T(H)1-biased immunogenicity and reduced allergenicity. It may offer a more effective and safer approach for allergen immunotherapy than currently available methods.

Immunotherapy has undergone rigorous trials to assess its therapeutic benefit in the treatment of allergic respiratory disease. The tools of molecular biology have provided a framework with which to begin to understand the mechanistic effects of immunotherapy on the underlying inflammatory component of allergic respiratory disease. The clinical relevance of these observations belies our understanding of allergic inflammation as the subsoil for the development of abnormal airway physiology, heightened bronchial reactivity, and the development of chronic asthmatic symptoms. Immunotherapy provides the potential to downregulate this inflammatory cascade, reduce IgE antibody production, and attenuate symptoms. Conceptually, early intervention of allergic disease holds the most promise as a therapeutic intervention capable of arresting the progression of the disease, altering the severity of the disease, and/or preventing the development of the respiratory disease process.

Background: Approximately one third of patients with allergy-induced asthma who are treated with aerosolized cromolyn sodium (CS) fail to achieve a full therapeutic effect. This lack of effectiveness could involve nonhomogeneous distribution of drug in the lung as a result of high inspiratory flow rates., Objective: We sought to determine the efficacy of slow versus faster inhalation of CS in protecting against allergen challenge in patients with asthma., Methods: Eight patients with asthma underwent two allergen challenges 30 minutes after pretreatment with CS that was inhaled from a large holding chamber at approximately 30 L/min or approximately 70 L/min. Percent decreases in FEV1 at a common dose of allergen on the two challenge days were compared. Values of skew (an indicator of aerosol distribution homogeneity) obtained from gamma camera lung images after slow and faster inhalation of radiolabeled CS were also compared., Results: Mean (+/- SD) allergen-induced decrease in FEV1 was 5.4% +/- 4.2% after slow inspiration of CS, which was significantly less than the allergen-induced decrease in FEV1 after faster inhalation of CS with 12.6% +/- 11% (p < 0.05). Mean skew values were also significantly decreased after slow inspiration of CS, and differences in decreases in allergen FEV1 and skew values for the two breathing maneuvers were significantly correlated., Conclusion: These data indicate that protection against allergen-induced asthma can be optimized by slowly inspiring CS from a large holding chamber compared with faster inhalation of the drug. These results appear to be related to enhanced distribution homogeneity of CS within the lungs.

Background: The metered dose inhaler (MDI) to treat respiratory diseases was introduced many years ago. Due to the recently proposed ban on chlorofluorocarbon (Freon) production, the survival of the conventional MDI is uncertain. It is therefore incumbent on asthma caretakers to familiarize themselves with newer versions of the inhaler., Objective: To review the different modalities of aerosolized treatment employed in the management of asthma. This article is specifically focused on issues related to MDIs, the propellants, and the modifications since its introduction., Data Source: The MEDLINE database was used to review MDI related literature in the English language., Conclusion: Dry powder inhalers (especially the multi-dose type) and Freon-free pressurized MDIs appear promising and probably will replace conventional freon-propelled pressurized MDIs when Freon is no longer available.

Background: Immunotherapy effectively treats the symptoms of allergic rhinitis and improves its pathophysiology. We studied whether the effects of immunotherapy on the early response to nasal challenge with antigen and seasonal symptoms persist after discontinuation., Methods: Twenty subjects with ragweed allergy who were receiving immunotherapy and who had nasal challenges performed before initiation of treatment were selected. The patients had been receiving maintenance therapy with aqueous ragweed extract at a dose of 12 microg of Amb a 1 equivalent for a minimum of 3 years, at which point they were randomized to receive either placebo injections or to continue with the maintenance dose. Nasal challenges were performed before and 1 year after randomization. Nasal challenges were monitored by counting the number of sneezes and measuring histamine, N-alpha-tosyl-L-arginine methyl ester-esterase activity, and kinins in recovered nasal lavages. In the same year symptom diaries were collected during the ragweed season., Results: The initial immunotherapy significantly reduced responses to nasal challenge in both groups. The group continuing to receive active treatment showed no significant changes from the response before randomization. In contrast, the group randomized to placebo treatment showed a partial return of histamine, kinins, and N-alpha-tosyl-L-arginine methyl ester-esterase in nasal secretions and the numbers of sneezes. IgG antibodies to ragweed declined only in the group switched to placebo treatment. Seasonal rises of IgE antibodies to ragweed did not return during the first season after treatment was stopped. Symptoms reported during the ragweed season were not different between the groups., Conclusions: One year after discontinuation of ragweed immunotherapy, nasal challenges showed partial recrudescence of mediator responses even though reports during the season appeared to indicate continued suppression of symptoms.

Peptides have been designed to be T cell tolerogenic for the principal allergens of the cat. These have been administered in several dosage programs to cat-sensitive patients in multicenter blinded studies. In contrast to proteins in standard extracts, IgE sensitization to peptides is an uncommon event. Pretreatment prick tests with peptides will identify the occasional sensitized patient. Other side reactions consist of allergic symptoms occurring on the day of injections. These become less severe with subsequent injections and are easily treatable with antihistamines or bronchodilators, depending on the symptoms. Treatment with cat peptides ameliorated symptoms that occur upon exposure to cats 1-6 or more weeks later. A 2-week course of 4 injections is the most effective of the regimens so far tried. T-cell-active peptides offer a promising low-risk alternative for specific treatment of respiratory allergies.

We induced in allergic humans the counterpart of murine experimental T-cell tolerance. T-cell lines from cat-allergic humans were used to map T-cell epitopes for the principal allergen of cat dander, Fel d 1. Two peptides of 27 amino acids each were synthesized to contain the dominant epitopes (ALLERVAX CAT). After a safety trial, we carried out a blinded study of the dose required for efficacy. We randomly divided 95 cat-sensitive patients into placebo, 7.5 micrograms, 75 micrograms, and 750 micrograms groups. Patients received a subcutaneous injection weekly for 4 wk. Before and after treatment, patients were exposed in a room inhabited by live cats and scored by nose and lung symptoms. Baseline nasal and lung scores (+/-SEM) were 6.2 +/- 0.56 and 5.4 +/- 0.73 in the 750 micrograms group; 7.8 +/- 0.53 and 4.7 +/- 0.68 in the placebo group. Six weeks after treatment, scores adjusted for baseline differences were reduced in the 750 micrograms group: -2.3 +/- 4.9 and -2.3 +/- 0.59 compared with -0.84 +/- 0.50 and -0.85 +/- 0.62 in the placebo group. The 75 micrograms group showed intermediate effects and the 7.5 micrograms group no effect. Linear trend analysis indicated a significant dose response effect: p = 0.05 for nose and 0.03 for lung symptoms. Allergic side effects occurred an hour or more after the first 750 micrograms dose in 16 of 24 patients but required little or no treatment with one exception. T-cell reactive treatment peptides safely improved allergic responses to cats.

This review cites clinical evidence demonstrating that nedocromil sodium can reverse the clinical features of airway inflammation in asthma, as shown by decreased bronchial responsiveness, decreased diurnal variation in peak expiratory flow, improved baseline lung function, and a decrease in the frequency and severity of chronic symptoms. Clinical trials have also shown that nedocromil sodium has a statistically significant and clinically relevant effect on daytime and nighttime asthma symptoms within 3 days of starting treatment. On an analysis of relevant trials, the effect on asthmatic cough was significant within 24 hours. This rapid effect on symptoms, together with a reversal of the underlying airways inflammation, is a beneficial combination in the management of asthma.

Background: Few clinical trials have directly compared the efficacy of antihistamines with topical nasal corticosteroids., Objective: The study was performed to compare the efficacy and safety of triamcinolone acetonide nasal spray at a dose of 110 micro g in each nostril once daily with 10 mg of oral astemizole once daily for the treatment of seasonal allergic rhinitis., Methods: A multicenter, double-blind, parallel-group study was conducted in 239 patients who were randomized to receive either triamcinolone acetonide or astemizole. A 5-day, drug-free, lead-in period was followed by 4 weeks of double-blind treatment. One hundred four patients treated with triamcinolone acetonide and 105 patients treated with astemizole could be evaluated., Results: Overall, triamcinolone acetonide was more effective than astemizole in reducing total nasal symptoms, nasal stuffiness, nasal itching, and sneezing (p

We performed two seasonal studies to evaluate the effect of continuous treatment with intranasal steroids, beginning approximately 1 week before the appearance of ragweed pollen, on the level of ragweed-specific IgE antibodies in serum. In both studies the control groups showed the anticipated rise in ragweed-specific IgE antibodies after the ragweed season. In the first study, employing aqueous beclomethasone dipropionate (168 micrograms twice daily), no rise occurred in serum ragweed IgE after seasonal exposure and the level actually decreased in eight of 12 treated subjects. In the second study, with triamcinolone acetonide (220 micrograms twice daily), the expected rise in ragweed IgE antibody was also reduced, although less dramatically, probably as a result of the lower potency of the dose delivered. Our studies not only support the benefits of intranasal steroids in the treatment of seasonal allergic rhinitis but also suggest that specific IgE production may be down-regulated by their continuous use, which may alter the subsequent clinical course of the disease.