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By selectively targeting specific steps of the immune inflammation cascade, biologic drugs for severe asthma have substantially contributed to increase the standard of care, to reduce drug-related morbidity. and most importantly to ameliorate patients' quality of life. Upcoming molecules are going to provide a chance for severe phenotypes besides Th2 high through the interaction with epithelial and innate immunity. Some practical aspects including optimal treatment duration, the possibility of a dose treatment modulation, the place and relevance of ICS in best responders are still under debate. Long-term safety, especially when interacting with innate immunity needs to be further investigated., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We review the history of the classification and coding changes for anaphylaxis and provide current and perspective information in the field. In 2012, an analysis of Brazilian data demonstrated undernotification of anaphylaxis-related deaths because of the difficulties of coding using the International Classification of Diseases, 10th Revision. This work triggered strategic international actions supported by the Joint Allergy Academies and the International Classification of Diseases World Health Organization (WHO) leadership to update the classification of allergic disorders for the International Classification of Diseases, 11th Revision (ICD-11), which resulted in construction of the pioneer "Allergic and hypersensitivity conditions" chapter. The usability of the new framework has been tested by evaluating the same data published in 2012 from the ICD-11 perspective. Coding accuracy was much improved, reaching 95% for definite anaphylaxis. As the results were provided to the WHO Mortality Reference Group, coding rules have been changed, allowing anaphylaxis to be recorded as an underlying cause of death in official mortality statistics. The mandatory use of ICD-11 from January 2022 for documenting cause of death could have 2 immediate consequences: (1) the reported number of anaphylaxis-related deaths might increase because of more appropriate coding and (2) the cross-sectional and longitudinal mortality data generated might ultimately lead to a better understanding of anaphylaxis epidemiology and improved health policies directed at reducing anaphylaxis-related mortality., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The immune system possesses a vast number of potential targets for therapeutic intervention. Although therapies for many pathways have been pursued, only few have yielded significant success. Hindrances in altering biologic pathways include the potential for unwanted downstream effects, ineffectiveness owing to biological redundancy, recognition of a therapeutic molecule as foreign by the body's innate immune system, and the risks of subsequent malignancy and/or autoimmunity. This article covers currently available biotherapeutic agent classes as well as potential direction for future therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A significant body of work in the genetics of asthma currently exists. However, current knowledge has not been clarifying in understanding the pathophysiology of asthma and therapeutic treatment of the disease. Severe asthma in adults and children is a significant burden in relation to disproportionate disease morbidity, mortality, and health utilization. This disease phenotype is not well understood; current effective treatment regimens are limited. Genetic studies may lead to improved understanding of the pathophysiology of severe asthma and identification of relevant subsets, which allow more targeted and effective therapies and the realization of Precision Medicine in asthma., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Allergy and hypersensitivity intervention management procedures, such as desensitization and/or tolerance induction and immunotherapy, have not been pondered up to now in the content of International Classification of Diseases (ICD) context because the focus has been on prioritizing the condition implementations. Tremendous efforts have been devoted to implementing allergic and hypersensitivity conditions in the forthcoming ICD-11. However, we consider that it is crucial now to have nomenclature and classification universally accepted for these procedures to be able to provide scientifically consistent proposals into the new ICD-11 platform for the best practice parameters of our specialty. With the aim of promoting a harmonized comprehension and aligning it with the ICD-11 revision, we have reviewed the definitions and concepts currently used for desensitization and/or tolerance induction and immunotherapy. We strongly believe that this review is a key instrument to support the allergy specialty identity into the ICD-11 framework and serves as a platform to perform positive quality improvement in clinical practice., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.

CD23 is the low-affinity Fc receptor for IgE. When expressed on B cells, CD23 appears to play a role in regulation of IgE synthesis. Polymorphisms within FCER2, the gene encoding CD23, have been associated with atopy, increased risk of exacerbations in patients with asthma, and high serum IgE levels. A single-nucleotide polymorphism (rs2228137) present in exon 4 of FCER2 encodes a nonsynonymous amino acid change (R62W) and is the subject of the present analysis. Human B cell stable transfectants were established to characterize the functional relevance of the R62W SNP. We demonstrate that CD23b-R62W-expressing human B cells bind IgE with greater affinity than wild-type cells and display differences in kinetics of CD23-mediated ERK1/2 activation that may be responsible for the increased levels of Egr-1 mRNA observed after stimulation through CD23. Finally, the R62W SNP seems to alter the tertiary or quaternary structure of CD23 because in the absence of N-glycosylation the CD23b-R62W-expressing cells appear to be less sensitive to endogenous proteases. These observations may have implications in mechanisms responsible for the atopic phenotypes observed in patients with asthma who possess this genotype.

Background: Forty million children are regularly exposed to environmental tobacco smoke (ETS) each year, increasing their risk for premature death and middle ear and acute respiratory infections. Early life exposure to ETS also is clearly associated with wheezing. However, there is no clear understanding of the influence of ETS on the development of allergic sensitization., Objective: To determine the association of combined exposure to ETS and indoor allergens on IgE sensitization to aeroallergens in children., Methods: This case-control study enrolled 116 cases and 121 controls from low-income families from Kansas City, Missouri. The adjusted odds ratio was calculated using a logistic model to assess the association between ETS and allergic sensitization using dust allergen levels as a covariate., Results: Thirty-six percent of atopic children and 39% of controls were exposed to ETS (P < .05). Unadjusted analyses showed no significant influence of ETS on IgE sensitization to indoor allergens. Logistic regression analyses also showed no significant influence of ETS on sensitization when adjusted for levels of allergens in the home dust and family history of allergic rhinitis., Conclusion: These data suggest that ETS exposure was not associated with IgE sensitization to indoor allergens, even when home allergen levels were taken into consideration. Further understanding of how components of tobacco smoke influence the immune response is necessary to interpret the disparate findings across studies., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HESs., Objective: We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES., Methods: MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored., Results: Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ≥ 12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons., Conclusion: Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES., (Published by Mosby, Inc.)

Eosinophilia is commonly seen in medical practice and can underlie a variety of medical conditions. Eosinophilia, defined as peripheral blood eosinophil counts greater than 500 per microliter, may vary from mild-severe. Idiopathic hypereosinophilic syndrome has been identified as an unusual cause of moderate to severe eosinophilia. Progress in treatment of this condition has accompanied greater understanding about the basic biology of eosinophils. This review will highlight the approach to patients with eosinophilia, along with associated conditions and syndromes.

The immune response to an allergen depends on an initial sensitization process, with future exposures triggering a 2-part allergic response including an early and late phase. The process by which an allergen is recognized has become clearer. Similarly, the roles of the preformed mediators responsible for many of the signs and symptoms of the early-phase response have been elucidated. Recent work also has shed some light on the cells and mediators involved in the late-phase reactions. This article discusses some of this recent work and reviews the basics behind of all of the stages of the allergic response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The prevalence of diseases such as allergic asthma and rhinitis continues to increase in the United States, affecting millions of people. It is well-established that allergy contributes to the pathogenesis of most asthma, especially in children and young adults. Despite current therapy (eg, inhaled corticosteroids, anti-leukotrienes, and bronchodilators), patients with moderate to severe asthma remain symptomatic and experience frequent exacerbations of disease requiring oral corticosteroids, emergency department treatments, and hospitalizations. Allergic diseases are traditionally referred to as immediate or type 1 hypersensitivity reactions, with IgE as a critical factor. IgE is involved in allergic inflammation, especially in early-phase response, but it may also be involved in the late-phase allergic response. A direct correlation between serum IgE levels and asthma exists. As logarithm IgE values increase, asthma prevalence increases linearly, even in patients who are categorized as having nonallergic asthma. In addition, there is a significant, although low association in allergic rhinitis with IgE levels and positive skin test reactivity to pollens. Recent advances in our understanding of the role of IgE in allergic inflammation have led to the development of a monoclonal antibody to IgE that reduces IgE levels, thereby reducing allergic inflammation. This review aims to provide an overview of the basic science of the IgE molecule and the clinical efficacy of anti-IgE therapy in allergic and asthmatic diseases.

The association of immunoglobulin E (IgE) with allergic diseases and asthma is well established. IgE binds to two receptors on various immune and inflammatory cells. The lower-affinity IgE Fc receptor, CD23, has multiple functions in enhancing the regulation of IgE production itself, and that of various pro-inflammatory activities and mediators. The data in this report are derived from an analysis of variation in the CD23 gene that leads to a coding exchange and to a single nucleotide polymorphism (SNP) associated with the substitution of an arginine residue for a tryptophan residue in the protein structure of CD23. This genetic variation is associated with three findings identified in this report. First, the tryptophan exchange is associated with greater expression of RNA for the interleukin (IL)-4 receptor alpha chain and greater expression of RNA for egr-1 transcription factor, both of which are proinflammatory gene products that influence allergy-related immune functions. Second, the exchange is associated with cell surface expression of IL-4R. Third, an analysis of potential arginine-to-tryptophan exchanges in the entire human genome has identified a number of interesting exchanges in immunologic genes of interest for their role in allergic responses. A discussion of these three findings is presented.

Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition.

The many roads leading to the syndrome of asthma have proven to be intricately interconnected. The chronic inflammation of asthma is characterized by airway hyperreactivity and variable reversibility. Past classification systems relied on assessment of daily impairment and the distinction between intrinsic (nonallergic) and extrinsic (allergic). With more precise asthma phenotypes, association studies likely will have greater significance. In addition, patients at higher risk for severe disease can be more effectively managed, and treatments can be directed to responders. In this review, we look at eight identified phenotypes: atopic and nonatopic status, pre-asthma wheezing, inflammatory mediator predominance, aspirin-sensitive, exercise-induced, severe, and flare-prone asthma. Although significant overlap exists among the distinctions, any future phenotype classification system will need to incorporate these eight clinical asthmatic populations.

Background: Although inhaled corticosteroids (ICSs) generally protect against severe exacerbations in asthma, they may result in elevated IgE levels, which are associated with exacerbations., Objective: To determine whether variation in the low-affinity IgE receptor gene, FCER2, is associated with severe exacerbations defined as emergency department visits and/or hospitalizations in patients with asthma on ICSs., Methods: We resequenced, then genotyped 10 FCER2 single nucleotide polymorphisms (SNPs) in 311 children randomized to inhaled budesonide as part of the Childhood Asthma Management Program. We evaluated the association of FCER2 variants with IgE levels and presence or absence of severe exacerbations over the 4-year clinical trial. We also evaluated differences in cellular expression of the novel FCER2 SNP, T2206C., Results: In white subjects, 3 FCER2 SNPs were significantly associated (P < .05) with elevated 4-year IgE level; each was also associated with increased severe exacerbations. Final multivariable models demonstrated associations between T2206C and severe exacerbations in both white and African American children (hazard ratio, 3.95; 95% CI, 1.64-9.51; and hazard ratio, 3.08; 95% CI, 1.00-9.47), despite ICS use. Interaction models supported a true gene-environment effect in white subjects (interaction P = .004). T2206C was also associated with decreased FCER2 expression (P = .02)., Conclusion: FCER2 predicts the likelihood of treatment protocol success in asthma. The associations of T2206C with IgE level, severe exacerbations, and FCER2 expression may provide a mechanistic basis for the observed findings., Clinical Implications: Genetic variation in FCER2 may help form a prognostic model for ICS response in asthma.

Risk assessment of individuals with anaphylaxis is currently hampered by lack of (1) an optimal and readily available laboratory test to confirm the clinical diagnosis of an anaphylaxis episode and (2) an optimal method of distinguishing allergen-sensitized individuals who are clinically tolerant from those at risk for anaphylaxis episodes after exposure to the relevant allergen. Our objectives were to review the effector mechanisms involved in the pathophysiology of anaphylaxis; to explore the possibility of developing an optimal laboratory test to confirm the diagnosis of an anaphylaxis episode, and the possibility of improving methods to distinguish allergen sensitization from clinical reactivity; and to develop a research agenda for risk assessment in anaphylaxis. Researchers from the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergology and Clinical Immunology held a PRACTALL (Practical Allergy) meeting to discuss these objectives. New approaches being investigated to support the clinical diagnosis of anaphylaxis include serial measurements of total tryptase in serum during an anaphylaxis episode, and measurement of baseline total tryptase levels after the episode. Greater availability of the test for mature beta-tryptase, a more specific mast cell activation marker for anaphylaxis than total tryptase, is needed. Measurement of chymase, mast cell carboxypeptidase A3, platelet-activating factor, and other mast cell products may prove to be useful. Consideration should be given to measuring a panel of mediators from mast cells and basophils. New approaches being investigated to help distinguish sensitized individuals at minimum or no risk from those at increased risk of developing anaphylaxis include measurement of the ratio of allergen-specific IgE to total IgE, determination of IgE directed at specific allergenic epitopes, measurement of basophil activation markers by using flow cytometry, and assessment of allergen-specific cytokine responses. Algorithms have been developed for risk assessment of individuals with anaphylaxis, along with a research agenda for studies that could lead to an improved ability to confirm the clinical diagnosis of anaphylaxis and to identify allergen-sensitized individuals who are at increased risk of anaphylaxis.

Background: Placebos are hypothesized to exert positive effects on medical conditions by enhancing patient expectancies. Recent reviews suggest that placebo benefits are restricted to subjective responses, like pain, but might be ineffective for objective physiologic outcomes. Nevertheless, mind-body links and placebo responsivity in asthma are widely believed to exist., Objective: We carried out a randomized, double-blind investigation to (1) determine whether placebo can suppress airway hyperreactivity in asthmatic subjects, (2) quantify the placebo effect, (3) identify predictors of the placebo response, and (4) determine whether physician interventions modify the placebo response., Methods: In a double-blind, crossover design investigation, 55 subjects with mild intermittent and persistent asthma with stable airway hyperreactivity were randomized to placebo or salmeterol before serial methacholine challenges. Subjects were additionally randomized to physician interactions that communicated either positive or neutral expectancies regarding drug effect., Results: Placebo bronchodilator administration significantly reduced bronchial hyperreactivity compared with baseline (the calculated concentration of methacholine required to induce a 20% decrease in FEV(1) nearly doubled); 18% of subjects were placebo responders by using conservative definitions. Experimental manipulation of physician behavior altered perceptions of the physician but not the magnitude or frequency of the placebo response., Conclusions: Objective placebo effects exist in asthma. These responses are of significant magnitude and likely to be meaningful clinically. The placebo response was not modulated by alterations in physician behavior in this study., Clinical Implications: The placebo response in patients with asthma is important in understanding the limitations of clinical research studies and in maximizing safe and effective therapies. This article confirms the existence of a strong placebo response in an objective and clinically relevant measure of disease activity.

Background: Inhaled corticosteroids (ICSs) are the preferred maintenance therapy for adults and children with mild, moderate and severe persistent asthma, with the addition of a long-acting beta(2)-adrenoceptor agonist to ICS therapy recommended for patients with moderate or severe persistent asthma. The efficacy and safety of the combination of budesonide and formoterol delivered via dry powder inhaler (DPI) is well documented., Objective: To compare the efficacy and safety of budesonide/formoterol pressurised metered-dose inhaler (budesonide/formoterol pMDI; Symbicort pMDI, AstraZeneca LP, Wilmington, DE, USA) with budesonide pMDI (Pulmicort pMDI, Astra [corrected] Zeneca, Lund, Sweden), formoterol DPI (Oxis Turbuhaler, AstraZeneca, Lund, Sweden), budesonide plus formoterol in separate inhalers (budesonide pMDI + formoterol DPI) and placebo., Study Design: This was a 12-week randomised, double-blind, double-dummy, placebo-controlled study., Setting: This multicentre study was conducted in the respiratory specialty clinical practice setting., Patients: The study included 596 patients > or =12 years of age with moderate to severe persistent asthma previously receiving ICSs., Interventions: After 2 weeks on budesonide pMDI 80 microg x two inhalations (160 microg) twice daily, patients received budesonide/formoterol pMDI 160 microg/4.5 microg x two inhalations (320 microg/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) + formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo twice daily., Main Outcome Measures: There were two prespecified primary efficacy variables: mean change from baseline in morning predose forced expiratory volume in 1 second (FEV(1)), obtained approximately 12 hours after the most recent administration of study medication at home and immediately before the next administration of study medication at the clinic; and mean change from baseline in 12-hour FEV(1), assessed as the average change in FEV(1) from serial spirometry over the 12-hour period after administration of the morning dose of study medication at the clinic., Results: Mean changes from baseline in morning predose FEV(1) at end of treatment were greater (p < or = 0.049) with budesonide/formoterol pMDI (0.19L) versus budesonide pMDI (0.10L), formoterol DPI (-0.12L) and placebo (-0.17L). Mean changes from baseline in 12-hour FEV(1) were greater (p < or = 0.001) with budesonide/formoterol pMDI after 1 day (0.37L), 2 weeks (0.34L) and at end of treatment (0.37L) versus budesonide pMDI (0.11, 0.15 and 0.15L) and placebo (0.09, -0.03 and -0.03L), and after 2 weeks and at end of treatment versus formoterol DPI (0.19 and 0.17L). Fewer (p < or = 0.025) patients receiving budesonide/formoterol pMDI versus monoproducts or placebo met worsening asthma criteria. Results were similar in the budesonide/formoterol pMDI group and the budesonide pMDI + formoterol DPI group on all measures. All treatments were well tolerated with similar safety profiles., Conclusions: In this population, twice-daily budesonide/formoterol pMDI provides asthma control significantly greater than the monocomponents or placebo and comparable with budesonide pMDI + formoterol DPI. Safety profiles were similar for all treatments.

Background: CD23 plays a role in the regulation of IgE production and allergy-induced immune and inflammatory responses. A novel anti-CD23 monoclonal antibody, lumiliximab, is a potential therapeutic antibody recently demonstrated to be safe in human beings., Objective: This study investigated the effects of lumiliximab on allergen-induced immune responses from atopic subjects compared with blocking HLA-DR and costimulatory molecules, CD80 and CD86., Methods: Allergen-stimulated PBMCs from atopic subjects were pretreated with lumiliximab or antibodies to CD80, CD86, and HLA-DR. Cultures were analyzed for cell proliferation and IL-1beta, TNF-alpha, and IL-5 cytokine secretion. An allergen-specific T-cell line was developed and analyzed for lymphocyte proliferation in response to allergen with or without lumiliximab. Lumiliximab's effect on CD86 expression was evaluated by flow cytometry in the U937 monocytic cell line., Results: Lumiliximab reduced allergen-induced PBMC proliferation by 50% (n = 6; P = .006). In addition, cultures pretreated with lumiliximab had a reduction in the proinflammatory cytokines IL-1beta (P < .003) and TNF-alpha (P = .05) and the T(H)2 cytokine IL-5 (P = .002). Blocking CD86 resulted in greater reduction in proliferation than lumiliximab (P = .003) but similar effects in cytokine secretion. The anti-CD80 blocking antibody had no effect on cytokine production but did reduce proliferation. Furthermore, the addition of lumiliximab to cytokine stimulated U937 cells reduced surface expression of CD86 (P = .012)., Conclusion: These results indicate that the anti-CD23 mAb, lumiliximab, may be involved in modulating antigen presenting cells and reducing TH2-type immune responses. The use of this antibody may provide clinical benefit for treating allergic diseases.

Background: A single nucleotide polymorphism (SNP) C-509T within the tumor growth factor beta1 (TGFbeta1) gene has been associated with atopic asthma and asthma severity. To further understand the mechanisms involved, the association of C-509T with allergy, T-lymphocyte proliferation and plasma TGFbeta1 concentration has been explored in a case-control study with allergic and non-allergic subjects., Methods: The recruited subjects including allergic (n = 38) and nonallergic (n = 25) participants have been genotyped for C-509T using allele discrimination assay. Association of C-509T with allergy status was examined using logistic regression analysis in both dominant and recessive models. Association of C-509T with T-cell proliferation in control and antigen-stimulated peripheral blood mononuclear cells (PBMCs), plasma TGFbeta1 and total IgE level were tested by multiple regression analysis., Results: Individuals with homozygous mutant TT genotype showed a higher risk of allergy (TT: odds ratio = 5.099, 95% confidence limit: 1.355-19.190, p = 0.016) after covariates were adjusted. A trend to increased plasma TGFbeta1 in subjects with T allele has been discovered. In the meantime, the T allele is associated with lower T cell proliferation in controls and maximum response to above antigens. A low T-cell proliferation is correlated with higher plasma TGFbeta1 concentration (p < 0.01). The in vitro studies confirmed the suppressing effect of TGFbeta1 on T-cell proliferation at physiological range. A significant inhibitory effect on IL-4 production was also observed., Conclusions: A C to T base change in TGFbeta1 SNP C-509T has been associated with a higher risk of allergy. The mechanisms are not clear. Elevated TGFbeta1 levels associated with the C-509T polymorphism might suppress immune activation as well as Th2 cytokine production., ((c) 2005 S. Karger AG, Basel)

CD23, the low-affinity immunoglobulin (Ig)E receptor (FcepsilonRII), is widely distributed on the surface of various human cells. CD23 mediates numerous IgE-related immune responses (including allergen focusing) by enhancing IgE antigen complex presentation, regulating IgE synthesis, influencing cell differentiation and growth of both B- and T-cells, and stimulating production of pro-inflammatory mediators from monocytes/macrophages, eosinophils, and even airway smooth muscle cells. Both membrane and soluble CD23 play an important role in allergic reactions. Cellular contacts and cytokines modulate its expression in a concerted manner as needed for allergic reactions. Expression of CD23 and soluble CD23 has been associated with allergic diseases. Targeting CD23 with monoclonal antibody (MAb) is a promising candidate therapy in allergic diseases. A newly developed agent known as Lumiliximab, which is an anti-CD23 MAb (Lumiliximab), was demonstrated to be a well-tolerated agent in a phase I clinical trial (a placebo-controlled study with allergic asthma). Adverse events were mild, and no relationship was apparent between the dose of Lumilixilab and the frequency, severity, or type of event. Sustained and dose-dependent decreases in mean serum total IgE concentrations were noted. The serum half-life of Lumilixilab increased from 2 to 10 d with increasing doses. Blocking antigen presentation, preventing costimulation signals, and reducing production of pro-inflammatory mediators are some of the potential mechanisms involved for anti-CD23 activity. Although the safety and clinical efficacy of Lumilixilab in allergic asthma and rhinitis require confirmation, the observed data imply that anti-CD23 is a promising candidate therapy option for future treatment of allergic diseases.

Immunoglobulin E (IgE) plays a critical role in the allergic inflammatory process in diseases such as allergic rhinitis. Cross-linking IgE bound to its receptor on cells by multivalent allergens initiates a chain of events resulting in allergic immune responses. Mast cells and basophils are involved in the early, immediate response, which is marked by cellular degranulation and the release of proinflammatory mediators, including histamine. Antigen-presenting cells are also activated by allergen-loaded IgE, resulting in immunomodulation of T-cell responses. The IgE molecule binds to two types of receptors, the high-affinity (Fc epsilonRI) and low-affinity (Fc epsilonRII or CD23) receptors, that have differing properties important in mediating allergen-induced responses. New therapies targeting the IgE molecule reduce allergen-stimulated immune responses and improve the clinical symptoms in subjects with allergic rhinitis. Understanding the role of the IgE molecule is necessary to appreciate the development and use of novel therapies targeting its actions.

Background: The immunologic response to allergen immunotherapy with 3 serial 5-fold doses of cat extract has been studied after approximately 5 weeks of immunotherapy. The highest dose containing 15 mug of Fel d 1 produced the most consistent and favorable response. It is unknown whether the comparative response on reaching a maintenance dose is maintained with long-term maintenance therapy., Objective: The purpose of this investigation was to evaluate the immunologic responses with these 3 serial doses of cat hair and dander extract at baseline, after reaching the maintenance dose (approximately 5 weeks), and after 1 year of maintenance immunotherapy., Methods: Twenty-eight patients with cat allergy randomized in a double-blind study were assigned to one of 4 treatment groups: placebo or cat hair and dander extract containing 0.6 mug of Fel d 1, 3 mug of Fel d 1, and 15 mug of Fel d 1 at maintenance. Studies included skin prick tests and late cutaneous reactions with cat hair and dander extract, titrated nasal challenges with the extract, serum cat allergen-specific IgG4 and IgE measurement, and flow cytometric and ELISA analysis of whole blood and intranasal cytokines (TGF-beta, IL-10, IFN-gamma, IL-4, and IL-5)., Results: Twenty-six subjects completed the study. After both 5 weeks and 1 year, significant and dose-dependent differences were seen with total symptom scores on nasal challenge ( P < .0001), with titrated skin prick testing with cat dander extract at 5 weeks ( P = .014) and 1 year ( P < .0001), and with cat-specific IgG4 measurement at 5 weeks ( P = .004) and 1 year ( P = .003). At 1 year, neither flow cytometry of whole blood nor ELISA evaluation of nasal cytokines demonstrated any significant differences among the treatment groups., Conclusion: The response to titrated nasal allergen challenge, titrated skin prick testing, and allergen-specific IgG4 measurement to cat immunotherapy at 5 weeks is predictive of the response at 1 year.

Background: Beta-blocker therapy postmyocardial infarction is generally recommended because it reduces mortality. However, beta-blockers may increase anaphylaxis mortality in the growing population of patients with peanut-induced anaphylaxis., Objective: We sought to assess the risks and benefits of beta-blocker therapy among patients with peanut allergy and heart disease., Methods: We created a Markov model for patients with heart disease at risk for peanut-induced anaphylaxis to compare life expectancy with the following strategies: (1) beta-blocker and (2) no beta-blocker. Meta-analysis and a literature review were used to estimate model parameters. We performed sensitivity analysis to explore parameter uncertainty., Results: For peanut-allergic patients who are postmyocardial infarction or who have congestive heart failure, the heart disease benefit of beta-blockers outweighs the increased likelihood of dying from anaphylaxis, increasing life expectancy by 9.4 and 17.4 months, respectively. Beta-blocker was preferred unless (1) the annual rate of moderate to severe anaphylaxis exceeded 6.0% for postmyocardial infarction and 15% for congestive heart failure patients; (2) beta-blocker therapy increased the incidence of moderate to severe anaphylaxis >2.5-fold for postmyocardial infarction and >5.8-fold for congestive heart failure patients; (3) anaphylaxis case fatality exceeded 6.5% postmyocardial infarction; or (4) beta-blocker therapy increased anaphylaxis case fatality >25-fold postmyocardial infarction., Conclusion: Our results suggest that for patients postmyocardial infarction or with congestive heart failure who are at risk for peanut-induced anaphylaxis, beta-blocker use should still improve survival. However, the epidemiology of anaphylaxis and effects of beta-blocker therapy on anaphylaxis incidence and mortality require further study.