The Journal of Allergy and Clinical Immunology

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2012-05-01

Brief Overview of This Month's JACI

2012-05-01

Editorial Board

2012-05-01

Information for Readers

2012-05-01

News & Notes

2012-05-01

This month, we continue our interviews with the newly-elected members of the AAAAI Board of Directors. Jonathan Bernstein, MD, FAAAAI, is Professor of Medicine at the University of Cincinnati (UC) Department of Internal Medicine, Division of Immunology/Allergy Section and Director of Clinical Research for the Division of Immunology. He is also a partner at the Bernstein Allergy Group/Clinical Research Center.

CME Activities Calendar

2012-05-01

▪ Continue your 2012 Annual Meeting Experience

News Beyond Our Pages

Marc E. Rothenberg, Jean Bousquet — 2012-05-01

Genome-wide association studies and other genetic studies have identified common variants of more than 100 genes associated with asthma, but most alleles provide relatively small increases in risk and contribute little to the disease heritability. Advances in sequencing technology have now made it possible to directly evaluate for the contribution of rare genetic variants to asthma susceptibility. Torgerson et al (Am J Hum Genet 2012;90:273-81) selected 9 candidate genes for resequencing of the coding exons and flanking noncoding regions in 450 asthmatic cases and 515 nonasthmatic control subjects. Their results suggested a contribution of rare variants of angiotensinogen (AGT), dipeptidyl peptidase 10 (DPP10), inhibitor of κ light polypeptide gene enhancer in B cells (IKBKAP), and IL-12 receptor β1 (IL12RB1) to asthma susceptibility. They also found evidence for significant associations with asthma for rare variants in the noncoding regions of these genes. The authors propose that rare variants might have an important role in asthma susceptibility. Furthermore, they suggest that noncoding regions flanking exons should not be ignored in sequencing studies in the future.Senior author Carole Ober, from the University of Chicago, told us about the significance of this study: “We believe this study will be the first of many providing evidence for a role of rare variants in asthma susceptibility. Ongoing whole genome sequencing studies in many of these same populations will allow us and others to explore the role of rare noncoding versus coding variants more broadly, and whether molecular signatures of natural selection will help to identify genes harboring rare variants that contribute to disease risk.”

A European perspective on immunotherapy for food allergies

Kirsten Beyer — 2012-05-01

Food allergies are common, and frequently, the only treatment option is strict avoidance. Unfortunately, many patients accidentally ingest allergenic foods, which can result in severe anaphylactic reactions. Several immunotherapies are being developed for food allergies; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. Oral immunotherapy seems to be the most promising approach based on results from small uncontrolled and controlled studies. However, it is a challenge to compare results among immunotherapy trials because of differences in protocols. Studies conducted thus far have tested the most prevalent food allergens: it is not clear whether their results can be extended to other allergens. Sublingual administration of immunotherapy has shown some efficacy and fewer side effects than oral administration in some trials, yet neither approach can be recommended for routine practice. Controlled studies with larger numbers of subjects are needed to determine short- and long-term efficacy and side effects. In Europe immunotherapy trials for food allergies face many ethical and regulatory issues. Guidelines from the European Medicine Agency on the clinical development of products for specific immunotherapy of allergic diseases do not adequately address immunotherapy for food allergies, especially for therapies that orally administer native food or that include pediatric patients.

A European perspective on immunotherapy for food allergies

2012-05-01

Update on risk factors for food allergy

Gideon Lack — 2012-04-01

Despite efforts to prevent food allergy (FA) in children, IgE-mediated FAs are increasing in westernized countries. Previous preventive strategies, such as prolonged exclusive breast-feeding and delayed weaning onto solid foods, have recently been called into question. The present review considers possible risk factors and theories for the development of FA. An alternative hypothesis is proposed, suggesting that early cutaneous exposure to food protein through a disrupted skin barrier leads to allergic sensitization and that early oral exposure to food allergen induces tolerance. Novel interventional strategies to prevent the development of FA are also discussed.

Update on risk factors for food allergy

2012-05-01

Asthma: The paradox of heterogeneity

Jeffrey M. Drazen — 2012-05-01

Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. It seems so simple. A 25-year-old, otherwise healthy woman with a history of multiple visits to an emergency department for asthma treatment in her childhood is in your office. She vaguely remembers using an inhaler every day when she “was little” but does not remember much else about it. She had no problems with her breathing from age 12 years until a few months ago, when she started to note increasing shortness of breath during her spinning sessions at the gym. She was ignoring this problem but now that she has a cold, she cannot sleep through the night because of wheeze and cough. Her history did not identify any environmental triggers, and the results of her skin test panel are negative. She has diffuse wheezes, her FEV1 is 60% of her predicted value, and with 2 puffs of albuterol, her FEV1 increases to 85% of her predicted value. She has asthma.

A fascinating look at the world with a new microscope

Erika von Mutius — 2012-02-10

In the mid-17th century in Delft, Antony Leeuwenhoek was the first to invent the microscope. He was enormously skilled in making lenses and mounted them on frames that would eventually become the first microscope, allowing a new look at tiny little things no one had seen before. Leeuwenhoek put everything he could possibly get hold of under his lenses and discovered a new form of life that no longer remained invisible to human eyes. This was the beginning of microbiology.

The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites

2012-05-01

The human body harbors 10 to 100 trillion microbes, mainly bacteria in our gut, which greatly outnumber our own human cells. This bacterial assemblage, referred to as the human microbiota, plays a fundamental role in our well-being. Deviations from healthy microbial compositions (dysbiosis) have been linked with important human diseases, including inflammation-linked disorders, such as allergies, obesity, and inflammatory bowel disease. Characterizing the temporal variations and community membership of the healthy human microbiome is critical to accurately identify the significant deviations from normality that could be associated with disease states. However, the diversity of the human microbiome varies between body sites, between patients, and over time. Environmental differences have also been shown to play a role in shaping the human microbiome in different cultures, requiring that the healthy human microbiome be characterized across life spans, ethnicities, nationalities, cultures, and geographic locales. In this article we summarize our knowledge on the microbial composition of the 5 best-characterized body sites (gut, skin, oral, airways, and vagina), focusing on interpersonal and intrapersonal variations and our current understanding of the sources of this variation.

Does “autoreactivity” play a role in atopic dermatitis?

Ting Seng Tang, Thomas Bieber, Hywel C. Williams — 2012-03-12

The role of autoimmunity in atopic dermatitis (AD) is unclear. We sought to critically examine the occurrence, correlation with severity, and possible causative role of autoreactivity in patients with AD. Our systematic review of studies identified from MEDLINE included 31 experiments that described autoreactivity in patients with AD. We defined autoreactivity as in vitro or in vivo evidence of immune response to autologous human, generic human, or recombinant human proteins or other tissue/cellular components. Autoreactivity prevalence in patients with AD ranged from 23% to 91% in 14 studies involving 2644 participants, although it did not appear to vary with age, sex, or disease duration. In contrast to studies of AD, IgE autoreactivity was not found in healthy subjects or in those with allergic rhinoconjunctivitis, psoriasis, systemic lupus erythematosus, or other inflammatory diseases (8 studies of 816 participants). Two reports found a positive correlation between autoreactivity and AD severity. We suggest that autoreactivity might be playing a causative role in AD based on the magnitude and specificity of the associations found; plausible mechanisms through IgE autoantibodies, IgG autoantibodies, and TH1 autoreactivity; and experimental elicitation of eczematous lesions after provocation. Whether autoantibodies contribute to AD chronicity now needs to be examined in longitudinal studies.

The Editors' Choice

Donald Y.M. Leung, Stanley J. Szefler, Associate Editors of the JACI — 2012-05-01

Intranasal corticosteroids (INSs) are the most effective therapy for the treatment of allergic rhinitis (AR). Little evidence exists to support the benefit of one INS over another. Furthermore, there is a paucity of head-to-head data involving INS therapy, with most studies focusing on patient preference and not on efficacy and safety. In the current issue of the Journal, Carr et al (p 1282) compare, for the first time, the efficacy of MP29-02 (a novel azelastine/fluticasone propionate formulation) with fluticasone propionate, azelastine, and placebo using the same formulation in 3398 patients with moderate-to-severe seasonal AR in 3 multicenter, randomized, double-blind, placebo-controlled, 14-day, parallel-group trials. In these 3 head-to-head comparisons, they reproducibly demonstrate that MP29-02 is significantly more effective than intranasal fluticasone or azelastine (see Figure). The improvement of MP29-02 over standard therapy was substantial, occurred faster (up to 5 days faster than fluticasone and up to 7 days faster than azelastine), and was more complete, with 1 of 8 MP29-02–treated patients exhibiting complete/near-complete symptom resolution. With this improved efficacy, there were no new safety concerns beyond those of currently marketed fluticasone and azelastine. Given these findings, MP29-02 can be considered the drug of choice for the treatment of AR.

Genome-wide association study of lung function decline in adults with and without asthma

2012-03-19

Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function.Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status.Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV1 and FEV1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study).Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10−6; replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 × 10−8), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline.Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.

Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma

2012-02-13

Background: Health care costs increase in patients with more severe asthma, but the effect of asthma exacerbations on costs among patients with more severe asthma has not been quantified.Objective: This study compared direct health care costs between patients with moderate/severe persistent asthma with and without exacerbations.Methods: Patients who had an asthma diagnosis (International Classification of Diseases–ninth revision–Clinical Modification code 493.x), were 12 to 64 years old, and were receiving controller therapy were identified from a large administrative claims database. Patients were categorized as having moderate/severe persistent asthma and were further evaluated for exacerbations during a 12-month exacerbation identification period. Patients with 1 or more exacerbations (asthma-related inpatient or emergency department visit or corticosteroid prescription) were matched to patients without exacerbations on demographic characteristics and asthma severity. Total and asthma-related health care costs during the 1-year study period after the exacerbation index date were calculated.Results: Patients with exacerbations had significantly higher total health care costs ($9223 vs $5011, P < .0001) and asthma-related costs ($1740 vs $847, P < .0001). The cost differences remained significant after controlling for patient differences by using multivariate models. Patients with exacerbations (n = 3830) had higher rates of sinusitis, allergy-related diagnoses or medications, pneumonia, and mental disorders and higher average Charlson Comorbidity Index scores at baseline. Patients with exacerbations filled their prescriptions for controllers more often and had higher asthma-related drug costs.Conclusions: Patients with moderate/severe persistent asthma who had exacerbations had higher total and asthma-related health care costs than those without exacerbations. Moreover, controller medication use was higher in patients with exacerbations.

Influence of maternal asthma on the cause and severity of infant acute respiratory tract infections

2012-02-16

Background: Respiratory syncytial virus (RSV) and rhinovirus infections are the most common significant infant respiratory tract illnesses and are associated with increased but differential risks of childhood asthma.Objective: We sought to determine whether maternal asthma is associated with higher odds of infant respiratory tract infection with rhinovirus versus RSV and increased infection severity.Methods: Mother-infant dyads were enrolled from 2004-2008 during an infant respiratory tract infection (104 with rhinovirus and 279 with RSV). Mothers were classified into mutually exclusive groups (atopic asthma, nonatopic asthma, and no asthma). We determined viral cause using PCR and the severity of the infant’s respiratory tract infection using the bronchiolitis severity score. Adjusted relative odds of maternal asthma with viral cause were calculated by using logistic regression. Proportional odds models assessed the association of maternal asthma and infant infection severity.Results: Infants with a mother with atopic asthma compared with infants whose mothers did not have asthma were more likely to have rhinovirus versus RSV infection (adjusted odds ratio, 2.42; 95% CI, 1.19-4.90). Similarly, among infants with rhinovirus, having a mother with atopic asthma was associated with increased infection severity (adjusted odds ratio, 3.10; 95% CI, 1.21-7.98). This relationship was not seen among infants with RSV.Conclusions: Clinically significant rhinovirus infection during infancy was more strongly associated with having a mother with atopic asthma than clinically significant RSV infection. Having a mother with atopic asthma was associated with increased severity of infant rhinovirus but not RSV infections. Infants with rhinovirus were more likely to have a familial atopic predisposition, which might partly explain the subsequent increased asthma risk.

Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma

2012-02-13

Background: The effects of serum vitamin D status on atopy, steroid requirement, and functional responsiveness to corticosteroids in children versus adults with asthma have not been studied systematically.Objective: We sought to explore the age-specific effects of vitamin D in asthmatic patients.Methods: Serum vitamin D levels were examined in a prospective study of adults and children (102 healthy control subjects and 103 asthmatic patients). PBMCs were cultured for 3 hours with or without 100 nmol/L dexamethasone, and the expression of corticosteroid-regulated genes was detected by using real-time PCR. Serum IgE levels were measured, and information about asthmatic patients’ steroid requirements was collected.Results: Deficient serum vitamin D levels (<20 ng/mL) were found in 47.6% of asthmatic patients and 56.8% of healthy control subjects, with means ± SDs of 20.7 ± 9.8 and 19.2 ± 7.7 ng/mL, respectively. In multivariate regression models a significant positive correlation between serum vitamin D levels and the expression of vitamin D–regulated targets, cytochrome P450, family 24, subfamily a (cyp24a) expression by PBMCs (P = .0084, pediatric asthma group only) and serum LL-37 levels (P = .0006 in the pediatric group but P = .0067 in the adult asthma group), was found. An inverse association between vitamin D and serum IgE levels was observed in the pediatric (P = .006) asthma group. Serum vitamin D level (P = .05), as well as PBMC cyp24a expression (P = .0312), demonstrated a significant inverse relationship with daily inhaled corticosteroid dose in the pediatric asthma group only. Cyp24a expression in PBMCs correlated positively with in vitro suppression of TNF-α by dexamethasone (P = .05) and IL-13 (P = .0094) in PBMCs in the pediatric asthma group only.Conclusions: This study demonstrated significant associations between serum vitamin D status and steroid requirement and in vitro responsiveness to corticosteroids in the pediatric but not the adult asthma group. Vitamin D was also related to IgE levels in children but not in adults.

Age-related differences in clinical outcomes for acute asthma in the United States, 2006-2008

Chu-Lin Tsai, Wen-Ya Lee, Nicola A. Hanania, Carlos A. Camargo — 2012-03-02

Background: Little is known about the effect of age on acute asthma outcomes.Objective: We sought to investigate age-related differences in the emergency department (ED) presentation and clinical outcomes for patients with acute asthma.Methods: We analyzed the 2006-2008 Nationwide Emergency Department Sample, the largest, all-payer, US ED and inpatient database. ED visits for acute asthma were identified with a principal diagnosis of International Classification of Disease, ninth revision, Clinical Modification code 493.xx. Patients were divided into 3 age groups: children (<18 years), younger adults (18-54 years), and older adults (≥55 years). The outcome measures were in-hospital all-cause mortality, near-fatal asthma-related events (noninvasive or mechanical ventilation), hospital charges, admission rates, and hospital length of stay.Results: There were an estimated 1,813,000 visits annually for acute asthma from approximately 4,700 EDs. The estimated overall annual number of in-hospital asthma-related deaths was 1,144 (0.06%); 101 died in the ED, and 1,043 died as inpatients. By age group, there were 37 asthma-related deaths per year in children, 204 in younger adults, and 903 in older adults. Compared with younger adults, older adults had higher mortality, had higher rates of near-fatal asthma-related events, had higher hospital charges, were more likely to be hospitalized, and had a longer hospital length of stay (P < .001 for all). After adjusting for comorbidities, older asthmatic patients had a 5-fold increased risk of overall mortality (adjusted odds ratio, 5.2; 95% CI, 4.0-6.9), compared with younger adults.Conclusions: Older adults with acute asthma have a substantial burden of morbidity and mortality. With the US population aging, there is an urgent need for targeted interventions for this high-risk population.

An ex vivo model of severe asthma using reconstituted human bronchial epithelium

2012-03-12

Background: Structural changes to the airways are features of severe asthma. The bronchial epithelium facilitates this remodeling process. Learning about the changes that develop in the airway epithelium could improve our understanding of asthma pathogenesis and lead to new therapeutic approaches.Objective: We sought to determine the feasibility and relevance of air-liquid interface cultures of bronchial epithelium derived from endobronchial biopsy specimens of patients with different severities of asthma for studying the airway epithelium.Methods: Human bronchial epithelial cells derived from endobronchial biopsy specimens of patients with mild and severe asthma were maintained in culture for 21 days in an air-liquid interface to reproduce a fully differentiated airway epithelium. Initially, features of remodeling that included epithelial and subepithelial layers, as well as mucus production, were assessed in paraffin-embedded endobronchial biopsy specimens to evaluate morphologic characteristics of asthmatic patients’ epithelia. Ex vivo differentiated epithelia were then analyzed for morphology and function based on ultrastructural analysis, IL-8 release, lipoxin A4 generation, mucin production, and lipoxygenase gene expression.Results: Morphologic and inflammatory imbalances initially observed in endobronchial biopsy specimens obtained from patients with severe or mild asthma persisted in the air-liquid interface reconstituted epithelium throughout the differentiation process to 21 days. Epithelium from patients with severe asthma produced greater levels of mucin, released more IL-8, and produced lower levels of lipoxin A4 than that from patients with mild asthma. Expression of 15-lipoxygenase 2 was increased in epithelium from patients with severe asthma, whereas expression levels of MUC5AC, MUC5B, 5-lipoxygenase, and 15-lipoxygeanse 1 were similar to those of patients with mild asthma.Conclusion: Ex vivo cultures of fully differentiated bronchial epithelium from endobronchial biopsy specimens maintain inherent phenotypic differences specifically related to the severity of asthma.

Antiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life

2012-03-29

Background: Viral respiratory tract infections are the leading cause of acute illness during infancy and are closely linked to chronic inflammatory airway diseases later in life. However, the determinants of susceptibility to acute respiratory tract infections still need to be defined.Objective: We investigated whether the individual variation in antiviral response at birth determines the risk for acute respiratory tract illness in the first year of life.Methods: We studied 82 children who were enrolled in a birth cohort study of inner-city children with at least 1 parent with allergy or asthma. We cultured cord blood monocytes and assessed IFNG and CCL5 mRNA production at 24 hours after inoculation with respiratory syncytial virus. We also monitored the frequency of acute respiratory tract illness at 3-month intervals and analyzed nasal lavage samples for respiratory tract viruses at the time of illness during the first year.Results: Respiratory tract infection was reported for 88% of subjects, and respiratory tract viruses were recovered in 74% of symptomatic children. We observed a wide range of antiviral responses in cord blood monocytes across the population. Furthermore, a decrease in production of IFNG (but not CCL5) mRNA in response to respiratory syncytial virus infection of monocytes was associated with a significant increase in the frequency of upper respiratory tract infections (r = −0.42, P < .001) and the prevalence of ear and sinus infections, pneumonias, and respiratory-related hospitalizations.Conclusion: Individual variations in the innate immune response to respiratory tract viruses are detectable even at birth, and these differences predict the susceptibility to acute respiratory tract illness during the first year of life.

The relationship between combination inhaled corticosteroid and long-acting β-agonist use and severe asthma exacerbations in a diverse population

2012-01-27

Background: Safety concerns surround the use of long-acting β-agonists (LABAs) for the treatment of asthma, even in combination with inhaled corticosteroids (ICSs) and particularly in high-risk subgroups.Objective: To estimate the effect of ICS therapy and fixed-dose ICS/LABA combination therapy on severe asthma exacerbations in a racially diverse population.Methods: ICS and ICS/LABA exposure was estimated from pharmacy data for patients with asthma aged 12 to 56 years who were members of a large health maintenance organization. ICS and ICS/LABA use was estimated for each day of follow-up to create a moving window of exposure. Proportional hazard models were used to assess the relationship between ICS and ICS/LABA combination therapy and severe asthma exacerbations (ie, use of oral corticosteroids, asthma-related emergency department visit, or asthma-related hospitalization).Results: Among the 1828 patients who met the inclusion criteria, 37% were African American, 46% were treated with ICS therapy alone, and 54% were treated with an ICS/LABA combination. Models assessing the risk of severe asthma exacerbations among individuals using ICS treatment alone and ICS/LABA combination therapy suggested that the overall protective effect was as good or better for ICS/LABA combination therapy when compared with ICS treatment alone (hazard ratio, 0.65 vs 0.72, respectively). Analyses in several subgroups, including African American patients, showed a similar statistically significant protective association for combination therapy.Conclusion: Treatment with ICS/LABA fixed-dose combination therapy appeared to perform as well as or better than ICS treatment alone in reducing severe asthma exacerbations; this included multiple high-risk subgroups.

Combination inhaled corticosteroid and long-acting β2-agonist use and severe asthma exacerbations

Søren Pedersen, Paul M. O'Byrne — 2012-04-01

Over the last decade, the aims of asthma management have altered to focus on achieving and maintaining good asthma control and reducing future risks, such as decrease in lung function, asthma exacerbations, hospitalizations, death, and adverse effects from treatment. The benefits of good asthma control include a variety of asthma outcomes that are important to both patients and society. These include no restriction in lifestyle, better physical fitness and quality of life, reductions in patients' perception of the asthma burden, health care resource use, and lower risk of exacerbations, hospitalizations, and death.

A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis

2012-03-14

Background: Moderate-to-severe allergic rhinitis (AR) is a challenge to treat, with many patients using multiple therapies and achieving limited symptom control. More effective therapies must be developed and tested in well-controlled, randomized, prospective studies with a direct comparison to current standards.Objectives: The aim of these studies was to investigate the efficacy of MP29-02 (a novel formulation of azelastine and fluticasone propionate [FP]) in patients with moderate-to-severe seasonal allergic rhinitis (SAR) and to compare its efficacy with 2 first-line therapies (ie, intranasal azelastine and intranasal FP) in this population.Methods: Three thousand three hundred ninety-eight patients (≥12 years old) with moderate-to-severe SAR were enrolled into 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group trials (MP4002 [NCT00651118], MP4004 [NCT00740792], and MP4006 [NCT00883168]). Each trial was conducted for 14 days during different allergy seasons. The primary efficacy variable was the sum of the morning and evening change from baseline in reflective total nasal symptom score (range, 0-24) over the treatment period. Outcomes for the meta-analysis included efficacy according to disease severity and time to response in relevant responder criteria.Results: In the meta-analysis MP29-02 reduced the mean reflective total nasal symptom score from baseline (−5.7 [SD, 5.3]) more than FP (−5.1 [SD, 4.9], P < .001), azelastine (−4.4 [SD, 4.8], P < .001), or placebo (−3.0 [SD, 4.2], P < .001). This benefit was observed from the first day of assessment, with improvement in each individual nasal symptom, even in the patients with the most severe disease. MP29-02 achieved response consistently days earlier and showed greater efficacy in patients with moderate-to-severe rhinitis than FP and azelastine.Conclusions: MP29-02 represents a novel therapy that demonstrated superiority to 2 first-line therapies for AR. Patients with moderate-to-severe SAR achieved better control, and their symptoms were controlled earlier with MP29-02 than with recommended medications according to guidelines.

Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections

2012-04-01

Background: Subcutaneous allergen-specific immunotherapy frequently causes allergic side effects and requires 30 to 80 injections over 3 to 5 years.Objective: We sought to improve immunotherapy by using intralymphatic allergen administration (intralymphatic immunotherapy [ILIT]) and by targeting allergen to the MHC class II pathway.Methods: Recombinant major cat dander allergen Fel d 1 was fused to a translocation sequence (TAT) and to part of the human invariant chain, generating a modular antigen transporter (MAT) vaccine (MAT–Fel d 1). In a randomized double-blind trial ILIT with MAT–Fel d 1 in alum was compared with ILIT with placebo (saline in alum) in allergic patients (ClinicalTrials.gov NCT00718679).Results: ILIT with MAT–Fel d 1 elicited no adverse events. After 3 placebo injections within 2 months, nasal tolerance increased less than 3-fold, whereas 3 intralymphatic injections with MAT–Fel d 1 increased nasal tolerance 74-fold (P < .001 vs placebo). ILIT with MAT–Fel d 1 stimulated regulatory T-cell responses (P = .026 vs placebo) and increased cat dander–specific IgG4 levels by 5.66-fold (P = .003). The IgG4 response positively correlated with IL-10 production (P < .001).Conclusion: In a first-in-human clinical study ILIT with MAT–Fel d 1 was safe and induced allergen tolerance after 3 injections.

Mechanisms of IFN-γ–induced apoptosis of human skin keratinocytes in patients with atopic dermatitis

2012-03-27

Background: Enhanced apoptosis of keratinocytes is the main cause of eczema and spongiosis in patients with the common inflammatory skin disease atopic dermatitis (AD).Objective: The aim of the study was to investigate molecular mechanisms of AD-related apoptosis of keratinocytes.Methods: Primary keratinocytes isolated from patients with AD and healthy donors were used to study apoptosis by using annexin V/7-aminoactinomycin D staining. Illumina mRNA Expression BeadChips, quantitative RT-PCR, and immunofluorescence were used to study gene expression. In silico analysis of candidate genes was performed on genome-wide single nucleotide polymorphism data.Results: We demonstrate that keratinocytes of patients with AD exhibit increased IFN-γ–induced apoptosis compared with keratinocytes from healthy subjects. Further mRNA expression analyses revealed differential expression of apoptosis-related genes in AD keratinocytes and skin and the upregulation of immune system–related genes in skin biopsy specimens of chronic AD lesions. Three apoptosis-related genes (NOD2, DUSP1, and ADM) and 8 genes overexpressed in AD skin lesions (CCDC109B, CCL5, CCL8, IFI35, LYN, RAB31, IFITM1, and IFITM2) were induced by IFN-γ in primary keratinocytes. The protein expression of IFITM1, CCL5, and CCL8 was verified in AD skin. In line with the functional studies and AD-related mRNA expression changes, in silico analysis of genome-wide single nucleotide polymorphism data revealed evidence of an association between AD and genetic markers close to or within the IFITM cluster or RAB31, DUSP1, and ADM genes.Conclusion: Our results demonstrate increased IFN-γ responses in skin of patients with AD and suggest involvement of multiple new apoptosis- and inflammation-related factors in the development of AD.

Chronic urticaria and autoimmunity: Associations found in a large population study

2012-02-16

Background: Chronic urticaria (CU) is a common disease in which most cases were considered to be idiopathic. Recent evidence indicates that at least a subset of cases of chronic idiopathic urticaria are autoimmune in origin.Objective: We aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population.Methods: Data on 12,778 patients given a diagnosis of CU by either allergy or dermatology specialists during 17 years in a large health maintenance organization in Israel were collected. For each patient, we collected information on diagnosis of major, well-defined autoimmune diseases and autoimmunity- and inflammatory-related serologic markers. Similar data were collected for a control group comprised of 10,714 patients who visited dermatologists, family physicians, or allergy specialists and had no indication of CU.Results: Having CU was associated with an increased odds ratio for hypothyroidism, hyperthyroidism, and antithyroid antibodies. Female patients with CU had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the diagnosis of CU. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all significantly more prevalent in patients with CU.Conclusions: A strong association was found between CU and major autoimmune diseases. A common pathogenic mechanism is implied by the high prevalence of autoantibodies and the existence of a chronic inflammatory process expressed by the high mean platelet volume. These findings have implications for the diagnosis, management, and prognosis of patients with CU.

In situ imaging of honeybee (Apis mellifera) venom components from aqueous and aluminum hydroxide–adsorbed venom immunotherapy preparations

2011-11-21

Background: Treatment with aqueous and aluminum hydroxide (Al[OH]3)–adsorbed purified honeybee (Apis mellifera) venom (HBV) preparations can reduce the incidence of side effects associated with venom immunotherapy.Objective: The aim of the present study was to assess these purified HBV immunotherapy preparations in situ.Methods: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize the distribution of HBV components. The preparations were administered on the back legs of naive Wistar rats. The rats were killed, and cryosectioned tissue sections were subjected to hematoxylin and eosin staining and MALDI-MSI analyses.Results: Low-density maps of tissue distribution of HBV peptides, such as secapin, mast cell degranulating peptide, and melittin (Api m 4) were detected in the tissue after administration of HBV immunotherapy preparations. In addition, release of biogenic amines, cytokines, and leukotrienes was observed, and the distribution of HBV allergens, such as Api m 1 and Api m 2, was shown. At the 24-hour time point, the major HBV allergen Api m 1 was still detected at the site of Al(OH)3-adsorbed HVB injection, whereas in the case of aqueous HBV preparation, all the allergens, as well as most of the biogenic amines, were cleared at the 24-hour time point.Conclusion: The present study shows that the majority of low-molecular-weight HBV components are rapidly removed from the site of venom immunotherapy administration. Furthermore, Al(OH)3-adsorbed HBV preparation demonstrated a depot effect, prolonging the availability of bee venom allergens at the site of administration.

A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay

2012-03-26

Background: Peanut allergy is relatively common, typically permanent, and often severe. Double-blind, placebo-controlled food challenge is considered the gold standard for the diagnosis of food allergy–related disorders. However, the complexity and potential of double-blind, placebo-controlled food challenge to cause life-threatening allergic reactions affects its clinical application. A laboratory test that could accurately diagnose symptomatic peanut allergy would greatly facilitate clinical practice.Objective: We sought to develop an allergy diagnostic method that could correctly predict symptomatic peanut allergy by using peptide microarray immunoassays and bioinformatic methods.Methods: Microarray immunoassays were performed by using the sera from 62 patients (31 with symptomatic peanut allergy and 31 who had outgrown their peanut allergy or were sensitized but were clinically tolerant to peanut). Specific IgE and IgG4 binding to 419 overlapping peptides (15 mers, 3 offset) covering the amino acid sequences of Ara h 1, Ara h 2, and Ara h 3 were measured by using a peptide microarray immunoassay. Bioinformatic methods were applied for data analysis.Results: Individuals with peanut allergy showed significantly greater IgE binding and broader epitope diversity than did peanut-tolerant individuals. No significant difference in IgG4 binding was found between groups. By using machine learning methods, 4 peptide biomarkers were identified and prediction models that can predict the outcome of double-blind, placebo-controlled food challenges with high accuracy were developed by using a combination of the biomarkers.Conclusions: In this study, we developed a novel diagnostic approach that can predict peanut allergy with high accuracy by combining the results of a peptide microarray immunoassay and bioinformatic methods. Further studies are needed to validate the efficacy of this assay in clinical practice.

Effect of epinephrine on platelet-activating factor–stimulated human vascular smooth muscle cells

Peter Vadas, Boris Perelman — 2012-03-29

Background: Animal and human data show that platelet-activating factor (PAF) mediates the life-threatening manifestations of anaphylaxis. Although administration of epinephrine is the mainstay of therapy of acute anaphylaxis, the interaction between epinephrine and PAF has not been studied. In particular, the effect of the timing of epinephrine administration on the action of PAF has not been examined.Objective: Using human vascular smooth muscle cells (HVSMCs), we examined the effect of timing of epinephrine addition on the action of PAF.Methods: The effect of epinephrine on PAF-mediated prostaglandin E2 (PGE2) release from human aortic smooth muscle cells was examined. Epinephrine was added at various times before and after PAF stimulation.Results: HVSMCs stimulated with PAF released PGE2 in a concentration- and time-dependent manner. Whereas preincubation of HVSMCs with epinephrine before the addition of PAF suppressed PGE2 release, treatment with epinephrine after PAF stimulation was less effective with time after PAF stimulation. PGE2 release was suppressed by means of preincubation with 8-bromo–cyclic AMP and forskolin.Conclusions: PAF induced PGE2 release from HVSMCs in a concentration- and time-dependent manner, and early addition of epinephrine was essential for the control of PAF-induced PGE2 release. Epinephrine was most effective when administered before stimulation with PAF but was progressively less effective with time after PAF stimulation.

Relationship between red meat allergy and sensitization to gelatin and galactose-α-1,3-galactose

Raymond James Mullins, Hayley James, Thomas A.E. Platts-Mills, Scott Commins — 2012-04-05

Background: We have observed patients clinically allergic to red meat and meat-derived gelatin.Objective: We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test result, and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and galactose-α-1,3-galactose (α-Gal).Methods: Adult patients evaluated in the 1997-2011 period for suspected allergy/anaphylaxis to medication, insect venom, or food were skin tested with gelatin colloid. In vitro (ImmunoCAP) testing was undertaken where possible.Results: Positive gelatin test results were observed in 40 of 1335 subjects: 30 of 40 patients with red meat allergy (12 also clinically allergic to gelatin), 2 of 2 patients with gelatin colloid–induced anaphylaxis, 4 of 172 patients with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02-0.4 g), and 4 of 368 patients with drug allergy. Test results were negative in all patients with venom allergy (n = 241), nonmeat food allergy (n = 222), and miscellaneous disorders (n = 290). ImmunoCAP results were positive to α-Gal in 20 of 24 patients with meat allergy and in 20 of 22 patients with positive gelatin skin test results. The results of gelatin skin testing and anti–α-Gal IgE measurements were strongly correlated (r = 0.46, P < .01). α-Gal was detected in bovine gelatin colloids at concentrations of approximately 0.44 to 0.52 μg/g gelatin by means of inhibition RIA.Conclusion: Most patients allergic to red meat were sensitized to gelatin, and a subset was clinically allergic to both. The detection of α-Gal in gelatin and correlation between the results of α-Gal and gelatin testing raise the possibility that α-Gal IgE might be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, α-Gal, and gelatin (with or without clinical reactivity) remains uncertain.

Induction and suppression of allergic diarrhea and systemic anaphylaxis in a murine model of food allergy

2012-04-02

Background: The clinical manifestations of food allergy include diarrhea and systemic anaphylaxis (shock), which can occur together or by themselves in different subjects. Although ingested food antigens need to be absorbed to induce shock, it is not known whether they need to be absorbed to induce diarrhea.Objective: We sought to identify mechanisms that determine whether food allergy induces diarrhea versus shock and determine whether diarrhea requires absorption of ingested antigens.Methods: These issues were studied in mice in active, passive, and hybrid immunization models. The active model was used to determine the allergic diarrhea susceptibility of J chain– and polymeric immunoglobulin receptor–deficient mice, which are unable to secrete IgA. The hybrid model was used to determine whether intravenously administered antigen-specific IgG antibody, which is not secreted into the gut, can protect against allergic diarrhea, as well as shock.Results: Shock, but not diarrhea, was induced in naive mice by using intravenous IgE anti-trinitrophenyl (TNP) antibody, followed by oral TNP-BSA, whereas both were induced in mice presensitized with intraperitoneal ovalbumin/alum plus oral ovalbumin. More TNP-BSA was required to induce shock than diarrhea in presensitized mice, and intravenous IgG anti-TNP antibody, which is not secreted into the gut, protected these mice against both diarrhea and shock. Consistent with this, chicken ovalbumin–immunized J chain– and polymeric immunoglobulin receptor–deficient mice, which have high serum IgA levels but little intestinal IgA, resisted diarrhea induction.Conclusion: Intestinal immunity and oral antigen dose determine whether diarrhea, systemic anaphylaxis, or both are induced, and ingested antigen must be absorbed to induce either response.

Influence of cytomegalovirus infection on immune cell phenotypes in patients with common variable immunodeficiency

2012-03-26

Background: A subset of patients with common variable immunodeficiency (CVID) have debilitating inflammatory complications strongly associated with cytomegalovirus (CMV) infection and a hyperproliferative CMV-specific T-cell response.Objectives: We studied the T-cell response to CMV and the global effect of this virus on immune effector cell populations in patients with CVID.Methods: Antibody staining, peptide stimulation, and proliferation assays were used to profile CMV-specific T-cell function.Results: CMV infection drives the CD4/CD8 ratio inversion that is characteristic of CVID. The late effector CD8+ T-cell subset is expanded in CMV-infected patients with CVID. This expansion is largely attributable to CMV-specific cells and correlates with inflammatory disease; within the CMV-specific population, the frequency of late effector cells correlates inversely with the frequency of cells expressing programmed death 1. Supernatants from proliferating CMV-specific CD8+ cells from patients with inflammatory disease can confer proliferative potential on cells from patients with noninflammatory CVID and healthy subjects. Blocking experiments showed that this proliferation is mediated in part by IFN-γ and TNF-α.Conclusions: These data strengthen the association of CMV with inflammatory pathology in patients with CVID, explain some of the well-known T-cell abnormalities associated with this condition, and provide a plausible mechanism for the documented therapeutic activity of anti–TNF-α and antiviral chemotherapy in managing CVID-associated inflammatory disease.

Transcription factor E3, a major regulator of mast cell–mediated allergic response

2012-02-23

Background: Microphthalmia transcription factor, an MiT transcription family member closely related to transcription factor E3 (TFE3), is essential for mast cell development and survival. TFE3 was previously reported to play a role in the functions of B and T cells; however, its role in mast cells has not yet been explored.Objective: We sought to explore the role played by TFE3 in mast cell function.Methods: Mast cell numbers were evaluated by using toluidine blue staining. FACS analysis was used to determine percentages of Kit and FcεRI double-positive cells in the peritoneum of wild-type (WT) and TFE3 knockout (TFE3−/−) mice. Cytokine and inflammatory mediator secretion were measured in immunologically activated cultured mast cells derived from either knockout or WT mice. In vivo plasma histamine levels were measured after immunologic triggering of these mice.Results: No significant differences in mast cell numbers between WT and TFE3−/− mice were observed in the peritoneum, lung, and skin. However, TFE3−/− mice showed a marked decrease in the number of Kit+ and FcεRI+ peritoneal and cultured mast cells. Surface expression levels of FcεRI in TFE3−/− peritoneal mast cells was significantly lower than in control cells. Cultured mast cells derived from TFE3−/− mice showed a marked decrease in degranulation and mediator secretion. In vivo experiments showed that the level of plasma histamine in TFE3−/− mice after an allergic trigger was substantially less than that seen in WT mice.Conclusion: TFE3 is a novel regulator of mast cell functions and as such could emerge as a new target for the manipulation of allergic diseases.

Increased activation of fibrocytes in patients with chronic obstructive asthma through an epidermal growth factor receptor–dependent pathway

2012-02-13

Background: Fibrocytes are circulating progenitor cells that are increased in asthmatic patients with chronic obstructive asthma (COA) and rapid decrease in lung function. Fibrocytes from patients with COA have a greater capacity for proliferation and differentiation.Objective: We investigated whether epidermal growth factor receptor (EGFR) activation mediated the proliferation of fibrocytes in patients with COA and whether oxidative stress was involved in this activation.Methods: Circulating fibrocytes from nonadherent non–T-cell mononuclear cell fractions from healthy subjects, asthmatic patients with normal pulmonary function, and patients with COA were determined by using flow cytometric coexpression of collagen I, CD45, and CD34 or EGFR or a disintegrin and metalloprotease domain 17 and placed in culture.Results: Expression of EGFR was increased in fibrocytes from patients with COA compared with that seen in patients with NPF. AG1478 and gefitinib, inhibitors of EGFR tyrosine kinase, reduced fibrocyte proliferation and myofibroblast transformation. Increased expression of EGFR and fibrocyte proliferation and transformation were induced by hydrogen peroxide, and these effects were inhibited by N-acetylcysteine.Conclusions: Enhanced fibrocyte proliferation and transformation found in patients with COA might be mediated through an oxidant-sensitive EGFR-dependent pathway.

Naive T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel TH2 immunity

2012-03-29

Background: Sensitization to protease allergens, such as papain, or helminth infection is associated with basophil recruitment to draining lymph nodes (LNs). Basophils have the capacity to present antigen to naive T cells and promote TH2 differentiation directly or indirectly through IL-4 production.Objective: We studied how papain induces basophil migration to LNs and the contribution of various leukocytes to papain-induced immune responses.Methods: We immunized mice in the footpad with papain and studied leukocyte recruitment and inflammatory cytokine and chemokine production in the draining popliteal LNs.Results: Papain directly activated naive T cells through protease-activated receptor (PAR) 2 to initiate a chemokine/cytokine program that includes CCL17, CCL22, and IL-4. Papain-triggered innate immune responses were dependent on both CD4 T cells and PAR2 and were strongly reduced in the absence of CCR4, the primary receptor for CCL17/CCL22.Conclusion: These results elucidate a novel innate allergen-recognition pathway mediated by naive T cells through PAR2, which provide an immediate source of chemokines and IL-4 upstream of basophils and antigen-restricted TH2 differentiation. PAR2 antagonism might thus hold promise for the treatment of allergic disease.

Eosinophilic esophagitis: Epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment

2012-04-02

Background: Mechanisms underlying esophageal remodeling with subepithelial fibrosis in subjects with eosinophilic esophagitis (EoE) have not been delineated.Objectives: We sought to explore a role for epithelial mesenchymal transition (EMT) in subjects with EoE and determine whether EMT resolves with treatment.Methods: Esophageal biopsy specimens from 60 children were immunostained for epithelial (cytokeratin) and mesenchymal (vimentin) EMT biomarkers, and EMT was quantified. Subjects studied had EoE (n = 17), indeterminate EoE (n = 15), gastroesophageal reflux disease (n = 7), or normal esophagus (n = 21). EMT was analyzed for relationships to diagnosis, eosinophil counts, and indices of subepithelial fibrosis, eosinophil peroxidase, and TGF-β immunostaining. EMT was assessed in pretreatment and posttreatment biopsy specimens from 18 subjects with EoE treated with an elemental diet, 6-food elimination diet, or topical corticosteroids (n = 6 per group).Results: TGF-β1 treatment of esophageal epithelial cells in vitro for 24 hours induced upregulation of mesenchymal genes characteristic of EMT, including N-cadherin (3.3-fold), vimentin (2.1-fold), and fibronectin (7.5-fold). EMT in esophageal biopsy specimens was associated with EoE (or indeterminate EoE) but not gastroesophageal reflux disease or normal esophagus and was correlated to eosinophil counts (r = 0.691), eosinophil peroxidase (r = 0.738), and TGF-β (r = 0.520) immunostaining and fibrosis (r = 0.644) indices. EMT resolved with EoE treatments that induced clinicopathologic remission with reduced eosinophil counts. EMT decreased significantly after treatment by 74.1% overall in the 18 treated subjects with EoE; pretreatment versus posttreatment EMT scores were 3.17 ± 0.82 versus 0.82 ± 0.39 (P < .001), with similar decreases within treatment groups. Pretreatment/posttreatment EMT was strongly correlated with eosinophil counts for combined (r = 0.804, P < .001) and individual treatment groups.Conclusions: EMT likely contributes to subepithelial fibrosis in subjects with EoE and resolves with treatments that decrease esophageal inflammation, and its resolution correlates with decreased numbers of esophageal eosinophils.

The developmental trajectory of pediatric asthma in 3- to-10-year-olds

2012-02-10

Longitudinal studies have suggested that early childhood asthma follows different temporal trajectories. Children with early childhood recurrent wheezing frequently have “symptom- or disease-free” periods, followed by “relapse” of disease, or do not have diagnosed asthma for the first time until later childhood. Some children or young adults develop asthma for the first time later in life. However, the childhood trajectory and patterns of disease development and remittance are not well figuratively characterized. The objective of this study was to describe and figuratively present the pattern of first asthma diagnosis and remittance and to characterize the episodic nature of the disease by gender and race/ethnicity.

Relationship between complotype and reported severity of systemic allergic reactions to peanut

2012-02-13

Peanut allergy affects up to 3% of children, but the severity of systemic allergic reactions to peanut is variable, and fatal peanut-induced anaphylaxis is rare. The factors that determine the severity of allergic reactions to peanut are not clear, although reduced activity of platelet-activating factor acetylhydrolase has been reported. Recent murine data suggest that peanut extract activates complement more than other allergenic foods; this complement activation might influence sensitization to peanut or affect the threshold of reactivity, and it might be an important factor in the increased severity of clinical reactions seen with peanut compared with other food allergens. We tested the hypothesis that genetic variations in control of complement activation might be associated with the severity of reaction to peanut in children with primary peanut allergy. We evaluated all known polymorphic variants in the regulatory complement Factors H, B, and C3, which have previously been associated with alterations in complement activation and with disease risk in human subjects, including polypoidal choroidal vasculopathy, meningococcal disease, and age-related macular degeneration.

Effect of precautionary statements on the purchasing practices of Canadians directly and indirectly affected by food allergies

2012-03-15

Precautionary labeling advises consumers that a priority allergen might be inadvertently present in a food, even though it is not listed as an ingredient. Although several publications have examined how precautionary statements influence the purchasing behavior of informed allergic consumers recruited from allergists’ offices or food advocacy associations, none have examined how these statements might influence the behavior of subjects with food allergy recruited from the general public. Furthermore, the attitudes of consumers who are indirectly affected by food allergy because they purchase or prepare food for an allergic subject outside of their households have never been explored. Here we describe the effect of precautionary statements on the purchasing habits of Canadian consumers either directly or indirectly affected by food allergy. Our study also included participants randomly sampled from the general population and examined sociodemographic factors potentially associated with purchasing behaviors.

CD203c expression–based basophil activation test for diagnosis of wheat-dependent exercise-induced anaphylaxis

2012-04-01

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a special form of wheat allergy induced by the combination of wheat ingestion and physical exercise. We previously identified wheat ω-5 gliadin, a component of the water/salt-insoluble protein (gluten), as a major allergen in patients with WDEIA. Recently, increased incidence of a new WDEIA subtype caused by hydrolyzed wheat protein (HWP) has been observed. We have encountered several patients with WDEIA who were sensitized to HWP primarily through percutaneous routes, rhinoconjunctival routes, or both by using HWP-containing facial soaps. Patients with this type of WDEIA showed HWP-positive results in a skin prick test (SPT) and had serum HWP-specific IgE. In addition, these patients had characteristic features of facial angioedema distinct from those seen in patients with conventional WDEIA (CO-WDEIA). Thus they were designated as having WDEIA sensitized by HWP (HWP-WDEIA). We examined the sera of several patients with HWP-WDEIA using the CAP-FEIA (Phadia, Uppsala, Sweden; detection range, 0.35-100 kUA/L) and found that these patients have no or only low levels of ω-5 gliadin–specific IgE.

High sensitivity of CAP-FEIA rVes v 5 and rVes v 1 for diagnosis of Vespula venom allergy

2012-01-27

Ves v 5 (antigen 5) is a 23-kDa protein from Vespula venom, and it is recognized as the most potent allergen in venoms of the Vespidae family. There is a high sequence similarity of Ves v 5 within species of the same genus, such as yellow jacket, that is, Vespula (>95%); however, when it is compared with other genera such as Dolichovespula or Polistes, the sequence identity is much lower (about 60%). Another potential Vespula allergen is a 37-kDa phospholipase A1, known as Ves v 1. Neither Ves v 5 nor Ves v 1 is found in honeybee venom. Ves v 5 and Ves v 1 recombinant allergen components, both expressed in insect cells, became available in 2010 and 2011, respectively, for analyses on the ImmunoCAP solid-phase IgE assay (CAP-FEIA; Phadia, Uppsala, Sweden).

Specific allergen concentration of WHO and FDA reference preparations measured using a multiple allergen standard

2012-01-27

Allergen measurements require well-defined allergen standards. Allergists rely on these measurements for dosing patients on immunotherapy with the aim of achieving maintenance doses of 5 to 20 μg of specific allergen that have been associated with clinical efficacy. Allergists need to know that allergen measurements made by manufacturers are consistent and can reliably be used in clinical practice. Allergen measurements are widely used in the indoor air quality industry to assess exposure in homes, the workplace, schools, and commercial buildings. They are routinely used for assessing health risks associated with allergen exposure, for assessing the efficacy of allergen avoidance procedures, and for developing new allergen control products.

Increased serum CRH levels with decreased skin CRHR-1 gene expression in psoriasis and atopic dermatitis

2012-02-23

Autoimmune skin diseases, such as psoriasis and atopic dermatitis (AD), are chronic inflammatory skin disorders mediated primarily by T cells, but mast cells are also implicated. Symptoms of both psoriasis and AD worsen with stress. Acute stress leads to increased vascular permeability and inflammation of skin, through mast-cell activation by corticotropin-releasing hormone (CRH) both in rodents and in humans. CRH and CRH receptor 1 (CRHR-1) are both expressed in human skin, leading to the hypothesis that CRH may be involved in the pathophysiology of skin diseases.

Epistatic interaction between Toll-like receptor 3 (TLR3) and prostaglandin E receptor 3 (PTGER3) genes

2012-03-15

We previously reported that conjunctival eosinophilic infiltration in murine experimental allergic conjunctivitis (EAC) was significantly less marked in Toll-like receptor 3 gene (TLR3) knockout (KO) mice and significantly more marked in prostaglandin E receptor 3 (EP3) gene (PTGER3) KO mice than in wild-type mice. Considering the opposite roles of TLR3 and EP3 in allergic conjunctivitis, we speculate the possibility of unknown functional interaction between TLR3 and EP3.

Esophageal eosinophilia caused by milk proteins: From suspicion to evidence based on 2 case reports

2012-04-01

The First International Gastrointestinal Eosinophilic Research Symposium defined eosinophilic esophagitis (EoE) as a primary clinicopathologic disorder of the esophagus characterized by esophageal symptoms, upper gastrointestinal tract symptoms, or both in association with esophageal mucosal biopsy specimens containing more than 15 intraepithelial eosinophils/high-power field (hpf) in 1 or more biopsy specimens and absence of pathologic gastroesophageal reflux disease, as evidenced by a normal pH-monitoring study of the distal esophagus or lack of response to high-dose proton pump inhibitor medication. EoE mostly occurs in male subjects (80%) and appears to have a common familial form and a strong association with atopy (70%). IgE and non-IgE immune mechanisms might cooperate in the pathogenesis of EoE, as supported by a series of recent studies.

Successful treatment of eosinophilic esophagitis with ciclesonide

2012-04-05

Swallowed topical steroids, allergen elimination diets, or both are the primary treatment for patients with eosinophilic esophagitis (EoE). To date, 2 steroid preparations, fluticasone and budesonide, have been shown to offer therapeutic benefit for patients with EoE. Clinical experience suggests that some patients are unresponsive to either of these topical steroids. Whether this is related to inadequate dosing, improper technique of administration, low steroid concentrations on the epithelial surface, genetically determined steroid unresponsiveness, or poor adherence is uncertain, but additional therapeutic options are necessary.

Oral food challenges in a practice setting apart from hospitals and academic centers

S. Allan Bock, Lois Cherrington — 2012-03-12

On reading the letter from Lieberman et al, it seemed interesting to compare the results of challenges performed in a private-practice setting not connected to an academic medical center or within a hospital facility. We perform about 12 to 15 open food challenges per month in an office setting. For comparison, we reviewed the last 100 challenges performed. The foods challenged were peanut, almond, walnut, pecan, hazelnut, cashew, pistachio, pine nut, egg, baked egg, milk, baked milk, shrimp, scallops, lobster, soy, sesame, and wheat. Challenges were performed in patients 3 to 18 years of age. Sixty percent were male. Criteria for selection included no reaction to the selected foods in the previous year and no history of anaphylaxis.

Reply

Jay A. Lieberman, Amanda L. Cox, Michelle Vitale, Hugh A. Sampson — 2012-03-12

We appreciate the comments by Bock and Cherrington regarding our report on the outcomes of office-based, open oral food challenges. We understand that many allergists are concerned about performing oral food challenges when their practice is not in close proximity to a hospital or emergency department and therefore welcome these data reported by Dr Bock favoring the safety of office-based oral food challenges.

Food allergy diagnostic practice in Italian children

2012-04-01

The recently published letter on the anonymous survey on the practices of oral food challenges (OFCs) among allergists in the United States revealed that 69.9% of allergists perform 1 to 5 OFCs per months and that open nonblinded challenges are most commonly performed (87.6%).

Correction

2012-05-01

With regard to 2012 AAAAI Annual Meeting abstract 576, “Hypovitaminosis D is Very Frequent but not Associated with Asthma Control in a Low-Income Pediatric Population Seen in an Allergy and Immunology Clinic” (J Allergy Clin Immunol 2012;129:AB153), several coauthors were not listed in the published version. The authors are F Neagu, K Lindgren, M Merchant-Uddin, and B Yu, from Rush University Medical Center and John H. Stroger Jr Hospital of Cook County, Chicago, Illinois.

Common variable immunodeficiency

Charlotte Cunningham-Rundles, Paul J. Maglione — 2012-05-01

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below:

The Journal of Allergy and Clinical Immunology

Cover 1

Brief Overview of This Month's JACI

Table of Contents

Editorial Board

Information for Readers

News & Notes

CME Activities Calendar

News Beyond Our Pages

A European perspective on immunotherapy for food allergies

A European perspective on immunotherapy for food allergies

Update on risk factors for food allergy

Update on risk factors for food allergy

Asthma: The paradox of heterogeneity

A fascinating look at the world with a new microscope

The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites

Does “autoreactivity” play a role in atopic dermatitis?

The Editors' Choice

Genome-wide association study of lung function decline in adults with and without asthma

Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma

Influence of maternal asthma on the cause and severity of infant acute respiratory tract infections

Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma

Age-related differences in clinical outcomes for acute asthma in the United States, 2006-2008

An ex vivo model of severe asthma using reconstituted human bronchial epithelium

Antiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life

The relationship between combination inhaled corticosteroid and long-acting β-agonist use and severe asthma exacerbations in a diverse population

Combination inhaled corticosteroid and long-acting β2-agonist use and severe asthma exacerbations

A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis

Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections

Mechanisms of IFN-γ–induced apoptosis of human skin keratinocytes in patients with atopic dermatitis

Chronic urticaria and autoimmunity: Associations found in a large population study

In situ imaging of honeybee (Apis mellifera) venom components from aqueous and aluminum hydroxide–adsorbed venom immunotherapy preparations

A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay

Effect of epinephrine on platelet-activating factor–stimulated human vascular smooth muscle cells

Relationship between red meat allergy and sensitization to gelatin and galactose-α-1,3-galactose

Induction and suppression of allergic diarrhea and systemic anaphylaxis in a murine model of food allergy

Influence of cytomegalovirus infection on immune cell phenotypes in patients with common variable immunodeficiency

Transcription factor E3, a major regulator of mast cell–mediated allergic response

Increased activation of fibrocytes in patients with chronic obstructive asthma through an epidermal growth factor receptor–dependent pathway

Naive T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel TH2 immunity

Eosinophilic esophagitis: Epithelial mesenchymal transition contributes to esophageal remodeling and reverses with treatment

The developmental trajectory of pediatric asthma in 3- to-10-year-olds

Relationship between complotype and reported severity of systemic allergic reactions to peanut

Effect of precautionary statements on the purchasing practices of Canadians directly and indirectly affected by food allergies

CD203c expression–based basophil activation test for diagnosis of wheat-dependent exercise-induced anaphylaxis

High sensitivity of CAP-FEIA rVes v 5 and rVes v 1 for diagnosis of Vespula venom allergy

Specific allergen concentration of WHO and FDA reference preparations measured using a multiple allergen standard

Increased serum CRH levels with decreased skin CRHR-1 gene expression in psoriasis and atopic dermatitis

Epistatic interaction between Toll-like receptor 3 (TLR3) and prostaglandin E receptor 3 (PTGER3) genes

Esophageal eosinophilia caused by milk proteins: From suspicion to evidence based on 2 case reports

Successful treatment of eosinophilic esophagitis with ciclesonide

Oral food challenges in a practice setting apart from hospitals and academic centers

Reply

Food allergy diagnostic practice in Italian children

Correction

Common variable immunodeficiency