The Journal of Allergy and Clinical Immunology

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2010-08-01

A Brief Overview of This Month's JACI

2010-08-01

Editorial Board

2010-08-01

Information for Readers

2010-08-01

Footnotes1

2010-08-01

This month, we interviewed one of the three newly-elected members of the Board of Directors.

CME Activities Calendar

2010-08-01

▪ 2010 Virtual Annual Meeting: The AAAAI is pleased to offer the 2010 Virtual Annual Meeting for your convenience. It will be available 365 days-a-year on Data DVD to be viewed at your discretion. Along with the DVD, you will receive online access to claim CME/CE credits. Earn over 100 CME or CE credits! To place your order, visit annualmeeting.aaaai.org and click on the “Virtual Annual Meeting” button.

News Beyond Our Pages

Marc E. Rothenberg, Jean Bousquet — 2010-08-01

Huber et al (J Immunol 2010, doi:10.4049/jimmunol.1000469) have delivered an unexpected finding: data supporting the possible use of IFN-α/β as a therapy for asthma and other atopic diseases. Contrary to findings in mice, the authors found that IFN-α/β does, in fact, act as a negative regulator of TH2 cell commitment. They demonstrated that IFN-α/β destabilized GATA-3 autoactivation, the process that maintains the TH2 environment after IL-4 secretion has diminished, by decreasing GATA-3 protein levels. Additionally, Huber et al found that IFN-α/β blocked expression of prostaglandin receptors on committed TH2 cells, suggesting that IFN-α/β might be effective in chronic atopic conditions. The authors suggested that currently available IFN-α/β therapy might be applied to allergy and asthma.Dr J. David Farrar, senior author, gave us this comment: “TH2 cells are remarkably stable in their ability to consistently secrete inflammatory cytokines because of their expression of the transcriptional master regulator GATA-3. In this study we discovered that this natural antiviral cytokine, IFN-α/β, can turn off cytokine expression in TH2 cells by downregulating GATA-3 expression. This puts us in an excellent position to investigate novel therapeutic approaches to atopic diseases involving IFN-α/β.”

Long-term studies of the natural history of asthma in childhood

Hans Bisgaard, Klaus Bønnelykke — 2010-08-01

Segmentation of children with asthma and other wheezy disorders remains the main research challenge today, as it was when described 2 centuries ago. Early childhood wheezy disorders follow different temporal trajectories, probably representing different underlying mechanisms (endophenotypes). Prospective identification of endophenotypes allowing accurate prediction of the clinical course is currently not possible. The variability of the clinical course remains an enigma and difficult to predict. Three of 4 school-aged children with asthma have outgrown disease by midadulthood. The risk of persistence increases with severity, sensitization, smoking, and female sex. Genetic risk variants might help disentangle the heterogeneity of asthma and other wheezy disorders. At early school age, children with asthma have reduced lung function. It is an important and unresolved question whether the airflow limitation associated with asthma already existed at birth or developed along with symptoms. Likewise, the association between the infant's bronchial responsiveness and development of asthma and other wheezy disorders is unclear. Neither primary prevention through manipulation of environmental factors nor secondary prevention through the use of inhaled corticosteroids can effectively halt the long-term disease progression in childhood. In conclusion, the natural history of asthma and the associated airway changes is still poorly understood, and we have not managed to translate findings from long-term studies into a deeper understanding of the underlying endophenotypes or improved disease management. We propose the need for a translational research approach based on long-term clinical studies of birth cohorts with comprehensive and objective assessments of intermediate phenotypes and environmental exposures combined with interdisciplinary basic research and a systems biology approach.

Long-term studies of the natural history of asthma in childhood

2010-08-01

Using genetics to predict the natural history of asthma?

John W. Holloway, Syed H. Arshad, Stephen T. Holgate — 2010-08-01

Clinical practice reminds us that there is considerable variability in the course of asthma over time. Treatment of patients with asthma would be considerably improved if one could accurately predict the likely course of disease over the life course. Recently, with the advent of the era of genome-wide association studies, there has been a monumental shift in our understanding of the genetic factors that underlie inherited susceptibility to asthma. Genes have been identified that modulate many aspects of the natural history of asthma, such as susceptibility to atopy, altered lung development, and susceptibility to more severe disease. Heritability studies have even suggested a role for genetic factors in remission of asthma. However, although the discovery of novel genetic factors underlying disease susceptibility has undoubtedly improved our understanding of disease pathogenesis, whether these advances have improved the ability to predict the natural history in individual patients is questionable, and the application of genetic testing to clinical practice remains some way off.

Using genetics to predict the natural history of asthma?

2010-08-01

The Asthma Predictive Index: A very useful tool for predicting asthma in young children

Jose A. Castro-Rodriguez — 2010-07-12

Recurrent wheezing is a common problem in young children: approximately 40% of children wheeze in their first year of life. However, only 30% of preschoolers with recurrent wheezing still have asthma at the age of 6 years. Nevertheless, asthma, the most prevalent chronic disease in children, is difficult to diagnose in infants and preschoolers. This article reviews the importance of determining at an early age which infants/preschoolers will have asthma later in life, analyzes the pros and cons of different predictive indices, and discusses the efficacy of the Asthma Predictive Index.

Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children

Milo F. Vassallo, Carlos A. Camargo — 2010-07-12

Epidemiologic data suggest that the incidence of food allergy (FA) is increasing among children, yet a satisfactory model of its pathogenesis remains elusive. FA is the consequence of maladaptive immune responses to common and otherwise innocuous food antigens. Concurrent with the increase in FA is an epidemic of vitamin D deficiency (VDD) caused by several factors, especially decreased sunlight/UVB exposure. There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity. We propose a “multiple-hit” model in which VDD in a developmentally critical period increases susceptibility to colonization with abnormal intestinal microbial flora and gastrointestinal infections, contributing to abnormal intestinal barrier permeability and excess and inappropriate exposure of the immune system to dietary allergens. A compounding effect (and additional “hit”) of VDD is the promotion of a pro-sensitization immune imbalance that might compromise immunologic tolerance and contribute to FA. We propose that early correction of VDD might promote mucosal immunity, healthy microbial ecology, and allergen tolerance and thereby blunt the FA epidemic in children.

The Editors' Choice

Donald Y.M. Leung, Stanley J. Szefler, Associate Editors of the JACI — 2010-08-01

As reported in this issue of the Journal, Simões et al (p 256) used protection by passively administered mAbs against respiratory syncytial virus (RSV) to separate the effects of RSV-induced lower respiratory tract infections and an atopic diathesis on subsequent recurrent wheezing. Although it has been known that RSV-induced lower respiratory tract infections in early life are associated with later airway hyperreactivity, it has been unclear whether there is a causal relationship. In a prospective, multicenter, matched study conducted in 27 centers in Europe and Canada, the authors compared the rates of physician-diagnosed recurrent wheezing in premature infants of less than 36 weeks' gestation who had not received palivizumab in the first year of life (see Figure). They found that in 146 palivizumab-treated infants compared with 171 untreated infants, the relative protective effect of palivizumab on physician-diagnosed recurrent wheezing through 2 to 5 years of age was 68% in those with no family history of asthma and 80% in those with no family history of atopy or food allergies (n = 101 palivizumab-treated subjects and 100 untreated subjects). In contrast, no effect was seen in the 90 children with a family history of atopy or food allergies in comparison with 130 untreated infants with atopic families. This suggests that RSV predisposes to recurrent wheezing in an atopy-independent mechanism.

A cluster-randomized trial to provide clinicians inhaled corticosteroid adherence information for their patients with asthma

2010-05-31

Background: Inhaled corticosteroid (ICS) nonadherence is common among patients with asthma; however, interventions to improve adherence have often been complex and not easily applied to large patient populations.Objective: To assess the effect of supplying patient adherence information to primary care providers.Methods: Patients and providers were members of a health system serving southeast Michigan. Providers (88 intervention; 105 control) and patients (1335 intervention; 1363 control) were randomized together by practice. Patients were age 5 to 56 years, had a diagnosis of asthma, and had existing prescriptions for ICS medication. Adherence was estimated by using prescription and fill data. Unlike clinicians in the control arm, intervention arm providers could view updated ICS adherence information on their patients via electronic prescription software, and further details on patient ICS use could be viewed by selecting that option. The primary outcome was ICS adherence in last 3 months of the study period.Results: At the study end for the intention-to-treat analysis, ICS adherence was not different among patients in the intervention arm compared with those in the control arm (21.3% vs 23.3%, respectively; P = .553). However, adherence was significantly higher among patients whose clinician elected to view their detailed adherence information (35.7%) compared with both control arm patients (P = .026) and intervention arm patients whose provider did not view adherence data (P = .002).Conclusions: Overall, providing adherence information to clinicians did not improve ICS use among patients with asthma. However, patient use may improve when clinicians are sufficiently interested in adherence to view the details of this medication use.

Gene-environment interactions influence airways function in laboratory animal workers

2010-06-25

Background: Most diseases, including asthma, result from the interaction between environmental exposures and genetic variants. Functional variants of CD14 negatively affect lung function in farm workers and children exposed to animal allergens and endotoxin.Objective: We hypothesized that CD14 polymorphisms interact with inhaled endotoxin, mouse allergen, or both to decrease airways function in laboratory animal workers.Methods: Three hundred sixty-nine Caucasian workers completed a symptom and work exposure questionnaire, skin prick testing, and spirometry. Individual exposure estimates for endotoxin and murine allergen were calculated by weighting task-based breathing zone concentrations by time reported for each task and length of time in the current job. Real-time PCR was used to assess CD14/−1619, −550, and −159 alleles. Multiple linear regression predicting airways function included an interaction term between genotype and exposure.Results: Workers at the highest quartile of the natural log-transformed cumulative endotoxin exposure and with the endotoxin-responsive CD14/−1619 G allele had significantly lower FEV1 and forced expiratory flow, midexpiratory phase (FEF25-75) percent predicted compared with workers with an AA genotype, with no significant differences noted at lower endotoxin levels for either genotype. The gene-environment effect was marked for atopic workers. Laboratory animal allergy, murine allergen exposure, CD14/−159 or −550 genotype, and a gene-exposure interaction term for these genotypes and exposures did not predict changes in lung function.Conclusions: A significant gene-environment interaction affects airways function in laboratory animal workers. More highly endotoxin-exposed workers with CD14/−1619G alleles have significantly lower FEV1 and FEF25-75 percent predicted than those with CD14/−1619AA alleles. Atopic workers are particularly affected by cumulative endotoxin exposures.

Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

2010-07-12

Background: The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation.Objective: We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility.Methods: A combination of gene resequencing for single nucleotide polymorphism (SNP) discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was used.Results: Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in lungs of asthmatic patients compared with those of nonasthmatic subjects (P < .05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in 3 case-control cohorts from Chicago and New York totaling 1,061 subjects (502 cases and 559 control subjects). The promoter SNP rs2038366 (−1557G/T) was found to be associated with asthma (P = .03) in European Americans. In African Americans an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.−164+170A/G; P = .006 and P = .040, respectively) and for promoter SNP rs59317557 (−532C/G) with severe asthma (P = .028). Consistent with predicted in silico functionality, alleles of the promoter SNPs rs2038366 (−1557G/T) and rs59317557 (−532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor) known to be increased in asthmatic airways.Conclusion: These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity.

Maternal dietary pattern during pregnancy is not associated with recurrent wheeze in children

2010-06-28

Background: The rise in asthma prevalence over the last few decades may be a result of changes in prenatal or early-life environment, including maternal diet during pregnancy. Previous studies have found associations between individual foods or nutrients consumed during pregnancy and asthma or wheeze in children, but these may be confounded by overall dietary pattern.Objective: To determine whether overall maternal dietary pattern during pregnancy is associated with recurrent wheeze in children.Methods: A total of 1376 mother-infant pairs from Project Viva, a longitudinal prebirth cohort, who had responses for food frequency questionnaires in the first and second trimester and outcome data at 3 years of age were included. Multivariable logistic regression was used to look at associations between dietary pattern and the primary outcome of recurrent wheeze at 3 years. Overall dietary pattern was examined by using Mediterranean diet score, Alternate Healthy Eating Index modified for pregnancy (AHEI-P), and principal components analysis to look at Western and Prudent diets.Results: None of these dietary patterns was associated with the primary outcome of recurrent wheeze in children in either the crude or the multivariable model (multivariable model, odds ratio per 1-point increase in Mediterranean diet, 0.98 [95% CI, 0.89-1.08]; AHEI-P, 1.07 [0.87-1.30]; Prudent, 1.02 [0.83-1.26]; Western, 0.98 [0.81-1.19]).Conclusion: Overall dietary pattern during pregnancy is not associated with recurrent wheeze in this cohort. Maternal intake of individual nutrients may be more important determinants of offspring wheeze-associated illness than is dietary pattern.

The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children

2010-07-12

Background: Although respiratory syncytial virus (RSV) lower respiratory tract infections (LRTIs) in early life are followed by later airway hyperreactivity, it is unclear whether there is a causal relationship between this and an atopic diathesis.Objectives: To separate the effects of RSV LRTI and an atopic diathesis on subsequent recurrent wheezing, we examined the protective effect of previous palivizumab administration against subsequent recurrent wheeze in infants with and without a family history of atopy.Methods: A prospective multicenter, matched, double cohort study was conducted in 27 centers in Europe and Canada. The rates of physician-diagnosed recurrent wheezing in premature infants <36 weeks gestation who had received palivizumab in the first year of life were compared to those of gestational age–matched controls.Results: The relative protective effect of palivizumab on physician-diagnosed recurrent wheezing through the ages of 2 to 5 years was 68% in those with no family history of asthma (odds ratio, 0.32; (95% CI, 0.14-0.75; N = 146 palivizumab-treated, 171 untreated) and 80% in those with no family history of atopy or food allergies (odds ratio, 0.20; 95% CI, 0.07-0.59; N = 101 palivizumab-treated, 100 untreated). In contrast, there was no effect of palivizumab on subsequent recurrent wheezing in the 90 children with a family history of atopy or food allergies compared to 130 untreated infants with atopic families.Conclusion: Respiratory syncytial virus prophylaxis in nonatopic children decreases by 80% the relative risk of recurrent wheezing but does not have any effect in infants with an atopic family history. This suggests that RSV predisposes to recurrent wheezing in an atopy-independent mechanism.

A randomized trial to test the effectiveness of art therapy for children with asthma

Anya Beebe, Erwin W. Gelfand, Bruce Bender — 2010-05-12

Background: Art therapy has been used to help children cope with chronic illness but has not been specifically tested with children who have asthma.Objective: To test an art therapy intervention in a randomized controlled trial in children with asthma.Methods: Twenty-two children with asthma were randomized to an active art therapy or wait-list control group. Those in the active art therapy group participated in 60-minute art therapy sessions once a week for 7 weeks. Sessions included specific art therapy tasks designed to encourage expression, discussion, and problem-solving in response to the emotional burden of chronic illness. Measures taken at baseline, immediately after, and 6 months after the final art therapy session included the Formal Elements Art Therapy Scale applied to the Person Picking an Apple from a Tree assessment, the parent and child versions of the Pediatric Quality of Life Asthma Module, and the Beck Youth Inventories. Those children assigned to the wait-list control group completed all evaluations at the same intervals as the children receiving art therapy but did not receive the art therapy interventions.Results: Score changes from baseline to completion of art therapy indicated (1) improved problem-solving and affect drawing scores; (2) improved worry, communication, and total quality of life scores; and (3) improved Beck anxiety and self concept scores in the active group relative to the control group. At 6 months, the active group maintained some positive changes relative to the control group including (1) drawing affect scores, (2) the worry and quality of life scores, and (3) the Beck anxiety score. Frequency of asthma exacerbations before and after the 6-month study interval did not differ between the 2 groups.Conclusion: This was the first randomized trial demonstrating that children with asthma receive benefit from art therapy that includes decreased anxiety and increased quality of life.

The Childhood Asthma Control Test∗: Retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma

2010-07-12

Background: The Childhood Asthma Control Test (C-ACT) has demonstrated validity in classifying children aged 4 to 11 years as having either “well-controlled” or “not well-controlled” asthma. However, new asthma management guidelines distinguish 3 levels of asthma control.Objective: We sought to determine a second cut point on the C-ACT to identify children with “very poorly controlled” asthma.Methods: Binomial logistic regression was performed on data from 671 children. The specialist's rating of control was the criterion measure. Specialists' severity ratings, specialists' assessment of therapy, and FEV1 percent predicted were used to assess the clinical validity of the cut point.Results: A cut point of 12 was selected because it correctly classified the highest percentage of participants (66.3%) as having “very poorly controlled” (vs “not well controlled”) asthma and demonstrated high specificity (89.8%) and moderate positive predictive value (69.1%). Children scoring 12 or less versus 13 to 19 had lower mean FEV1 percent predicted (79.8% vs 92.6%, P = .0002) and were more frequently stepped up in therapy (72.9% vs 53.6%, P = .0131) and rated as having severe asthma (13.6% vs 4.5%, P = .0005). One month later, significant differences in C-ACT scores and lung function between these 2 groups persisted. The mean C-ACT score of participants classified as “very poorly controlled” was significantly lower than that of participants classified as “not well-controlled” (17.2 vs 20.3, respectively; P = .0001).Conclusion: A second cut point of 12 or less on the C-ACT identifies children with the lowest level of control, who are at risk for poorer outcomes, and is conceptually consistent with the classification of “very poorly controlled” asthma adopted by asthma management guidelines.

Indoor pet exposure and the outcomes of total IgE and sensitization at age 18 years

2010-06-25

Background: Early-life exposure to household pets has been shown to be protective against allergic sensitization in childhood.Objective: We sought to evaluate the association between early-life pet exposure and allergic sensitization at age 18 years.Methods: Teenagers who had been enrolled in the Detroit Childhood Allergy Study birth cohort in 1987-1989 were contacted at age 18 years. Serum total and allergen-specific IgE levels to 7 common allergens (dust mite, cat, dog, ragweed, Timothy grass, Alternaria species, and peanut; atopy was defined as any specific IgE level ≥0.35 kU/L) were measured at age 18 years. Annual interview data from childhood were used to determine indoor dog and cat (≥50% of their time in the home) exposure during early life. Exposure was considered in various ways: first year, cumulative lifetime, and age groups, as well as multiple pets.Results: Dog or cat exposure in the first year of life was not associated with atopy (relative risk, 0.97; 95% CI, 0.83-1.12). Those living with pets in the first year and atopic at 18 years had lower total IgE levels. Neither cumulative exposure nor exposure at a particular age was strongly and consistently associated with either outcome. Although not statistically significant, there was a pattern of decreased odds of sensitization among those with 2 or more pets versus no pets in the first year of life.Conclusions: Early-life pet exposure can be associated with lower total IgE levels among atopic subjects but is not strongly associated with decreased likelihood of sensitization to common allergens at age 18 years.

Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells

2010-07-12

Background: CD4+CD25+ regulatory T (Treg) cells are involved in the downmodulation of numerous immune responses to pathogens, tumors, or allergens.Objective: In this study, we further characterized the nature of Treg cells that control skin inflammatory reactions to haptens.Methods: In a model of contact hypersensitivity to 2,4-dinitro-fluorobenzene, we have investigated the phenotype, the specificity, and the origin of Treg cells that modulate the priming of effector CD8+ T cells responsible for the development of the pathology.Results: 2,4-Dinitrofluorobenzene immunization induced a population of CD4+CD25+ Treg cells that controlled CD8+ T-cell effector responses in a hapten-specific manner in vivo. High levels of inducible costimulator (ICOS) expression defined a population of CD4+CD25+FoxP3+ (forkhead box protein 3) Treg cells that presented superior suppressive activity. Importantly, ICOS+ Treg cells were distinguishable from all other FoxP3+ Treg cells by the expression of IL-10, IL-17, and IFN-γ. Hapten-specific Treg cells proliferating in response to their cognate antigen in vivo predominantly displayed a CD25+FoxP3+ICOS+ phenotype. By using reporter mice, we showed that ICOS+ Treg cells derived from the expansion of natural CD4+FoxP3+ Treg cells rather than generation of adaptive Treg cells. Furthermore, the generation of ICOS+ Treg cells depended on innate cells rather than the effector CD8+ T-cell population.Conclusion: Taken together, our data show that a population of CD4+CD25+FoxP3+ T cells upregulates ICOS on in vivo sensitization and specifically suppresses hapten-reactive CD8+ T cells both in vivo and in vitro.

Thymic stromal lymphopoietin–activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis

2010-07-12

Background: Although invariant natural killer T (iNKT) cells have been shown to play a critical role in the pathogenesis of asthma, the role of iNKT cells in atopic dermatitis (AD) has not been well evaluated.Objective: We investigated whether iNKT cells in patients with AD increased and whether iNKT cells were activated by thymic stromal lymphopoietin (TSLP), which is highly expressed in keratinocytes of AD.Methods: We assessed the population of iNKT cells in PBMCs of patients with AD and healthy controls (HCs) using flow cytometry. Immunohistochemistry was used to evaluate iNKT cells and TSLP expression in AD and HC skin. We also evaluated whether iNKT cells expressed the TSLP receptor, the effects of TSLP on iNKT cells, and iNKT cell–dendritic cell interactions in a TSLP-rich environment.Results: There were more iNKT cells among PBMCs of patients with moderate to severe AD than mild AD (P < .05) and HC (P < .001). The number of iNKT cells was significantly larger in severe AD skin lesions than in mild (P < .001) or moderate AD skin lesions (P < .05). TSLP expression increased in lesional skin (P < .001) but not in the sera of patients with AD (P = .729) compared with HC. iNKT cells expressed TSLP receptor protein and mRNA. TSLP directly activated iNKT cells to secrete IL-4 and IL-13, and the concurrent addition of dendritic cells further activated IFN-γ expression.Conclusion: Increased iNKT cells activated by TSLP, especially in patients with severe AD, might play an essential role in the innate allergic immune response in AD.

Association between varicella zoster virus infection and atopic dermatitis in early and late childhood: A case-control study

2010-07-12

Background: Wild-type varicella zoster virus infection (WTVZV) early in childhood has been shown to protect against the development of asthma and atopy.Objective: To determine whether WTVZV in childhood protects against atopic dermatitis (AD).Methods: This retrospective, practice-based, case-control study randomly sampled 256 children and adolescents (age 1-18 years) with AD and 422 age-matched healthy controls from 2005 to 2007. Observations were made before the a priori hypothesis.Results: (1) A single episode of WTVZV in childhood is associated with decreased odds ratio (OR) of developing AD (conditional logistic regression; OR, 0.55; 95% CI, 0.34-0.89; P = .01). (2) When using intervals for age corresponding to bimodal distribution of age of WTVZV infection, the effects of WTVZV infection are significant when occurring at age 0 to 8 years (OR, 0.56; 95% CI, 0.35-0.90; P = .02), but not at 8 to 18 years (OR, 0.50; 95% CI, 0.19-1.31; P = .16). Considering 5-year intervals has similar findings. (3) WTVZV is associated with decreased odds of moderate AD (multinomial logistic regression; OR, 0.08, 95% CI, 0.04-0.15; P < .0001) or severe AD (OR, 0.04; 95% CI, 0.01-0.13; P < .0001). (4) WTVZV in children is associated with prolonged AD-free survival (Kaplan-Meier; median, 15.3 years; 95% CI, 10.9-18.0) compared with controls (median, 7.5 years; 95% CI, 4.8-11.9; log-rank test, P < .0001). (5) Children with WTVZV, compared with vaccine, who eventually develop AD require fewer pediatrician sick visits for management of AD (logistic regression; OR, 0.17; 95% CI, 0.06-0.51; P = .001).Conclusion: WTVZV in childhood protects up to 10 years of age against AD, delays onset of AD symptoms, and decreases AD severity and office visits.

Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway

2010-07-12

Background: Although implicated in the disease, the specific contributions of FcεRI and IL-13 to the pathogenesis of peanut-induced intestinal allergy are not well defined.Objectives: We sought to determine the contributions of FcεRI, IL-13, and mast cells to the development of intestinal mucosal responses in a murine model of peanut-induced intestinal allergy.Methods: Sensitized wild-type (WT), FcεRI-deficient (FcεRI−/−), and mast cell–deficient (KitW-sh/W-sh) mice received peanut orally every day for 1 week. Bone marrow–derived mast cells (BMMCs) from WT, FcεRI−/−, IL-4−/−, IL-13−/−, and IL-4/IL-13−/− mice were differentiated and transferred into WT, FcεRI−/−, and KitW-sh/W-sh recipients. BMMCs from WT and UBI-GFP/BL6 mice were differentiated and transferred into WT and KitW-sh/W-sh mice. Blockade of IL-13 was achieved by using IL-13 receptor α2 (IL-13Rα2)–IgG fusion protein.Results: FcεRI−/− mice showed decreased intestinal inflammation (mast cell and eosinophil numbers) and goblet cell metaplasia and reduced levels of IL4, IL6, IL13, and IL17A mRNA expression in the jejunum. Transfer of WT BMMCs to FcεRI−/− recipients restored their ability to develop intestinal allergic responses unlike transfer of FcεRI−/−, IL-13−/−, or IL-4/IL-13−/− BMMCs. FcεRI−/− mice exhibited lower IL-13 levels and treatment of WT mice with IL-13 receptor α2 prevented peanut-induced intestinal allergy and inflammation.Conclusions: These data indicate that the development of peanut-induced intestinal allergy is mediated through a mast cell–dependent IgE–FcεRI–IL-13 pathway. Targeting IL-13 might be a potential treatment for IgE-mediated peanut-induced allergic responses in the intestine.

Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine

2010-06-25

Background: Because influenza vaccine contains some residual egg protein, there is a theoretic risk of anaphylaxis when vaccinating patients with egg allergy. The objective of this study was to estimate the risk of anaphylaxis in children with egg allergy administered an adjuvanted monovalent 2009 pandemic influenza A/H1N1 influenza vaccine (Arepanrix; GlaxoSmithKline, Mississauga, Ontario, Canada).Methods: Patients with confirmed egg allergy with a history of respiratory or cardiovascular reactions after egg ingestion were vaccinated in 2 divided doses (10% and 90%) administered at a 30-minute interval, whereas children with other types of egg-induced allergic reactions were vaccinated with a single dose. All patients remained under observation for 60 minutes after vaccination. A 24-hour follow-up telephone call was made to detect any delayed reaction. The main outcome was the occurrence of an anaphylactic reaction according to criteria specified by the Brighton Collaboration.Results: Among the 830 patients with confirmed egg allergy, only 9% required the vaccine to be administered in divided doses. No patient had an anaphylactic reaction. Nine patients had minor allergic symptoms treated with an antihistamine (1 in the 60 minutes after vaccination and 8 in the following 23 hours), and 3 others received salbutamol (1 in the first 60 minutes after vaccination). Further vaccination of more than 3600 other children with reported egg allergy caused no anaphylaxis based on the criteria of the Brighton Collaboration, although 2 patients received epinephrine for symptoms compatible with allergy.Conclusion: Although anaphylaxis after influenza immunization is a theoretic risk, vaccination of patients with egg allergy with an adjuvanted monovalent pH1N1 influenza vaccine resulted in no cases of anaphylaxis and on that basis appears safe.

A population-based questionnaire survey on the prevalence of peanut, tree nut, and shellfish allergy in 2 Asian populations

2010-07-12

Background: There has been a substantial increase in the prevalence of peanut and tree nut allergy in Western populations in the last 2 decades. However, there is an impression that peanut and tree nut allergy is relatively uncommon in Asia.Objective: To evaluate the prevalence of peanut, tree nut, and shellfish allergy in schoolchildren in 2 Asian countries (Singapore and Philippines).Methods: A structured written questionnaire was administered to local and expatriate Singapore (4-6 and 14-16 years old) and Philippine (14-16 years old) schoolchildren.Results: A total of 25,692 schoolchildren responded to the survey (response rate, 74.2%). Of these, 23,425 responses fell within the study protocol's 4 to 6 and 14 to 16 year age groups and were included in the analysis. The prevalence of convincing peanut and tree nut allergy were similar in both local Singapore (4-6 years, 0.64%, 0.28%; 14-16 years, 0.47%, 0.3%, respectively) and Philippine (14-16, 0.43%, 0.33%, respectively) schoolchildren, but was higher in the Singapore expatriates (4-6 years, 1.29%, 1.12%; 14-16 years, both 1.21%, respectively; 4-6 years, expatriates vs local Singaporeans: peanut, P = .019; tree nut, P = .0017; 14-16 years, P > .05). Conversely, shellfish allergy was more common in the local Singapore (4-6 years, 1.19%; 14-16 years, 5.23%) and Philippine (14-16 years, 5.12%) schoolchildren compared with expatriate children (4-6 years, 0.55%; 14-16 years, 0.96%; P < .001). When data were pooled, respondents born in Western countries were at higher risk of peanut (adjusted odds ratios [95% CIs]: 4-6 years, 3.47 [1.35-8.93]; 14-16 years, 5.56 [1.74-17.76]) and tree nut allergy (adjusted odds ratios [95% CIs]: 4-6 years, 10.40 [1.61-67.36]; 14-16 years, 3.53 [1.00-12.43]) compared with those born in Asia.Conclusion: This study substantiates the notion that peanut and tree nut allergy is relatively low in Asian children, and instead shellfish allergy predominates. Environmental factors that are yet to be defined are likely to contribute to these differences.

Impaired T-cell receptor activation in IL-1 receptor–associated kinase-4–deficient patients

2010-07-12

Background: IL-1 receptor–associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.Objective: We sought to evaluate T-cell function in IRAK-4 deficient patients.Methods: We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-γ after stimulation of PBMCs from 4 IRAK-4–deficient patients and healthy control subjects with anti-CD3 and anti-CD28.Results: Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-γ, but not IL-2, was significantly reduced in IRAK-4–deficient patients.Conclusions: IRAK-4–deficient patients have defects in T-cell activation.

Gene-gene interaction in regulatory T–cell function in atopy and asthma development in childhood

2010-07-05

Background: Regulatory T–cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes involved in the development and function of regulatory T cells are associated with atopy and asthma development.Objective: To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T–cell function—IL6, IL6R, IL10, heme-oxygenase 1 (HMOX1), IL2, Toll-like receptor 2 (TLR2), TGFB1, TGF-β receptor (TGFBR)–1, TGFBR2, IL2RA, and forkhead box protein 3 (FOXP3)—in relation to atopy and asthma.Methods: Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by χ2 tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study).Results: Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications.Conclusion: Genes involved in the development and function of regulatory T cells, specifically IL2RA, TLR2, TGFBR2, and FOXP3, associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.

Expression of IL-4 receptor α on smooth muscle cells is not necessary for development of experimental allergic asthma

2010-06-25

Background: Airflow in the lungs of patients with allergic asthma is impaired by excessive mucus production and airway smooth muscle contractions. Elevated levels of the cytokines IL-4 and IL-13 are associated with this pathology. In vitro studies have suggested that IL-4 receptor α (IL-4Rα) signaling on smooth muscle cells is critical for airway inflammation and airway hyperresponsiveness.Objective: To define the contribution of IL-4 and IL-13 to the onset of asthmatic pathology, the role of their key receptor IL-4Rα in smooth muscle cells was examined in vivo.Methods: By using transgenic smooth muscle myosin heavy chaincreIL-4Rα-/lox mice deficient in IL-4Rα in smooth muscle cells, in vivo effects of impaired IL-4Rα signaling in smooth muscle cells on the outcome of asthmatic disease were investigated for the first time. Allergic asthma was introduced in mice by repeated sensitization with ovalbumin/aluminum hydroxide on days 0, 7, and 14, followed by intranasal allergen challenge on days 21 to 23. Mice were investigated for the presence of airway hyperresponsiveness, airway inflammation, allergen-specific antibody production, Th2-type cytokine responses, and lung pathology.Results: Airway hyperresponsiveness, airway inflammation, mucus production, Th2 cytokine production, and specific antibody responses were unaffected in smooth muscle myosin heavy chaincreIL-4Rα-/lox mice compared with control animals.Conclusion: The impairment of IL-4Rα on smooth muscle cells had no effect on major etiologic markers of allergic asthma. These findings suggest that IL-4Rα responsiveness in airway smooth muscle cells during the early phase of allergic asthma is not, as suggested, necessary for the outcome of the disease.

The leukocyte activation antigen CD69 limits allergic asthma and skin contact hypersensitivity

2010-07-12

Background: Allergic diseases have a major health care impact in industrialized countries. The development of these diseases is influenced by exposure to allergen and to immunological and genetic factors. However, the molecular mechanisms underlying the inflammatory response that triggers allergy are not well defined.Objective: We have investigated the role of the leukocyte activation antigen CD69 in the regulation of two allergic diseases, asthma and contact dermatitis.Methods: Analysis of two models of allergic diseases in CD69 knockout and wild-type mice: ovalbumin-induced allergic airway inflammation (BALB/c genetic background) and contact hypersensitivity to oxazolone (C57BL/6J genetic background).Results: CD69 deficiency dramatically enhanced the inflammatory response in the ovalbumin-induced asthma model of antigen-induced airway allergy. CD69 knockout mice showed exacerbated pulmonary eosinophil recruitment, high vascular cell adhesion molecule 1 expression levels in lung vasculature, and enhanced TH2 and TH17 cytokines in the bronchoalveolar space and lung tissue. In the hapten-induced cutaneous contact hypersensitivity model, both CD69 deficiency and treatment with anti-CD69 mAb increased inflammation. Treatment with contact allergens induced enhanced TH1 and TH17 responses in CD69 deficient mice, and neutralizing anti–IL-17 antibodies reduced skin inflammation. In both experimental systems, adoptive transfer of lymph node cells from CD69 knockout mice increased the inflammatory response in recipient mice.Conclusion: These results demonstrate that the early activation receptor CD69 is an intrinsic modulator of immune allergic processes through the negative regulation of allergen-induced T-cell effector responses.

IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells

2010-07-12

Background: Bronchial epithelial damage and activation likely contribute to the inflammatory and airway-remodeling events characteristic of severe asthma. Interaction of Fas receptor (CD95) with its ligand (FasL; CD95L) is an important mechanism of cell-mediated apoptosis. Bronchial epithelial FasL expression provides immune barrier protection from immune cell–mediated damage.Objectives: Membrane FasL (mFasL) is a cleavage target of matrix metalloproteinases (MMPs). We investigated whether the asthmatic TH2 environment might influence disease processes by increasing airway epithelial MMP-mediated cleavage of mFasL into proinflammatory soluble FasL.Methods: We used human airway epithelial cell lines and primary cells to model the human airway epithelium in vitro. Airway tissue from healthy subjects and patients with severe asthma was used to investigate MMP expression patterns in diseased airways.Results: We demonstrate that active MMP-7 is present in the ciliated epithelial cells of normal human airways. In patients with severe asthma, MMP-7 levels are increased in basal epithelial cells. Airway epithelial cell lines (1HAEo− and 16HBE14o−) in vitro express constitutively high levels of MMP-2 and MMP-9 but relatively low levels of MMP-7. TH2 cytokine (IL-4, IL-9, and IL-13) treatment of 1HAEo− cells increased MMP-7 mRNA and activity, triggered colocalization of intracellular MMP-7 with FasL, and caused mFasL cleavage with soluble FasL release. Small interfering RNA knockdown shows that cytokine-induced mFasL cleavage is dependent on MMP-7 activity.Conclusions: MMPs serve multiple beneficial roles in the lung. However, chronic disordered epithelial expression of MMP-7 in patients with asthma might increase mFasL cleavage and contribute to airway epithelial damage and inflammation.

Mechanisms of allergen-specific desensitization

2010-07-12

Background: Allergen-specific desensitization (SIT) is the most effective therapy for allergies. Although allergen-specific antibodies have an important role in the process, mechanisms of IgG-mediated inhibition of allergic reactions are not well defined.Objective: We investigated mechanisms by which SIT-induced allergen-specific IgGs inhibit allergic reactions.Methods: We generated mAbs that recognize 3 nonoverlapping epitopes of the major cat allergen Fel d 1. Each of the mAbs was produced as an IgE and different IgG isotype.Results: IgEs against 2 nonoverlapping epitopes on Fel d 1 are necessary and sufficient to sensitize mast cells for maximal FcεRI signaling and degranulation on exposure to monomeric Fel d 1. IgE antibodies of a third specificity did not further increase mast cell degranulation, indicating that formation of large FcεRI clusters are not required to induce maximal activation of mast cells. A single IgG that was specific for an epitope different from those recognized by the IgEs was a potent inhibitor of Fel d 1–mediated mast cell activation in vitro and in vivo. This inhibition required Fcγ receptor-IIB. In human beings, IgGs of a single specificity were able to block degranulation of basophils from individuals with cat allergy. The inhibitory potential of these antibodies increased when larger allergen-IgG complexes were formed.Conclusions: These data reconcile conflicting theories in the literature and might explain the reason IgE levels do not necessarily decrease during therapy, despite clinical efficacy. These findings have important implications for vaccine design.

Food allergen advisory labeling and product contamination with egg, milk, and peanut

2010-07-12

To the Editor: Allergen advisory labeling (eg, “may contain” and “made in a facility that processes”) used on manufactured products is voluntary, unregulated, and increasingly common. Consumers with food allergy appear to be increasingly ignoring these warnings, presumably because of frustration and doubt about their legitimacy and risks. Because the labeling is voluntary, consumers might additionally question whether products without such statements are safe, creating further anxiety and frustration. A better understanding of the risks would inform consumers, industry, regulators, and physicians how best to approach this problem.

Trends in pediatric emergency department visits for food-induced anaphylaxis

2010-07-12

To the Editor: Food-induced anaphylaxis is defined as an IgE-mediated hypersensitivity reaction to an ingested food that results in the rapid onset of multisystem and potentially life-threatening symptoms. Food allergy is the most common cause of anaphylaxis in children, and by most estimates, the prevalence of food allergies in children living in developed nations is increasing. The Centers for Disease Control and Prevention reported that in 2007 approximately 3 million school-aged children in the United States had food allergies, representing an 18% increase since 1997. Recent data from several national health surveys also support an increase in food allergy among US children. Because anaphylaxis is the most serious manifestation of food allergies, we sought to determine whether there has been a corresponding increase in children presenting to the emergency department (ED) with food-induced anaphylaxis.

Eight-year outcomes of the Childhood Asthma Prevention Study

2010-06-21

To the Editor: The Childhood Asthma Prevention Study is a randomized controlled trial to test the effectiveness of house dust mite (HDM) avoidance and dietary fatty acid modification during the first 5 years of life as strategies for the primary prevention of asthma and allergy in high-risk children. We have previously shown that although the interventions were successful in reducing HDM allergen concentration in dust collected from beds and increasing the ratio of ω-3 to ω-6 fatty acids in plasma at age 5 years, this was not accompanied by any effect on the prevalence of asthma, wheeze, or atopy at this age.

Risk of cataracts in the Childhood Asthma Management Program Cohort

2010-07-12

To the Editor: Use of systemic corticosteroids is a well-established risk factor for the development of posterior subcapsular cataracts (PSCs) in both children and adults. Dose and duration of inhaled corticosteroids (ICSs) have been reported to be independent risk factors for the development of PSCs in older patients. The occurrence of PSCs is rare in children, and studies of children treated with ICSs have not found an increased risk of PSCs. We previously reported no risk of cataracts in 955 children in the Childhood Asthma Management Program (CAMP) assessed by means of lens photography after 4 to 6 years (mean, 4.3 years) of 400 μg/d budesonide administered by means of Turbuhaler, 16 mg/d nedocromil, or placebo. However, one child in the budesonide group was given a diagnosis of a barely measurable PSC on slit lamp examination 5 months after photography.

Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome

2010-06-28

To the Editor: The hyper-IgE syndromes (HIESs) are rare primary immune deficiencies characterized by increased serum IgE levels, eczematous rash, and recurrent skin and lung infections. Both autosomal recessive and autosomal dominant inheritance have been described, but most HIES cases are sporadic. Autosomal dominant HIES (AD-HIES), the most common form, has various immunologic and nonimmunologic abnormalities arising as consequences of impaired cytokine signal transduction and TH17 cell deficiency caused by mutations in the signal transducer and activator of transcription 3 gene (STAT3). Although correction of the immunologic defect with allogeneic hematopoietic stem cell transplantation (HSCT) could be expected, the first transplantation attempts in 2 patients with HIES reported in 1998 and 2000 failed to show long-term benefits.

Biological agents: New drugs, old problems

2010-06-25

To the Editor: Monoclonal antibodies are innovative drugs used to treat different human diseases. Adverse events related to these drugs are typically mild but can be life-threatening. Potential adverse reactions also include IgE-, IgG-, or T cell–mediated hypersensitivity reactions. Natalizumab is a recombinant humanized IgG4κ mAb anti–α4-integrin produced in murine myeloma cells and used in multiple sclerosis treatment. It consists of 2 heavy and 2 light chains connected by 4 interchain disulfide bonds with a molecular weight of 146 kd. Several cases of hypersensitivity reactions to natalizumab have been reported, but no IgE-mediated mechanism has been demonstrated to date.

Infants aged 12 months can mount adequate serotype-specific IgG responses to pneumococcal polysaccharide vaccine

2010-06-28

To the Editor: Streptococcus pneumoniae is a major cause of bacterial pneumonia, meningitis, bacteremia, and otitis media leading to an estimated 1 million deaths per year worldwide in children younger than 5 years. The capsule of S pneumoniae is the major virulence factor by which pneumococci cause invasive disease. Immunity against S pneumoniae is mediated by phagocytosis of the organism in the presence of complement and serotype-specific antibody. Capsular polysaccharide antigens, classified as T-independent type II antigens, are considered to stimulate B-lymphocytes directly to produce antigen-specific opsonic antibody without inducing immunologic memory or affinity maturation. Polysaccharide antigens, with bound complement C3d, are recognized directly by the B lymphocyte through CD21, which associates with CD19 to enhance and prolong antigen signaling. On the basis of a limited number of small studies, the ability to mount T-independent responses is considered to be absent in the neonate and poor in children younger than 2 years. This may be a result of lower CD21 expression on neonatal and infant B cells and/or the immaturity of the splenic marginal zone.

Regulation and characterization of IL-17A expression in patients with chronic rhinosinusitis and its relationship with eosinophilic inflammation

2010-07-12

To the Editor: IL-17A is a proinflammatory cytokine synthesized by TH17 cells. Although several reports have demonstrated that IL-17A expression levels in sputum and lung tissue correlated with the severity of asthma symptoms, it remains unclear as to whether IL-17A is involved in the pathogenesis of severe chronic upper airway diseases, including chronic rhinosinusitis with nasal polyps (CRSwNPs). We investigated the local production and regulation of IL-17A in nasal polyps (NPs) by using a recently developed ex vivo system. In addition, local expression of IL-17A was compared among various chronic rhinosinusitis (CRS) phenotypes, and the role of IL-17A in the pathogenesis of CRS was discussed. Details on the methods are available in the Methods section of this article's Online Repository at www.jacionline.org.

Topical application of dehydroxymethylepoxyquinomicin improves allergic inflammation via NF-κB inhibition

2010-07-12

To the Editor: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with significant morbidity and an adverse impact on patient well-being. AD has become increasingly prevalent in industrialized countries, where it now occurs in 10% to 20% of children and 1% to 3% adults. Corticosteroids are generally prescribed to control the symptoms, yet repeated use can cause severe skin atrophy and susceptibility to infection. Tacrolimus, a calcineurin inhibitor, has recently gained widespread use as an AD treatment that avoids the typical side effects associated with topical corticosteroids. However, refractory AD can remain even in patients treated with both corticosteroid and tacrolimus.

A novel non–IgE-mediated pathway of mite-induced inflammation

Mario Sánchez-Borges, Arnaldo Capriles-Hulett, Fernan Caballero-Fonseca — 2010-07-12

To the Editor: In a recent article published in the Journal of Immunology, Barrett et al demonstrated that mite and Aspergillus fumigatus extracts stimulate the production of cysteinyl leukotrienes from bone marrow–derived dendritic and pulmonary CD11c+ cells through a glycan C–type lectin receptor (Dectin-2) interaction involving FcRγ and Syk signaling that activates arachidonic acid metabolism.

Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma

2010-07-12

To the Editor: Nitric oxide (NO) is a reactive molecule synthesized by NO synthases that are expressed by cells within the airway wall, and functionally, 2 isoforms exist: constitutive and inducible nitric oxide synthase (iNOS). In asthmatic patients the inducible isoform is overexpressed, leading to increased production of NO, which diffuses into the airway lumen, where it can be detected in exhaled breath. Fraction of exhaled nitric oxide (FeNO) is reported to be closely correlated to eosinophilic inflammation in the airways of patients with asthma and is recommended as a noninvasive marker to identify patients at risk for severe exacerbations and to monitor treatment that would decrease eosinophil numbers. Thus treatment algorithms for asthma have been developed to titrate the dose of inhaled corticosteroids based on FeNO levels. Such guidelines are most required for patients with asthma who require daily prednisone to control their eosinophilic bronchitis. The utility of monitoring FeNO levels in these patients is unknown. We report the lack of correlation between sputum eosinophil percentages and FeNO levels in patients with prednisone-dependent asthma and sputum eosinophilia who participated in a clinical trial of mepolizumab, a mAb against IL-5.

Comparison of the allergic and nonallergic CD4+ T-cell responses to the major dog allergen Can f 1

2010-07-12

To the Editor: Although it is well established that pathogenic TH2-deviated CD4+ T-cell responses dominate in individuals with allergy, the nature of allergen-specific CD4+ T-cell responses in individuals without allergy exposed to the same allergens is still largely unclear. A number of nonexclusive mechanisms, such as immune ignorance of nonpathogenic environmental antigens, anergy, or deletion of allergen-specific T cells, and immune deviation to TH0/TH1 phenotype, have previously been proposed to explain the tolerance to allergens in these individuals. In recent years, however, the role of regulatory T (Treg) cells in the induction and maintenance of peripheral tolerance to allergens has been emphasized.

Fluctuation of blood and skin plasmacytoid dendritic cells in drug-induced hypersensitivity syndrome

2010-07-12

To the Editor: Drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms, is a severe adverse systemic reaction that usually occurs about several weeks after exposure to certain drugs such as anticonvulsants. It is characterized by multiorgan involvement, high fever, hypogammaglobulinemia, and sequential reactivation of various latent herpesviruses, such as human herpesvirus (HHV)–6, HHV-7, cytomegalovirus, or EBV. However, the mechanism underlying the reactivation of these herpesviruses remains unknown.

Man's best friend? The effect of pet ownership on house dust microbial communities

2010-07-15

To the Editor: The prevalence of asthma among children has been steadily increasing in westernized nations. Although host genotype likely plays a role in predisposition to allergic disease, the rate at which asthma has increased and the geographically distinct location of this phenomenon implicate environmental factors as being important. Epidemiologic studies have suggested that contact with animals provides protection against allergic disease development; childhood farm exposure, specifically to livestock, is associated with a significant decrease in the risk of atopic sensitization, a protective effect that persists into early adulthood. More recently, in our own birth cohort, maternal prenatal exposure to household pets, particularly dogs, has been suggested to affect fetal immune response development. Higher concentrations of cord blood IgE were associated with mothers unexposed to pets, a notable finding given that previous studies have demonstrated a link between increased cord blood IgE levels and the risk for subsequent development of allergic disorders.

Reduced vitamin D levels in adult subjects with chronic urticaria

Warren Ancheta Thorp, Whitney Goldner, Jane Meza, Jill A. Poole — 2010-07-12

To the Editor: Hata et al published a provocative study implicating vitamin D as potential immunomodulator of allergic disease because of its role in regulating cathelicidin expression in the skin of subjects with atopic dermatitis. Chronic urticaria (CU) is another allergic skin dermatosis, and despite extensive evaluation for underlying causes or triggers, the etiology remains unclear. Given the interesting findings of an association of vitamin D and atopic dermatitis in the study by Hata et al and other studies suggesting a role for vitamin D in asthma, we sought to determine whether a relationship between vitamin D and CU exists.

Reply

Tissa Hata, Richard Gallo — 2010-07-12

To the Editor: We thank Thorp et al for their reference to our letter to the editor, in which we show induction of cathelicidin in lesional skin of subjects with atopic dermatitis with oral vitamin D. We read with interest their clinical study showing vitamin D levels to be significantly reduced in subjects with chronic urticaria compared with controls. As highlighted in these 2 observations, vitamin D appears to play a role in both innate and adaptive immunity and is associated with the development of autoimmune disease. Our study discovered a potential therapeutic role of vitamin D in the innate immune system of atopic subjects by increasing the production of the antimicrobial peptide cathelicidin in lesional skin after administration of 4000 IU of oral vitamin D3 for 3 weeks. Our study was based on previous findings that 1,25-dihydroxyvitamin D3 can increase the production of antimicrobial peptides in keratinocytes and monocytes. This phenomenon is caused in part by the action of a vitamin D response element in the cathelicidin promoter and the finding that pattern recognition molecules such as TLR2 and CD14 also increase after vitamin D stimulation. Importantly, keratinocytes and monocytes express both CYP27A1 and CYP27B1, enzymes that enable the active form of vitamin D (1,25-dihydroxyvitamin D3) to be rapidly produced from the stored precursor form after local skin injury. Thus by generating 1,25-dihydroxyvitamin D3 and subsequent binding of the vitamin D response element in the promoter region of the cathelicidin gene, cathelicidin expression was greatly increased. Presumably, by increasing nutritional stores of vitamin D, this enables atopics to compensate for an otherwise inadequate capacity to produce antimicrobial peptides in response to skin injury. Our data suggest that vitamin D induction of cathelicidin in the atopic scenario may be beneficial to the atopic subject, decreasing their susceptibility to infections.

Potent topical steroids are one of the treatments for cutaneous T-cell lymphoma

Pablo Fernandez-Peñas — 2010-07-12

To the Editor: I have read the article “Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom” with extreme interest. The article raises important questions regarding the possible association between the use of topical treatments and lymphoma. One of their conclusions is that there is a strong association between lymphoma—especially skin lymphoma—and the use of topical corticosteroids (TCSs). The authors discuss that “part of the association we observed is probably a result of confounding by indication” as “a precancerous stage presenting with chronic cutaneous inflammatory features is common in cutaneous T-cell lymphomas (CTCL), which can take years from the time of initial presentation to diagnosis and maybe treated with high-potency TCS.” The authors should be aware that one of the main treatments for early-stage (IA, IB, IIA) CTCL is the use of potent topical steroids, as is well described in all CTCL guidelines. In this regard, TCSs are used to treat the precancerous as well as the diagnosed CTCL. On the other hand, CTCL is a chronic disease, with >75% expected 5-year survival for clinical stage I, and these patients will use TCSs for more than 2 years in most cases.

Reply

Felix M. Arellano, Alejandro Arana, Charles E. Wentworth, Eulogio Conde — 2010-07-12

To the Editor: We agree with Dr Fernandez-Peñas when he says that potent topical corticosteroids (TCSs) are used for the treatment of cutaneous T-cell lymphoma through stages IA, IB, and IIA. As the author states, we already claim that our results could partially be explained by confounding by indication or protopathic bias (the cutaneous lesions may have been the cause of treatment). This has been argued in another study finding apparent increases in rates of lymphoma in TCS users compared with a dermatitis-free population. However, we determined exposure to TCS only in the period before the diagnosis of lymphoma (including cutaneous T-cell lymphoma) according to the temporal relationship causality criteria. Any use of TCS after the diagnosis of cutaneous T-cell lymphoma was not considered exposure and cannot explain the findings. The magnitude of the association reported makes confounding by indication alone an unlikely explanation. In addition, confounding by indication may not explain the association we found between Hodgkin disease and TCS because skin involvement in Hodgkin disease is rare.

Successful treatment of idiopathic anaphylaxis in an adolescent

Tracy J. Pitt, Nestor Cisneros, Chrystyna Kalicinsky, Allan B. Becker — 2010-07-12

To the Editor: Expanding on a letter in the June 2007 issue of the Journal by Carter et al, we provide additional data demonstrating the efficacy of omalizumab in the prevention of spontaneous episodic anaphylaxis in an adolescent with probable systemic mastocytosis.

Reply

Melody C. Carter — 2010-07-12

To the Editor: The case study entitled “Successful treatment of idiopathic anaphylaxis in an adolescent” presented by Pitt et al documents the effect of omalizumab on the frequency of anaphylactic events in a patient with anaphylaxis. The results of the allergy evaluation are not presented, but presumably no agent was identified that precipitated the episodes of anaphylaxis.

Identifying and managing the infant and toddler at risk for asthma

Theresa W. Guilbert — 2010-07-12

Recurrent wheezing is a common problem, with approximately 50% of children experiencing wheeze in the first year of life, resulting in a substantial effect on the children, their families, and the health care system. However, the diagnosis of persistent asthma remains imperfect, with only 40% of these infants experiencing continued wheezing symptoms in later childhood and with variation in expression of both symptoms and risk factors over time. The focus of this article is to provide evidence-based recommendations for identifying and managing infants and toddlers at risk for asthma.

The Journal of Allergy and Clinical Immunology

Cover 1

A Brief Overview of This Month's JACI

Table of Contents

Editorial Board

Information for Readers

Footnotes1

CME Activities Calendar

News Beyond Our Pages

Long-term studies of the natural history of asthma in childhood

Long-term studies of the natural history of asthma in childhood

Using genetics to predict the natural history of asthma?

Using genetics to predict the natural history of asthma?

The Asthma Predictive Index: A very useful tool for predicting asthma in young children

Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children

The Editors' Choice

A cluster-randomized trial to provide clinicians inhaled corticosteroid adherence information for their patients with asthma

Gene-environment interactions influence airways function in laboratory animal workers

Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

Maternal dietary pattern during pregnancy is not associated with recurrent wheeze in children

The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children

A randomized trial to test the effectiveness of art therapy for children with asthma

The Childhood Asthma Control Test∗: Retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma

Indoor pet exposure and the outcomes of total IgE and sensitization at age 18 years

Inducible costimulator (ICOS) is a marker for highly suppressive antigen-specific T cells sharing features of TH17/TH1 and regulatory T cells

Thymic stromal lymphopoietin–activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis

Association between varicella zoster virus infection and atopic dermatitis in early and late childhood: A case-control study

Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway

Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine

A population-based questionnaire survey on the prevalence of peanut, tree nut, and shellfish allergy in 2 Asian populations

Impaired T-cell receptor activation in IL-1 receptor–associated kinase-4–deficient patients

Gene-gene interaction in regulatory T–cell function in atopy and asthma development in childhood

Expression of IL-4 receptor α on smooth muscle cells is not necessary for development of experimental allergic asthma

The leukocyte activation antigen CD69 limits allergic asthma and skin contact hypersensitivity

IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells

Mechanisms of allergen-specific desensitization

Food allergen advisory labeling and product contamination with egg, milk, and peanut

Trends in pediatric emergency department visits for food-induced anaphylaxis

Eight-year outcomes of the Childhood Asthma Prevention Study

Risk of cataracts in the Childhood Asthma Management Program Cohort

Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome

Biological agents: New drugs, old problems

Infants aged 12 months can mount adequate serotype-specific IgG responses to pneumococcal polysaccharide vaccine

Regulation and characterization of IL-17A expression in patients with chronic rhinosinusitis and its relationship with eosinophilic inflammation

Topical application of dehydroxymethylepoxyquinomicin improves allergic inflammation via NF-κB inhibition

A novel non–IgE-mediated pathway of mite-induced inflammation

Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma

Comparison of the allergic and nonallergic CD4+ T-cell responses to the major dog allergen Can f 1

Fluctuation of blood and skin plasmacytoid dendritic cells in drug-induced hypersensitivity syndrome

Man's best friend? The effect of pet ownership on house dust microbial communities

Reduced vitamin D levels in adult subjects with chronic urticaria

Reply

Potent topical steroids are one of the treatments for cutaneous T-cell lymphoma

Reply

Successful treatment of idiopathic anaphylaxis in an adolescent

Reply

Identifying and managing the infant and toddler at risk for asthma