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Latest Articles Include:

• Cover 1
  - J Allergy Clin Immunol 123(4):OFC (2009)
  
• A Brief Overview of This Month's JACI
  - J Allergy Clin Immunol 123(4):3A-4A (2009)
  
• Table of Contents
  - J Allergy Clin Immunol 123(4):8A, 10A, 12A, 14A, 19A-20A, 22A-24A, 27A (2009)
  
• Editorial Board
  - J Allergy Clin Immunol 123(4):28A (2009)
  
• Information for Readers
  - J Allergy Clin Immunol 123(4):30A (2009)
  
• Footnotes1
  - J Allergy Clin Immunol 123(4):32A-34A (2009)
  
• CME Activities Calendar
  - J Allergy Clin Immunol 123(4):35A-36A (2009)
  
• News Beyond Our Pages
  - J Allergy Clin Immunol 123(4):733-734 (2009)
  
• Mechanisms and treatment of allergic disease in the big picture of regulatory T cells
  - J Allergy Clin Immunol 123(4):735-746 (2009)
  Various populations of regulatory T (Treg) cells have been shown to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses. Their identification as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4+CD25+ Treg cells and inducible populations of allergen-specific, IL-10–secreting Treg type 1 (TR1) cells inhibit allergen-specific effector cells in experimental models. Skewing of allergen-specific effector T cells to a regulatory phenotype appears to be a key event in the development of healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. Forkhead box protein 3–positive CD4+CD25+ Treg cells and TR1 cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression o! f dendritic cells that support the generation of effector T cells; suppression of effector TH1, TH2, and TH17 cells; suppression of allergen-specific IgE and induction of IgG4; suppression of mast cells, basophils, and eosinophils; interaction with resident tissue cells and remodeling; and suppression of effector T-cell migration to tissues. Current strategies for drug development and allergen-specific immunotherapy exploit these observations, with the potential for preventive therapies and cure for allergic diseases.
• Mechanisms and treatment of allergic disease in the big picture of regulatory T cells
  - J Allergy Clin Immunol 123(4):747-748 (2009)
  
• Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion
  - J Allergy Clin Immunol 123(4):749-755 (2009)
  Forkhead box protein 3–positive regulatory T (Treg) cells are indispensable for the maintenance of self-tolerance and immune homeostasis. They can also be exploited for the treatment of immunologic diseases, including autoimmune diseases and allergy, by way of activating and expanding antigen-specific Treg cells in vivo. Cell therapy with in vitro activated and expanded Treg cells can be another therapeutic modality. The feasibility of such Treg cell–based therapeutic strategies is discussed based on recent advances in our understanding of the molecular and cellular basis of Treg cell development and function.
• Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion
  - J Allergy Clin Immunol 123(4):756-757 (2009)
  
• IL-2– and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets
  - J Allergy Clin Immunol 123(4):758-762 (2009)
  IL-2 plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T (Treg) cells, which are required for the maintenance of immune tolerance. Moreover, IL-2 is implicated in the differentiation and homeostasis of effector T-cell subsets, including TH1, TH2, TH17, and memory CD8+ T cells. The IL-2 receptor is composed of 3 distinct subunits, namely the α (CD25), β (CD122), and γ (γc) chains. Of crucial importance for the delivery of IL-2 signals to Treg cells is the expression of CD25, which, along with CD122 and γc, confers high affinity binding to IL-2. Notably, recent findings suggest a novel role for CD25, whereby CD25 molecules on Treg cells and possibly other cells are capable of influencing T-cell homeostasis by means of IL-2 deprivation. This review explores these findings and integrates them into our current understanding of T-cell homeostasis.
• Multiallergen immunotherapy for allergic rhinitis and asthma
  - J Allergy Clin Immunol 123(4):763-769 (2009)
  The English and non–English language literature on allergen immunotherapy was reviewed for studies simultaneously using 2 or more distinct allergen extracts in either subcutaneous or sublingual immunotherapy. Thirteen studies were identified, 11 using subcutaneous injections, 1 using sublingual administration, and 1 using both. In studies with adequate information, administration of 2 extracts by means of either subcutaneous immunotherapy or sublingual immunotherapy was effective. In studies using multiple allergens, 3 studies showed clear efficacy, whereas in the other 2 studies, lack of efficacy might have been due to inadequate doses of extract or omission of clinically relevant allergens in the treatment regimen. It is concluded that simultaneous administration of more than 1 allergen extract is clinically effective. However, more studies are needed, particularly with more than 2 allergen extracts and with sublingual administration.
• Anti-IgE therapy: Clinical utility beyond asthma
  - J Allergy Clin Immunol 123(4):770-771.e1 (2009)
  
• The Editors' Choice
  - J Allergy Clin Immunol 123(4):772-773 (2009)
  
• Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells
  - J Allergy Clin Immunol 123(4):774-782.e5 (2009)
  Background Cross-sectional studies suggest that maternal exposure to farming decreases the risk of allergic diseases in offspring. The potential underlying immunologic mechanisms are not understood. Objective We sought to assess whether maternal farm exposure activates regulatory T (Treg) cells in cord blood, exerting TH2-suppressive effects after microbial stimulation. Methods Eighty-four pregnant mothers were recruited before delivery. Detailed questionnaires (60 nonfarming and 22 farming mothers with 2 exclusions) assessed the farming exposures. Cord blood was stimulated with the microbial stimulus peptidoglycan (Ppg), the mitogen PHA, house dust mite extracts (Der p 1), and combinations. Treg cells (CD4+CD25high cells; intracellular forkhead/winged-helix family transcriptional repressor p3 [FOXP3] expression, FOXP3 levels, lymphocyte activation gene 3 mRNA expression, functional studies, and DNA methylation of the FOXP3 locus), proliferation, and TH2/TH1/TH17 cytokines were examined. Results Cord blood Treg cell counts (both unstimulated and PHA stimulated) were increased with maternal farming exposures and associated with higher FOXP3 (Der p 1 + Ppg stimulation) and trendwise higher lymphocyte activation gene 3 (Ppg) expression. Furthermore, Treg cell function was more efficient with farming exposure (effector cell suppression, P = .004). In parallel, TH2 cytokine (IL-5) levels were decreased and associated with decreased lymphoproliferation and increased IL-6 levels (Ppg stimulation, Der p 1 + Ppg stimulation, or both; P < .05). Maternal exposure to increasing numbers of farm animals and stables was discovered to exert distinct effects on Treg cells, TH1/TH2 cells, or both. Additionally, FOXP3 demethylation in offspring of mothers with farm milk exposure was increased (P = .02). Conclusions Farm exposures during pregnancy increase the number and function of cord blood Treg cells associated with lower TH2 cytokine secretion and lymphocyte proliferation on innate exposure. One fascinating speculation is that maternal farm exposure might reflect a natural model of immunotherapy, potentially including a selection of innate stimuli in addition to allergen, shaping a child's immune system at an early stage.
• Is the prevalence of peanut allergy increasing? A 5-year follow-up study in children in Montreal
  - J Allergy Clin Immunol 123(4):783-788 (2009)
  Background Studies suggest that peanut allergy prevalence might be increasing, but these results have not yet been substantiated. Objective We conducted a follow-up study to determine whether peanut allergy prevalence in Montreal is increasing. Methods Questionnaires regarding peanut ingestion were administered to parents of children in randomly selected kindergarten through grade 3 classrooms between December 2000 and September 2002 and between October 2005 and December 2007. Respondents were stratified as (1) peanut tolerant, (2) never/rarely ingest peanut, (3) convincing history of peanut allergy, or (4) uncertain history of peanut allergy. Children in group 3 with positive skin prick test responses were considered to have peanut allergy. Children in groups 2 and 4 with positive skin prick test responses had peanut-specific IgE levels measured, and if the value was less than 15 kU/L, an oral peanut challenge was performed. Multiple imputation was used to generate prevalence estimates that incorporated respondents providing incomplete data and nonrespondents. Results Of 8,039 children surveyed in 2005-2007, 64.2% of parents responded. Among those providing complete data, the prevalence was 1.63% (95% CI, 1.30% to 2.02%) in 2005-2007 versus 1.50% (95% CI, 1.16% to 1.92%) in 2000-2002. After adjustment for missing data, the prevalence was 1.62% (95% credible interval, 1.31% to 1.98%) versus 1.34% (95% credible interval, 1.08% to 1.64%), respectively. The differences between the prevalences in 2005-2007 and 2000-2002 were 0.13% (95% credible interval, −0.38% to 0.63%) among those providing complete data and 0.28% (95% credible interval, −0.15% to 0.70%) after adjustment for missing data. Conclusions This is the first North American study to document temporal trends in peanut allergy prevalence by corroborating history with confirmatory tests. The results suggest a stable prevalence, but wide CIs preclude definitive conclusions.
• Allergen-specific basophil suppression associated with clinical tolerance in patients with milk allergy
  - J Allergy Clin Immunol 123(4):789-794.e20 (2009)
  Background Children with milk allergy who tolerate heat-denatured milk (HM) have less severe reactions and outgrow the condition earlier than those who react to HM, which might be related to differences in IgE-dependent effector cell function. Objective We sought to apply a novel assay to test the hypothesis that HM-tolerant children have suppressed IgE-mediated basophil responses. Methods Allergic, HM-tolerant, outgrown, or control subjects were defined based on oral food challenges. Whole blood cells were stimulated in vitro with a range of milk allergen doses in the presence or absence of autologous serum or with dilutions of autologous serum. Activated basophils were identified by means of flow cytometry as CD63brightCD123+CD203c+HLA-DR−CD41a−. Results HM-tolerant subjects' basophils were significantly less responsive to milk allergen stimulation at all doses than were basophils from HM-reactive (allergic) individuals. In the absence of autologous serum, HM-tolerant subjects' basophils were significantly more reactive at low allergen concentrations. To a lesser extent, autologous serum also inhibited IL-3– and anti-IgE–induced, but not N-formyl-methionyl-leucyl-phenylalanine–induced, responses. The allergen-specific responsiveness of HM-tolerant subjects' basophils increased with dilution of autologous serum with normal pooled serum. Conclusion Children with milk allergy with a favorable prognosis have evidence of extrinsically suppressed allergen-specific effector cell reactivity.
• Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung
  - J Allergy Clin Immunol 123(4):795-804.e8 (2009)
  Background Allergic asthma results from inappropriate TH2-mediated inflammation. Both IL-4 and IL-13 contribute to asthma pathogenesis, but IL-4 predominantly drives TH2 induction, whereas IL-13 is necessary and sufficient for allergen-induced airway hyperresponsiveness and goblet cell hyperplasia. Although these 2 cytokines share signaling components, the molecular mechanisms by which they mediate different phases of the allergic asthmatic response remain elusive. Objective We sought to clarify the role or roles of IL-4 and IL-13 in asthma-pathogenesis. Methods We used DNA Affymetrix microarrays to profile pulmonary gene expression in BALB/c mice inoculated intratracheally with ragweed pollen, house dust mite, IL-4, IL-13, or both cytokines. IL-13 dependence was confirmed by comparing pulmonary gene expression in house dust mite–inoculated wild-type and IL-13 knockout mice. Results A signature gene expression profile consisting of 23 genes was commonly induced by means of inoculation with house dust mite, ragweed pollen, or IL-4 plus IL-13. Although rIL-4 and rIL-13 treatment induced an overlapping set of genes, IL-4 uniquely induced 21 genes, half of which were interferon response genes and half of which were genes important in immunoregulation. IL-13 uniquely induced 8 genes, most of which encode proteins produced by epithelial cells. Conclusions IL-4 and IL-13 together account for most allergen-induced pulmonary genes. Selective IL-4 induction of IFN-γ response genes and other genes that might negatively regulate allergic inflammation could partially explain the greater importance of IL-13 in the effector phase of allergic airway disease.
• Allergic airway hyperresponsiveness, inflammation, and remodeling do not develop in phosphoinositide 3-kinase γ–deficient mice
  - J Allergy Clin Immunol 123(4):805-812 (2009)
  Background Bronchial asthma is characterized by chronic airway inflammation caused by inflammatory cells. Phosphoinositide 3-kinases (PI3Ks) are known to play a prominent role in fundamental cellular responses of various inflammatory cells, including proliferation, differentiation, and cell migration. PI3Ks therefore are expected to have therapeutic potential for asthma. Although some investigations of the involvement between the pathogenesis of asthma and PI3K have been performed, it is unknown whether PI3Kγ, a PI3K isoform, is involved in the pathogenesis of asthma. Objective We investigated the role of PI3Kγ in allergen-induced allergic airway inflammation, airway hyperresponsiveness (AHR), and airway remodeling with PI3Kγ-deficient mice. Methods After ovalbumin (OVA) sensitization, wild-type (WT) and PI3Kγ-deficient mice were exposed to aerosolized OVA 3 days per week for 5 weeks. Results In OVA-sensitized and OVA-challenged (OVA/OVA) PI3Kγ-deficient mice, levels of airway inflammation, AHR, and airway remodeling were significantly decreased compared with those in OVA/OVA WT mice. On the other hand, no significant differences were detected in serum OVA-specific IgE and IgG1 levels and CD4/CD8 balance in bronchoalveolar lavage fluid between OVA/OVA WT mice and OVA/OVA PI3Kγ-deficient mice. To determine in which phase of allergic responses PI3Kγ plays a role, we transferred splenocytes from OVA-sensitized WT or PI3Kγ-deficient mice to naive mice of either genotype. Similar increased levels of eosinophils were induced in both WT recipient mice but not in both PI3Kγ-deficient recipient mice. Conclusion PI3Kγ might be involved in allergic airway inflammation, AHR, and airway remodeling by regulating the challenge/effector phase of allergic responses.
• T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4+ T cells
  - J Allergy Clin Immunol 123(4):813-823.e3 (2009)
  Background Regardless of TH1/TH2 theory, CD4+ T cells of patients with allergic asthma, a typical TH2 disease, and those of healthy subjects expressed equivalent levels of IFN-γ, even though TH2 cytokines were significantly upregulated in asthmatic patients. Objective The mechanisms underlying distorted TH2 cell polarization in human T cells were elucidated. Methods Cytokine-producing activity and the expression of TH1/TH2–specific transcription factors in naïve, TH1/TH2, or both CD4+ T cells derived from human peripheral and cord blood were comparatively analyzed. The mechanisms of the differential expression of T-box 21 transcription factor (T-bet) in the cells were assessed by determining the chromatin accessibility at the TBX21 gene. The functional roles of T-bet and other transcription factors in human TH1/TH2 differentiation were further investigated. Results TH2 cells derived from naive CD4+ T cells in peripheral blood but not in cord blood produced IFN-γ. T-bet was expressed in peripheral, but not cord blood, resting naive T cells. Consistently, the accessibility at the proximal TBX21 gene promoter in peripheral naive T cells was higher than that in cord blood naive T cells. IFN-γ–producing activity was induced in TH2-differentiated cord blood T cells by means of ectopic expression of T-bet. In addition, a reduction of T-bet in peripheral T cells suppressed IFN-γ production. T-bet not only upregulated IFN-γ but also downregulated IL-4 and IL-13 gene transcription, independently of the modification of TH1/TH2 balance. Conclusion The expression of T-bet at a naive stage is crucial for the development of IFN-γ–producing T cells in human peripheral blood, even in TH2-related diseases.
• Parental support and cytokine activity in childhood asthma: The role of glucocorticoid sensitivity
  - J Allergy Clin Immunol 123(4):824-830 (2009)
  Background Stress is known to worsen the course of asthma, but the underlying mechanisms are poorly understood. This problem is especially difficult because stress elicits secretion of cortisol, a hormone that dampens airway inflammation and ameliorates asthma symptoms. Objective This article proposes that stress affects asthma by inducing resistance to the anti-inflammatory properties of glucocorticoids. To evaluate this hypothesis, we examine whether a particular kind of stress in children's lives, not feeling supported or understood by parents, is associated with in vitro measures of lymphocyte resistance to glucocorticoids and indices of eosinophil mobilization and activation. Methods Children with asthma (n = 67) and medically healthy children (n = 76) completed standardized questionnaires about support from their parents. PBMCs were collected and incubated with a mitogen cocktail in the presence of physiologic concentrations of hydrocortisone. Production of IL-5, IL-13, and IFN-γ was measured by means of ELISA. Circulating eosinophils were enumerated with a hematology analyzer, and the extent of their activation was indexed by means of ELISA for eosinophil cationic protein. Results To the extent that children with asthma perceived low support from their parents, children were more resistant to hydrocortisone's anti-inflammatory effects on IL-5 and IFN-γ production and had higher circulating levels of eosinophil cationic protein. These associations were independent of socioeconomic conditions, cigarette exposure, disease severity, and medication use. Conclusions These patterns suggest the hypothesis that strained parent-child relations, and perhaps stress more generally, brings about adverse outcomes in asthma by diminishing cortisol's ability to regulate cytokine activity and subsequent airway inflammation.
• Stress and acquired glucocorticoid resistance: A relationship hanging in the balance
  - J Allergy Clin Immunol 123(4):831-832 (2009)
  
• Individualized asthma self-management improves medication adherence and markers of asthma control
  - J Allergy Clin Immunol 123(4):840-846 (2009)
  Background Adherence to inhaled anti-inflammatory therapy and self-management skills are essential parts of the asthma treatment plan to improve asthma control and prevent exacerbations. Whether self-management education improves long-term medication adherence is less clear. Objective A 24-week prospective, randomized controlled trial was performed to study the effect of self-management education on long-term adherence to inhaled corticosteroid (ICS) therapy and markers of asthma control. Methods After stabilization on ICS medication during a run-in phase, 95 adults with moderate-to-severe asthma were recruited from a large metropolitan community, and 84 were randomized to individualized self-management education, including self-monitoring of symptoms and peak flow or usual care with self-monitoring alone. The key components of the 30-minute intervention were asthma information, assessment, and correction of inhaler technique; an individualized action plan based on self-monitoring data; and environmental control strategies for relevant allergen and irritant exposures. The intervention was personalized based on pulmonary function, allergen skin test reactivity, and inhaler technique and reinforced at 2-week intervals. Results Participants randomized to the self-management intervention maintained consistently higher ICS adherence levels and showed a 9-fold greater odds of more than 60% adherence to the prescribed dose compared with control subjects at the end of the intervention (P = .02) and maintained a 3-fold greater odds of higher than 60% adherence at the end of the study. Perceived control of asthma improved (P = .006), nighttime awakenings decreased (P = .03), and inhaled β-agonist use decreased (P = .01) in intervention participants compared with control subjects. Conclusion Our results show that individualized asthma self-management education attenuates the usual decrease in medication adherence and improves clinical markers of asthma control.
• Mothers' anxiety during pregnancy is associated with asthma in their children
  - J Allergy Clin Immunol 123(4):847-853.e11 (2009)
  Background Maternal stress in early life has been associated with the development of asthma in children, although it is unclear whether there are any critical periods of exposure. The association of asthma with prenatal exposure to maternal stress has not been reported. Objective We tested whether prenatal and postnatal anxiety and/or depression in pregnant women predicted the risk of their offspring developing asthma in childhood. Methods The Avon Longitudinal Study of Parents and Children is a population-based birth cohort recruited during pregnancy. Data were available on maternal anxiety scores and asthma at age 7½ years in 5810 children. Anxiety was assessed at 18 and 32 weeks of gestation by using the validated Crown-Crisp Experiential Index. Asthma was defined at age 7½ years as doctor-diagnosed asthma with current symptoms or treatment in the previous 12 months. Multivariable logistic regression was used to determine the association of prenatal anxiety with asthma (odds ratio; 95% CI). Results Independent of postnatal anxiety and adjusted for a number of likely confounders, there was a higher likelihood of asthma at age 7½ years (odds ratio, 1.64; 95% CI, 1.25-2.17) in children of mothers in the highest compared with lowest quartile of anxiety scores at 32 weeks of gestation, with evidence for a dose-response (P value for trend <0.001). Conclusions Maternal anxiety symptoms as an indicator of stress during fetal life may program the development of asthma during childhood.
• The effect of sex on asthma control from the National Asthma Survey
  - J Allergy Clin Immunol 123(4):854-860 (2009)
  Background Previous studies have demonstrated conflicting results with regard to differences in asthma control between the sexes. Objective We sought to identify sex differences in short-term and long-term measures of asthma control in adults from the National Asthma Survey. Methods This study analyzed data from the National Asthma Survey (Four-State sample) sponsored by the National Center for Environmental Health, Centers for Disease Control and Prevention. Asthma control was compared between the sexes based on short-term (recent symptoms, asthma attacks, and albuterol use) and long-term (asthma attacks, work days lost, and urgent-care visits and hospitalizations in the prior year) measures. Composite scores for short-term and long-term control were calculated based on any single measure of poor asthma control and based on a sum of poor asthma control measures. Results Women were more likely to have poor short-term asthma control based on any measure (adjusted odds ratio [OR], 1.20; CI, 1.01-1.44) or sum of measures (adjusted OR, 1.24; CI, 1.08-1.53) compared with men. Women also demonstrated worse asthma control based on any uncontrolled long-term measure (adjusted OR, 1.52; CI, 1.29-1.79) or sum of measures (adjusted OR, 1.68; CI, 1.45-1.93). These findings were present despite higher reported inhaled corticosteroid use and scheduled health care visits for asthma among women. Conclusions Women demonstrated worse asthma control compared with men with regard to several short-term and long-term measures, despite reporting higher rates of inhaled corticosteroid use and routine asthma care visits. Further studies are needed to elucidate whether these findings are due to differences in health reporting or to pathophysiologic differences in asthma between the sexes.
• Impulse oscillometry versus spirometry in a long-term study of controller therapy for pediatric asthma
  - J Allergy Clin Immunol 123(4):861-867.e1 (2009)
  Background Determination of the benefits and limitations of specific physiologic tests has not been well studied in long-term clinical pediatric trials. Objective We sought to determine the utility of impulse oscillometry in a long-term comparison of 3 controller regimens in children with persistent asthma. Methods Children 6 to 14 years of age with mild-to-moderate persistent asthma were characterized with oscillometry and spirometry before entry into a clinical trial and then serially during 48 weeks of therapy with either an inhaled corticosteroid, a combination inhaled corticosteroid with a long-acting β-agonist, or a leukotriene receptor antagonist. Results The FEV1/forced vital capacity ratio, as well as the forced expiratory flow from 25% to 75% of forced vital capacity in terms of spirometric parameters and the reactance area (XA) from impulse oscillometry, appeared to complement information provided by FEV1 when comparing the tests and factors that appeared to predict a response to treatment. XA was unique in that it, as distinct from spirometric variables, reflected ongoing improvement during the latter part of the trial. In general, improvements in XA during the latter part of the study occurred independently of indices of atopy and the level of airway responsiveness. Conclusion Assessment of respiratory mechanics over time with oscillometry might offer additional insights into the response of asthmatic patients to therapy. In particular, the pattern of improvement seen in XA over the course of therapy suggests this test might detect alterations in airway mechanics not reflected by spirometry. The possibility that changes in XA reflect ongoing improvement in small airway function deserves additional study.
• Prostaglandin E2 suppresses staphylococcal enterotoxin–induced eosinophilia-associated cellular responses dominantly through an E-prostanoid 2–mediated pathway in nasal polyps
  - J Allergy Clin Immunol 123(4):868-874.e13 (2009)
  Background Recent investigations have revealed that staphylococcal enterotoxins (SEs), COX metabolism, or both might participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyposis. Objective We sought to determine whether COX metabolism, especially prostaglandin (PG) E2, plays a significant role in SE-induced cellular responses in nasal polyps. Methods Dispersed nasal polyp cells (DNPCs) were prepared from nasal polyps by means of enzymatic digestion. DNPCs were cultured with SEB in the presence or absence of COX inhibitors (diclofenac and indomethacin) for 72 hours; then the levels of IL-5, IL-13, RANTES, and eotaxin in the supernatants were measured. The effect of PGE2 on SEB-induced responses by diclofenac-treated DNPCs was examined, especially in terms of receptor specificity. Results DNPCs produced significant amounts of IL-5, IL-13, and RANTES in response to SEB. COX inhibitors significantly increased the production of these cytokines. The degree of local eosinophilia was significantly and positively correlated with the changes in IL-5 production induced by diclofenac treatment. PGE2 significantly and dose-dependently inhibited SEB-induced IL-5, IL-13, and RANTES production by diclofenac-treated DNPCs. E-prostanoid (EP) 2 receptor–selective agonist strongly inhibited the production of all 3 cytokines. EP3 and EP4 receptor–selective agonists partially suppressed these responses, whereas EP1 receptor–selective agonist did not. Interestingly, all of the combined treatments with 2 of the 4 EP receptor–selective agonists significantly inhibited the SEB-induced responses by diclofenac-treated DNPCs. Conclusions These results suggest that PGE2 inhibits the pathogenesis of SEB-induced eosinophilic inflammation primarily through the EP2-mediated pathway in patients with chronic rhinosinusitis with nasal polyposis.
• Toll-like receptor 2 is important for the TH1 response to cutaneous sensitization
  - J Allergy Clin Immunol 123(4):875-882.e1 (2009)
  Background Atopic dermatitis and allergic contact dermatitis are skin disorders triggered by epicutaneous sensitization with protein antigens and contact sensitization with haptens, respectively. Skin is colonized with bacteria, which are a source of Toll-like receptor (TLR) 2 ligands. Objective We sought to examine the role of TLR2 in murine models of atopic dermatitis and allergic contact dermatitis. Methods TLR2−/− mice and wild-type littermates were epicutaneously sensitized with ovalbumin (OVA) or contact sensitized with oxazolone (OX). Skin histology was assessed by means of hematoxylin and eosin staining and immunohistochemistry. Ear swelling was measured with a micrometer. Cytokine mRNA expression was examined by means of quantitative RT-PCR. Antibody levels and splenocyte secretion of cytokines in response to OVA stimulation were measured by means of ELISA. Dendritic cells were examined for their ability to polarize T-cell receptor/OVA transgenic naive T cells to TH1 and TH2. Results In response to OVA sensitization, TLR2−/− mice experienced skin infiltration with eosinophils and CD4+ cells, as well as upregulation of TH2 cytokine mRNAs that was comparable with that seen in wild-type littermates. In contrast, epidermal thickening, IFN-γ expression in the skin, IFN-γ production by splenocytes, and IgG2a anti-OVA antibody levels were impaired in TLR2−/− mice. After OX ear challenge, contact sensitized TLR2−/− mice exhibited defective ear swelling with impaired cellular infiltration, decreased epidermal thickening and local IFN-γ expression, and impaired OX-specific IgG2a responses. Dendritic cells from TLR2−/− mice induced significantly lower production of IFN-γ but normal IL-4 and IL-13 production in naive T cells. Conclusions These results indicate that TLR2 promotes the IFN-γ response to cutaneously introduced antigens.
• Accidental allergic reactions in children allergic to cow's milk proteins
  - J Allergy Clin Immunol 123(4):883-888 (2009)
  Background Cow's milk is the main cause of food allergy in children. Patients allergic to food frequently experience accidental exposure. There are few studies analyzing this problem, most of them concerning peanut allergy. Objective We sought to calculate the frequency of accidental exposure reactions in children allergic to cow's milk during a 12-month period, to analyze the clinical characteristics and circumstances surrounding the reactions, and to identify risk factors for severe reactions. Methods Eighty-eight children allergic to cow's milk (44 boys; median age, 32.5 months) were included in the study. A systematized questionnaire about accidental exposure was used. Reactions were classified as mild, moderate, and severe. Cow's milk– and casein-specific IgE antibody titers were determined. Results Thirty-five (40%) children had 53 reactions in the previous year (53% mild, 32% moderate, and 15% severe). Most reactions took place at home (47%) under daily life circumstances (85%). Specific IgE levels to cow's milk were higher in children with severe reactions than in those with moderate (median, 37.70 vs 7.71 KUA/L; P = .04) or mild (3.37 KUA/L; P = .04) reactions. The frequency of severe reactions was 10-fold higher in asthmatic children (odds ratio, 10.2; 95% CI, 1.13-91.54). Conclusions Reactions to accidental exposure are frequent in children with cow's milk allergy. The proportion of severe reactions was 15%. The risk factors for such reactions included very high levels of specific IgE to cow's milk and casein and asthma.
• Antigen-primed splenic CD8+ T cells impede the development of oral antigen–induced allergic diarrhea
  - J Allergy Clin Immunol 123(4):889-894 (2009)
  Background Although CD4+ T-cell populations are thought to be involved in the pathophysiology of food allergy and oral tolerance, the role of CD8+ T cells remains uncertain. Objective We analyzed regulatory effects of adoptively transferred CD8+ T cells on the development of allergic diarrhea in antigen-sensitized mice that had a significantly reduced number of conventional TCRαβ+ CD8+ T cells. Methods Ovalbumin-specific T-cell receptor transgenic mice were systemically sensitized to ovalbumin. Splenic CD8+ T cells purified from ovalbumin-sensitized or nonsensitized wild-type mice or IL-10 knockout mice were adoptively transferred to ovalbumin-sensitized ovalbumin-specific T-cell receptor transgenic mice. Allergic diarrhea induced by oral administration of ovalbumin, ovalbumin-specific immunoglobulin production, and cytokine production in intestines and mesenteric lymph nodes were assessed. Results Adoptive transfer of splenic CD8+ T cells from ovalbumin-primed mice, but not from nonprimed mice, suppressed the development of allergic diarrhea, which was associated with in vivo increased IL-10 mRNA expression and in vitro antigen-specific IL-10 production by mesenteric lymph node cells. Upregulation of serum ovalbumin-specific IgE was not suppressed by ovalbumin-primed CD8+ T-cell transfer. Although administration of IL-10 before ovalbumin challenge failed to alleviate allergic diarrhea, transfer of splenic CD8+ T cells from IL-10 knockout mice showed diminished preventive effects. Conclusion Systemic immunization with allergen simultaneously induces regulatory CD8+ T cells that can inhibit the development of allergic diarrhea. IL-10 production by regulatory CD8+ T cells appears to be partially involved in these inhibitory mechanisms.
• Alternative algorithm for L-asparaginase allergy in children with acute lymphoblastic leukemia
  - J Allergy Clin Immunol 123(4):895-899 (2009)
  Background L-asparaginase is a crucial chemotherapeutic agent for the treatment of acute lymphoblastic leukemia. The alternatives to L-asparaginase are not available in many parts of the world, including Turkey. Objective We sought to evaluate the utility of premedication with or without a desensitization protocol in children with acute lymphoblastic leukemia and systemic hypersensitivity reactions to Escherichia coli–asparaginase. Methods In this prospective study patients with systemic hypersensitivity reactions to E coli–asparaginase for whom we were unable to ascertain/provide other alternatives to asparaginase were either premedicated, desensitized, or both to receive their chemotherapy as E coli–asparaginase according to the severity of the hypersensitivity reaction. Results Nineteen patients (13 male patients) with a mean age of 7.4 ± 4.7 years experienced a systemic hypersensitivity reaction to E coli–asparaginase during a 4-year period. Polyethylene glycol–asparaginase could be used for 3 patients. Eight of the remaining 16 children, who had experienced anaphylaxis, were premedicated and desensitized with E coli–asparaginase, and in 7 patients treatment was tolerated. The other 8 patients, with acute allergic reactions to E coli–asparaginase, were premedicated first, and 5 of them showed no reaction subsequently. Three of them demonstrated systemic hypersensitivity reactions again (anaphylaxis, n = 3), and premedication and desensitization with E coli–asparaginase resulted in anaphylaxis. Polyethylene glycol–asparaginase was administered uneventfully to the patients who could be provided it. Conclusion E coli–asparaginase could be administered to more than half of the patients who had a hypersensitivity reaction, and all of these patients were able to receive their planned doses of asparaginase. In countries with shortages of alternative asparaginase preparations, our approach might be a suitable option.
• Immune responses in adult female volunteers during the bed-rest model of spaceflight: Antibodies and cytokines
  - J Allergy Clin Immunol 123(4):900-905 (2009)
  Background It is unknown whether a prolonged period of bed rest will affect human immune responses, particularly in female subjects. Objective We sought to measure immune responses in adult female subjects exposed to prolonged bed rest. Methods Adult (25-40 years) female volunteers (n = 24) were maintained in a supine (6° tilt) head-down bed-rest (HDBR) position for 60 days: 8 with HDBR only, 8 with HDBR and regular muscular exercise, and 8 with HDBR and dietary protein supplementation. Subjects were immunized with bacteriophage φX-174. Antibody production and plasma cytokine levels were determined. Results The rate of primary antibody production of the HDBR plus exercise group increased faster (P = .01) and to a higher level versus that of the HDBR-only group (P = .03) and that of the HDBR plus diet group (trend P = .08). The rates of secondary antibody production between the 3 groups were similar, but the level of antibody in the HDBR plus exercise group remained higher versus that in the HDBR-only group (P = .03). Both the HDBR (P = .001) and HDBR plus diet (P = .02) groups had time-related progressive increases in TNF-α receptor levels, but the HDBR plus exercise group remained at baseline. The HDBR plus exercise group experienced an acute increase in IL-1 receptor antagonist levels versus the HDBR (P = .02) and the HDBR plus diet (P = .02) groups, with similar increases in RANTES levels. Conclusions The exercise countermeasure accelerated primary antibody production and increased antibody levels to bacteriophage φX-174 and also opposed the potentially harmful effects of increased TNF-α levels caused by prolonged bed rest, possibly by activating the anti-inflammatory cytokine IL-1 receptor antagonist and the chemotactic factor RANTES.
• Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema
  - J Allergy Clin Immunol 123(4):906-910 (2009)
  Background Recent studies reported a gain-of-function mutation in the gene encoding coagulation Factor XII (F12) among 5 German and French families with estrogen-associated angioedema who share a common ancestor. The role of this factor, additional pathways that might contribute to increased bradykinin levels, or both remain to be determined in other families with estrogen-dependent or estrogen-associated inherited angioedema. Objective The purpose of this study was to determine whether mutations in F12 and polymorphisms in the genes encoding aminopeptidase P (APP) and angiotensin I–converting enzyme (ACE), which have been associated with increased bradykinin levels, contribute to estrogen-dependent inherited angioedema in a large family of Italian origin. Methods We screened the coding regions of F12 and the gene encoding membrane-bound APP (XPNPEP2), for genetic variants in the 3 affected female subjects. In addition, we genotyped this family for the insertion/deletion polymorphism in the ACE gene, which accounts for variable ACE levels. Results The 3 affected female subjects all have the threonine-to-lysine (Thre328Lys) mutation, which is associated with higher Factor XII activity. In addition, they have at least one A allele of rs3788853 at the XPNPEP2 locus, which is associated with lower APP activity, and at least one I allele in ACE, which is associated with reduced ACE activity. Conclusion A missense mutation in F12 is present in the 3 affected female subjects of this family with estrogen-dependent inherited angioedema. In addition, these affected females have polymorphisms associated with lower levels of both APP and ACE, the major enzymes responsible for bradykinin degradation. Thus, our study suggests that multiple genes might contribute to estrogen-dependent or estrogen-associated inherited angioedema and explain some of the observed heterogeneity.
• An interaction between filaggrin mutations and early food sensitization improves the prediction of childhood asthma
  - J Allergy Clin Immunol 123(4):911-916 (2009)
  Background Asthma prediction in early infancy is essential for the development of new preventive strategies. Loss-of-function mutations in the filaggrin gene (FLG) were identified as risk factors for eczema and associated asthma. Objective We evaluated the utility of the FLG mutations for the prediction of asthma. Methods Eight hundred seventy-one individuals of the prospective German Multicenter Allergy Study cohort were genotyped for 3 FLG mutations. Information on asthma, eczema, and food sensitization was available from birth to 13 years of age. Pulmonary function was measured from 7 to 13 years of age. The predictive value of the FLG mutations and of atopic phenotypes in infancy was assessed for asthma. Results In infants with eczema and sensitization to food allergens, the FLG mutations predicted childhood asthma with a positive predictive value of 100% (95% CI, 65.5% to 100%). This subgroup was characterized by a significant decrease in pulmonary function until puberty and represented 8.1% of all asthmatic children and 19.1% of patients with asthma after infantile eczema. We found a strong synergistic interaction between the FLG-null alleles and early food sensitization in the disease transition from eczema to asthma (relative excess risk due to interaction, 2.64; 95% CI, 1.70-3.98; P = .00040). Conclusion FLG mutations and food sensitization represent 2 distinct mechanisms interacting in the pathogenesis of asthma. In infants with eczema and food sensitization, genotyping of the FLG mutations allows the prediction of asthma before the onset of symptoms. Our findings might facilitate the development of early subgroup-specific interventions to prevent the progression from eczema to asthma.
• Fms-like tyrosine kinase 3 ligand increases a lung DC subset with regulatory properties in allergic airway inflammation
  - J Allergy Clin Immunol 123(4):917-924.e2 (2009)
  Background Dendritic cell (DC) subsets display different functional roles in regulating immune responses and lead to various outcomes, including TH1 versus TH2 or regulatory versus immunologic responses. Administration of Fms-like tyrosine kinase 3 (Flt3) ligand prevents and reverses allergic airway inflammation and airway hyperresponsiveness in a mouse model. However, the underlying mechanisms are unclear. Objective We characterized and examined the role of lung DC subsets in the therapeutic effect of Flt3 ligand. Methods DCs were isolated from the lungs of ovalbumin (OVA)-sensitized and OVA-challenged mice treated with recombinant human Flt3 ligand. Two populations of CD11c+ cells labeled with fluorochrome-conjugated antibodies were sorted. The ability of the purified cells to stimulate T-cell proliferation and cytokine secretion patterns by different DC subsets was examined. Also, DCs were adoptively transferred in mice to examine their effect on pulmonary function. Results Two DC populations, CD11chighCD11blow and CD11clowCD11bhigh, were identified in the lungs of naive and OVA-sensitized and OVA-challenged mice with and without treatment with Flt3 ligand. The expression levels of CD8α, B220, CD19, F4/80, MHC II, CCR7, CD40, programmed death ligand 1, programmed death ligand 2, CD80, and CD86 were distinctly different between the 2 DC populations, which supports the notion that CD11chighCD11blow and CD11clowCD11bhigh DCs potentially have regulatory and immunogenic properties, respectively. Administration of Flt3 ligand increased the DCs with regulatory potential in the lungs of antigen-sensitized mice, and CD11chighCD11blow DCs acquired a maximum degree of regulatory capacity after Flt3 ligand treatment. Conclusion These data suggest that Flt3 ligand reverses airway hyperresponsiveness by regulating the function of lung DCs in a mouse model of allergic airway inflammation.
• Combined sensitization of mice to extracts of dust mite, ragweed, and Aspergillus species breaks through tolerance and establishes chronic features of asthma
  - J Allergy Clin Immunol 123(4):925-932.e11 (2009)
  Background Existing asthma models develop tolerance when chronically exposed to the same allergen. Objective We sought to establish a chronic model that sustains features of asthma long after discontinuation of allergen exposure. Methods We immunized and exposed mice to a combination of single, double, or triple allergens (dust mite, ragweed, and Aspergillus species) intranasally for 8 weeks. Airway hyperreactivity (AHR) and morphologic features of asthma were studied 3 weeks after allergen exposure. Signaling effects of the allergens were studied on dendritic cells. Results Sensitization and repeated exposure to a single allergen induced tolerance. Sensitization to double and especially triple allergens broke through tolerance and established AHR, eosinophilic inflammation, mast cell and smooth muscle hyperplasia, mucus production, and airway remodeling that persisted at least 3 weeks after allergen exposure. Mucosal exposure to triple allergens in the absence of an adjuvant was sufficient to induce chronic airway inflammation. Anti–IL-5 and anti–IL-13 antibodies inhibited inflammation and AHR in the acute asthma model but not in the chronic triple-allergen model. Multiple allergens produce a synergy in p38 mitogen-activated protein kinase signaling and maturation of dendritic cells, which provides heightened T-cell costimulation at a level that cannot be achieved with a single allergen. Conclusions Sensitivity to multiple allergens leads to chronic asthma in mice. Multiple allergens synergize in dendritic cell signaling and T-cell stimulation that allows escape from the single allergen-associated tolerance development.
• Selective deregulation in chemokine signaling pathways of CD4+CD25hiCD127lo/− regulatory T cells in human allergic asthma
  - J Allergy Clin Immunol 123(4):933-939.e10 (2009)
  Background CD4+CD25hiCD127lo/− regulatory T cells have been suggested to be critical regulators of inflammatory processes in allergic asthma. Recent studies reported a selective decrease in the frequency of regulatory T cells in the bronchoalveolar lavage fluid of allergic asthmatic (AA) subjects, prompting the possibility of defective recruitment of these cells to the airway in response to chemokines produced during asthmatic inflammation. Objectives This study aimed to characterize the chemotactic profile of circulating regulatory T cells in AA subjects in response to chemokines abundantly produced in airway inflammation, such as CCL1, CCL17, and CCL22. Methods The study was performed in a cohort of 26 AA, 16 healthy control, and 16 non-AA subjects. We used chemotaxis assays to evaluate cell migration, flow cytometry to examine chemokine receptor expression, and phospho-ELISA to study consequent signaling pathways in regulatory T cells. Results Regulatory T cells, but not CD4+CD25−T cells, from AA subjects showed decreased chemotactic responses, specifically to CCL1, in comparison with their healthy control and non-AA counterparts. Decreased CCL1-mediated chemotaxis in AA regulatory T cells was associated with decreased phosphorylation of protein kinase B (AKT), a protein involved in chemokine intracellular signaling. Furthermore, the decreased chemotactic response to CCL1 in AA regulatory T cells significantly correlated with asthma severity and decreased pulmonary function in AA subjects. Conclusions These results provide the first evidence of dysfunction in the chemokine signaling pathway in AA regulatory T cells.
• Adiposity, serum lipid levels, and allergic sensitization in Chinese men and women
  - J Allergy Clin Immunol 123(4):940-948.e10 (2009)
  Background Obesity and allergic diseases have increased dramatically in recent decades. Although adiposity has been associated with asthma, associations with allergic sensitization have been inconsistent. Objective To examine the association of adiposity and lipid profiles with allergic sensitization. Methods This study included 1187 rural Chinese twins (653 men) age 18 to 39 years, with skin prick tests, anthropometric and dual-energy x-ray absorptiometry–assessed adiposity measures, and lipid assessments. Allergic sensitization was defined as positive SPT to ≥1 allergen (9 foods and 5 aeroallergens tested). We applied sex-stratified generalized estimating equations to assess the association of adiposity and serum lipids with allergic sensitization, and structural equation models to estimate the genetic/environmental influences on any observed associations. Results Men had lower percent body fat (% BF) (13.9% vs. 28.8%) but higher rates of allergic sensitization (56.2% vs 36.7%) than women. Men in the highest %BF quartile were 2.1 times more likely to be sensitized than the lowest quartile (95% CI, 1.3-3.5; P trend = .003). In men, the risk of allergic sensitization increased with high-density lipoprotein (HDL) <40 mg/dL (odds ratio = 4.0; 95% CI, 1.8-9.2) and higher low-density lipoprotein quartiles (P trend = .007). This appeared to be partially explained by shared genetic factors between serum lipid levels and allergic sensitization. In females, lower HDL was associated with increased risk of allergic sensitization. Conclusion In this relatively lean Chinese population, higher %BF, lower HDL and higher LDL were associated with greater risk of allergic sensitization, most notable in men. The observed associations among adiposity, serum lipids, and allergic sensitization in men appear to be partially explained by common genetic influences on these traits.
• Mediator release assay for assessment of biological potency of German cockroach allergen extracts
  - J Allergy Clin Immunol 123(4):949-955.e1 (2009)
  Background Cockroach is an important allergen in inner-city asthma. The diagnosis and treatment of cockroach allergy has been impeded by the lack of standardized cockroach extracts. Objective We investigated the utility of a mediator release assay based on rat basophil leukemia (RBL) cells for comparing the potency of German cockroach extracts. Methods RBL cells (line 2H3) transfected with human FcεRI were passively sensitized with sera from subjects with cockroach allergy and stimulated with serial dilutions of 3 commercial cockroach extracts (1:10 weight/volume). In addition, the in-house prepared extract was tested in separate experiments with pooled sera that produced optimal performance in the RBL assay. N-hexosaminidase release (NHR) was used as a marker of RBL cell degranulation and was examined in relation to the intradermal skin test (ID50EAL) and serum cockroach-specific and total IgE levels. Results The median cockroach-specific IgE concentration in 60 subjects was 0.72 kUA/L (interquartile range, 0.35-2.97 kUA/L); 19 sera (responders) produced a minimum 10% NHR to more than 1 extract. Responders had higher median cockroach-specific IgE (7.4 vs 1.0 kUA/L) and total IgE (429 vs 300 kU/L) levels than nonresponders. Ranking of extract potency was consistent between the mediator release assay and the ID50EAL. For the in-house prepared cockroach extract, the dose-response curves were shifted according to the concentration of the extract. NHR was reproducible between different experiments by using pooled sera. Conclusion The mediator release assay measures biologic potency and correlates with the ID50EAL. It should be further evaluated to determine whether it could be used to replace intradermal skin test titration for assessing the potency of cockroach extract.
• A novel mutation in the linker domain of the signal transducer and activator of transcription 3 gene, p.Lys531Glu, in hyper-IgE syndrome
  - J Allergy Clin Immunol 123(4):956-958 (2009)
  
• Thymic stromal lymphopoietin as a mediator of crosstalk between bronchial smooth muscles and mast cells
  - J Allergy Clin Immunol 123(4):958-960.e2 (2009)
  
• Role of IL-7 in the regulation of T-cell homeostasis in partial DiGeorge syndrome
  - J Allergy Clin Immunol 123(4):960-962.e2 (2009)
  
• A Turkish family with a novel mutation in the promoter region of the C1 inhibitor gene
  - J Allergy Clin Immunol 123(4):962-964 (2009)
  
• Season of infant bronchiolitis and estimates of subsequent risk and burden of early childhood asthma
  - J Allergy Clin Immunol 123(4):964-966 (2009)
  
• Novel presentation of Omenn syndrome in association with aniridia
  - J Allergy Clin Immunol 123(4):966-969 (2009)
  
• Low-dose cyclosporine is a good option for severe chronic urticaria
  - J Allergy Clin Immunol 123(4):970 (2009)
  
• Reply
  - J Allergy Clin Immunol 123(4):970-971 (2009)
  
• The influence of hepatic damage on serum soluble Fas ligand levels of patients with drug rashes
  - J Allergy Clin Immunol 123(4):971-972 (2009)
  
• Reply
  - J Allergy Clin Immunol 123(4):972 (2009)
  
• Activation of the blood coagulation cascade is involved in patients with chronic urticaria
  - J Allergy Clin Immunol 123(4):972-973 (2009)
  
• Reply
  - J Allergy Clin Immunol 123(4):973-974 (2009)
  
• Test for Respiratory and Asthma Control in Kids (TRACK): A caregiver-completed questionnaire for preschool-aged children
  - J Allergy Clin Immunol 123(4):833-839.e9 (2009)
  Background A validated questionnaire is needed to monitor respiratory control in preschool-aged children. Objective We sought to develop and validate a caregiver-completed questionnaire that measures respiratory control in young children. Methods A 33-item questionnaire that included asthma impairment and risk items was administered to 486 caregivers of children aged younger than 5 years with a current, recent, or past history of respiratory symptoms. Stepwise regression was used to select a subset of items with the greatest discriminant validity in relation to guidelines-defined asthma control in a random two-thirds development sample. Reliability, validity, and ability to screen for respiratory control problems were tested in development and validation samples (remaining one-third sample). Results The content of the 5 items selected, the Test for Respiratory and Asthma Control in Kids (TRACK), included frequency of respiratory symptoms (wheeze, cough, shortness of breath), activity limitation, and nighttime awakenings in the past 4 weeks; rescue medication use in the past 3 months; and oral corticosteroid use in the previous year. Reliability was greater than 0.70 in both samples. ANOVA showed that mean scores differed significantly (P < .001) in the expected direction across both samples for 3 levels of guidelines-based respiratory control, physician-recommended change in therapy, and symptom status. In the development and validation samples, screening analyses revealed areas under the receiver operating characteristic curve of 0.88 and 0.82, respectively; control status was correctly classified in 81% and 78% of cases. Conclusion TRACK is a valid, easy-to-administer, caregiver-completed questionnaire of respiratory control in preschool-aged children with symptoms consistent with asthma.