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Article Outline

• Safety of formoterol in patients with asthma
• Severe asthma attacks related to air pollution are more common in children
• Asthma exacerbation is accompanied with increased CD203c expression on basophils
• Genome-wide association studies meet asthma
• Leukotriene receptor antagonists inhibit secretion, even from extracellular eosinophil granules
• Copyright

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Safety of formoterol in patients with asthma 

Concerns exist that the risk of serious asthma-related events might increase with regular use of long-acting β₂-adrenergic agonists (LABAs). In the most stringent assessment of formoterol safety data to date, Nelson et al (p 390) assessed the risk of serious asthma-related events with formoterol-containing treatment in a large data set (n = 23,510) of asthmatic patients aged 4 years or older. Data were from all blind, parallel-arm, randomized, active- and/or placebo-controlled, AstraZeneca-sponsored asthma studies with formoterol, a total of 42 studies in 13,542 subjects receiving formoterol and 9,968 receiving non-LABA regimens. Results showed no evidence of an increased risk for asthma-related hospitalizations with formoterol-containing versus non-LABA treatment (relative risk, 0.73; see Figure). In addition, there were no asthma-related deaths, and the incidence of asthma-related intubation (1 in the formoterol-containing group) and all-cause death (3 in the formoterol-containing group and 4 in the non-LABA group) was low. Secondary analyses based on formoterol dose, age, race, and concomitant inhaled corticosteroid (ICS) use showed no increased risk. These findings, along with studies demonstrating the clinical benefits of budesonide/formoterol therapy, support current guidelines recommendations for ICS/LABA use in patients with asthma not controlled with ICSs alone. However, because of the rarity of certain asthma-related events, an increased risk with formoterol cannot be ruled out by these data.

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• Risk of asthma-related hospitalization with formoterol-containing versus non-LABA therapy.

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Severe asthma attacks related to air pollution are more common in children 

Children are disproportionately affected by asthma and have higher hospitalization rates than adults. Air pollution is known to worsen asthma symptoms, and Silverman et al (p 367) sought to determine whether children with asthma were more susceptible to air pollution–related morbidity than adults. A second research question addressed whether air pollution was associated with life-threatening asthma requiring an intensive care unit admission. The study involved data from 74 hospitals and 75,383 hospitalizations in New York City over an 8-year period. Investigators found that increased ambient PM2.5 (small-particle air pollution) and ozone levels in the warm-weather months were associated with an increased number of asthma-related hospitalizations and that age influenced susceptibility to the adverse effects of both pollutants. Asthma hospitalizations on higher-pollution days were consistently greatest among children aged 6 to 18 years. Furthermore, increased air pollution was associated with very severe asthma episodes requiring admission to an intensive care unit, again disproportionally affecting children. The relationship between morbidity and air pollution levels were linear, indicating that subjects were at risk even when pollutants were below National Ambient Air Quality Standards considered harmful to the public health. The investigators conclude that warm-weather patterns of ozone and PM2.5 appear responsible for severe asthma attacks that could have been avoided and that alternative pollution standards are needed to decrease asthma-related morbidity.

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Asthma exacerbation is accompanied with increased CD203c expression on basophils 

CD203c is a basophil cell-surface marker used to diagnose and monitor various allergic diseases and considered to be the most useful marker of basophil activation and differentiation. As reported in this issue, Ono et al (p 483) examined the relationship between CD203c expression and the pathologic condition of asthma. The authors found that (1) spontaneous expression levels of CD203c were significantly higher on basophils from patients with asthma exacerbation than those from patients with stable asthma or healthy subjects, (2) asthma exacerbation was accompanied by increased anti-IgE–induced expression levels of CD203c that decreased significantly during remission, (3) low concentrations of Der p 1 or IL-3 induced higher expression levels of CD203c during asthma exacerbation than during clinical improvement, and (4) spontaneous CD203c expression levels correlate with airflow limitation during asthma exacerbation. This study demonstrates that basophils are activated by a number of factors during asthma exacerbation and that the changes in expression levels of CD203c on basophils correlate with asthma status and can be used as a biomarker for disease monitoring.

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Genome-wide association studies meet asthma 

Asthma is a common chronic childhood illness that is strongly influenced by genetic factors. Three articles in this issue of the Journal illustrate how genome-wide association studies (GWASs) to our developing understanding of asthma.

GWASs scan the whole genome to identify novel disease susceptibility genes (typically those with mild/moderate effects), unconstrained by prior knowledge. To date, only a few GWASs have been performed for asthma. Li et al (p 328) performed a GWAS on a population of patients with severe or difficult-to-treat asthma (TENOR) to identify genes that are involved in the pathogenesis of asthma. Multiple single nucleotide polymorphisms (SNPs) in the RAD50-IL13 and HLA-DR/DQ regions were associated with asthma (see Fig A). This GWAS confirmed the important role of T_Hcytokine and antigen presentation genes in asthma at a genome-wide level. The findings will stimulate more comprehensive research on these genes because of their structural complexity and functional importance in the pathogenesis of asthma. The findings also support the development of therapeutic agents that modulate the IL4/IL13 pathway.

Mathias et al (p 336) report findings from the first asthma GWAS for which the discovery populations are of African descent. Genotyping more than 650,000 SNPs in 935 African American subjects and 929 African Caribbean subjects, the team conducted a meta-analysis and identified SNPs with P values of less than 10⁻⁵ in 3 genes of potential relevance to asthma: α-1B-adrenergic receptor (ADRA1B), prion-related protein (PRNP), and dipeptidyl peptidase IV–related protein 3 (DPP10; see Fig B). Associations in DPP10, a candidate previously identified through positional cloning, were also observed in a cluster of SNPs downstream from the African ancestry signal (P < 10⁻² to <10⁻³) in United Kingdom and German family and case-control samples, supporting the hypothesis that there are both common and unique polymorphisms conferring risk of asthma in subjects of African descent.

Many asthma candidate genes have been proposed through the use of association, positional cloning, and knockout mouse approaches. However, most of these genes have not been systematically replicated in human populations. Using GWAS data, Wu et al (p 321) comprehensively evaluated associations of 237 previously reported candidate genes with childhood asthma in a Mexico City population. Their results suggest that genetic variants in multiple genes, including TGFB1, IL1RL1, IL18R1, and DPP10, might contribute to childhood asthma susceptibility in a Mexican population (see Fig C). This is the most comprehensive evaluation of literature-based asthma candidate genes to date. Findings from the study might provide insights into disease pathogenesis and suggest potential therapeutic targets.

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• Fig A. 

  Results of an asthma GWAS showing RAD50-IL13 and HLA-DR/DQ.

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• Fig B. 

  Meta-analysis of African American and African Caribbean GRAAD samples.

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• Fig C. 

  Manhattan plot for 2,933 SNPs tested for associations with asthma.

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Leukotriene receptor antagonists inhibit secretion, even from extracellular eosinophil granules 

Montelukast inhibits stimulatory actions of cysteinyl leukotrienes, as currently recognized by principally blocking a single cysteinyl leukotriene receptor (CysLT1R) expressed on surface membranes of cells, including eosinophils, a class of leukocytes associated with allergic diseases. In eosinophil-associated diseases lysis of eosinophils releases free, intact, membrane-bound granules; however, the functional capacities of these extracellular eosinophil granules and their pertinence to allergic diseases have never been defined. Neves et al (p 477), writing in this issue of the Journal, document that cell-free human eosinophil granules express on their granule surface membranes ligand-binding domains for 2 cysteinyl leukotriene receptors and a purinergic receptor responsive to cysteinyl leukotrienes and demonstrate that cysteinyl leukotrienes, including those formed extracellularly, stimulate isolated eosinophil granules to secrete eosinophil cationic protein. Moreover, montelukast and a purinergic receptor antagonist that blocks the same receptor as does clopidogrel inhibited secretion of eosinophil cationic protein from eosinophil granules. These findings not only demonstrate that extracellular eosinophil granules in sites of allergic inflammation are secretion-competent organelles but also indicate that therapeutics, such as montelukast, might be beneficial not solely by acting on a single receptor (CysLT1R) expressed on intact cells but also by acting more broadly on other cysteinyl leukotriene receptors, including those expressed on cell-free eosinophil granules in sites of allergic inflammation.