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Background Asthma epidemics associated with thunderstorms have had catastrophic impacts on individuals and emergency services. Seasonal allergic rhinitis (SAR) is present in the vast majority of people who develop thunderstorm asthma (TA), but there is little evidence regarding risk factors for TA among the SAR population. Objective We sought to identify risk factors for a history of TA and hospital presentation in a cohort of individuals with SAR. Methods This multi-centre study recruited adults from Melbourne (Australia) with a past diagnosis of TA and/or self-reported SAR. Clinical information, spirometry, white blood-cell count, ryegrass pollen specific IgE (RGP-spIgE) and fractional exhaled nitric oxide (FeNO) were measured to identify risk factors for a history of TA in individuals with SAR. Results From a total of 228 individuals with SAR, 35% (80/228) reported SAR only (I-SAR), 37% (84/228) reported TA symptoms but had not attended hospital for treatment (O-TA) and 28% (64/228) had presented to hospital for TA (H-TA). All H-TA patients reported a previous asthma diagnosis. Logistic regression analysis of factors associated with O-TA and H-TA indicated that lower forced expiratory volume in one second (FEV1) and asthma control questionnaire (ACQ) score >1.5 were associated with H-TA. Higher blood RGP-spIgE, eosinophil counts, and FeNO were significantly associated with both O-TA and H-TA. Receiver-operating curve (ROC) analysis showed RGP-spIgE >10·1 kU/L and pre-bronchodilator FEV1 ≤90% to be biomarkers of increased H-TA risk. Conclusion Clinical tests can identify risk for a history of TA in individuals with SAR and thereby inform patient-specific treatment recommendations.

Background The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. Objective We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (F eno ), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. Methods We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and F eno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in F eno from baseline to day 14. Baseline was defined as the average F eno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. Results Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean F eno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in F eno was −23% (95% CI, −37.3 to −9) for 15 mg QD and −42% (95% CI, −57 to −27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater F eno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. Conclusions GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in F eno in mild asthma and was well tolerated without evidence of systemic toxicity.

BackgroundThe use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown.ObjectivesWe aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects.MethodsWe performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups.ResultsOverall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r=0.33, P&nbsp

BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate

Background: Exhaled nitric oxide (eNO) is a biomarker of airway inflammation and seems to precede respiratory symptoms, such as asthma, in childhood. Identifying genetic determinants of postnatal eNO levels might aid in unraveling the role of eNO in epithelial function or airway inflammation and disease. Objective: We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life. Methods: Within a population-based birth cohort, eNO levels were measured in healthy term infants aged 5 weeks during quiet tidal breathing in unsedated sleep. We assessed associations of single nucleotide polymorphisms with eNO levels in a genome-wide association study and subsequent symptoms of lower respiratory tract infections during the first year of life and asked whether this was modified by prenatal and early-life environmental factors. Results: We identified thus far unknown determinants of infant eNO levels: rs208515 (P = 3.3 x 10(-8)), which is located at 6q12, probably acting in "trans'' and explaining 10.3% of eNO level variance, and rs1441519 (P = 1.6 x 10(-6)), which is located at 11p14, potentially affecting nitric oxide synthase 3 (NOS3) expression, as shown by means of in vitro functional analyses. Moreover, the 6q12 locus was inversely associated with subsequent respiratory symptoms (P < .05) and time to recovery after first respiratory symptoms during the first year of life (P < .05). Conclusion: The identification of novel genetic determinants of infant eNO levels might implicate that postnatal eNO metabolism in healthy infants before first viral infections and sensitization is related to mechanisms other than those associated with asthma, atopy, or increased risk thereof later in life.

Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm 3 ) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

In this year's Advances in Asthma review, we discuss viral infections in asthmatic patients and potential therapeutic agents, the microbiome, novel genetic associations with asthma, air quality and climate effects on asthma, exposures during development and long-term sequelae of childhood asthma, patient-centered outcomes research, and precision medicine. In addition, we discuss application of biomarkers to precision medicine and new information on asthma medications. New evidence indicates that rhinovirus-triggered asthma exacerbations become more severe as the degree of sensitization to dust mite and mouse increase. The 2 biggest drivers of asthma severity are an allergy pathway starting with allergic sensitization and an environmental tobacco smoke pathway. In addition, allergic sensitization and blood eosinophils can be used to select medications for management of early asthma in young children. These current findings, among others covered in this review, represent significant steps toward addressing rapidly advancing areas of knowledge that have implications for asthma management.

Background Sparse data address the effects of nitrogen dioxide (NO2) exposure in inner-city schools on obese students with asthma. Objective We sought to evaluate relationships between classroom NO2 exposure and asthma symptoms and morbidity by body mass index (BMI) category. Methods The School Inner-City Asthma Study enrolled students aged 4 to 13 years with asthma from 37 inner-city schools. Students had baseline determination of BMI percentile. Asthma symptoms, morbidity, pulmonary inflammation, and lung function were monitored throughout the subsequent academic year. Classroom NO2 data, linked to enrolled students, were collected twice per year. We determined the relationship between classroom NO2 levels and asthma outcomes by BMI stratification. Results A total of 271 predominantly black (35%) or Hispanic students (35%) were included in analyses. Fifty percent were normal weight (5-84th BMI percentile), 15% overweight (≥85-94th BMI percentile), and 35% obese (≥95th BMI percentile). For each 10-parts per billion increase in NO2, obese students had a significant increase in the odds of having an asthma symptom day (odds ratio [OR], 1.86; 95% CI, 1.15-3.02) and in days caregiver changed plans (OR, 4.24; 95% CI, 2.33-7.70), which was significantly different than normal weight students who exhibited no relationship between NO2 exposure and symptom days (OR, 0.90; 95% CI, 0.57-1.42; pairwise interaction P = .03) and change in caregiver plans (OR, 1.37; 95% CI, 0.67-2.82; pairwise interaction P = .02). Relationships between NO2 levels and lung function and fractional exhaled nitric oxide did not differ by BMI category. If we applied a conservative Holm-Bonferroni correction for 16 comparisons (obese vs normal weight and overweight vs normal weight for 8 outcomes), these findings would not meet statistical significance (all P > .003). Conclusions Obese BMI status appears to increase susceptibility to classroom NO2 exposure effects on asthma symptoms in inner-city children. Environmental interventions targeting indoor school NO2 levels may improve asthma health for obese children. Although our findings would not remain statistically significant after adjustment for multiple comparisons, the large effect sizes warrant future study of the interaction of obesity and pollution in pediatric asthma.

Background Sex influences the risk of wheezing illnesses and the prevalence of asthma throughout childhood. Objective To better understand the mechanisms of these effects, we analyzed longitudinal relationships between sex, lung physiology, and asthma in the Childhood Origins of ASThma birth cohort study. Methods Childhood Origins of ASThma birth cohort study children were followed prospectively from birth and assessed annually. Results of spirometry, fractional exhaled nitric oxide (Feno), mannitol provocation testing, and 3 He gas magnetic resonance imaging were assessed by sex using multivariate models including age, asthma diagnosis, and wheezing histories. Results Girls had higher prebronchodilator forced expiratory volume in 0.5 seconds/forced vital capacity values than did boys (mean difference, 0.017; 95% CI, 0.000-0.034; P = .05) of equivalent age. Postbronchodilator findings were more pronounced, with boys demonstrating reduced forced expiratory volume in 0.5 seconds/forced vital capacity values than did girls of equivalent age (mean difference, 0.032; 95% CI, 0.014-0.049; P = .0005). Conversely, girls were noted to have higher ventilation defects on 3 He magnetic resonance imaging than did boys ( P = .01). No differences were noted in the rate of positive responses to mannitol provocation or Feno measurements. Conclusions Lower airflow values are present by spirometry for prepubertal boys than for age-matched girls; however, greater 3 He ventilation defects were noted in girls. This could represent a greater degree of subclinical air trapping in prepubertal girls because residual volumes are not detected on standard spirometric readings. No differences were noted between the 2 sexes with airway hyperresponsiveness (mannitol provocation testing) or inflammation (Feno). Prospective peripubertal follow-up will determine whether these differences persist or change with the de novo expression and remission of asthma based on sex and age.

Background The added value of fractional exhaled nitric oxide (Feno) remains controversial in the investigation of occupational asthma (OA). Objective We sought to assess whether or not the increase of Feno levels following positive specific inhalation challenge (SIC) was restricted to phenotypes of subjects sharing common clinical characteristics by using a statistical cluster analysis. Methods Subjects were investigated for possible OA in a tertiary center using SICs from 2006 to 2012. Feno levels and sputum eosinophil counts were assessed at baseline and 24 hours after SIC. We performed a 2-step cluster analysis of the subgroup of subjects with OA. A multivariate logistic regression was performed in order to identify the variables associated with an increase in Feno in subjects with OA. Results One hundred and seventy-eight subjects underwent SIC; 98 had a positive test. The cluster analysis performed in the OA subgroup identified 3 clusters. Despite a positive SIC, there was no increase in the Feno levels after exposure to occupational agents in Cluster 3, in which subjects were only exposed to low-molecular-weight (LMW) agents. The molecular weight of the agent (high molecular weight vs LMW) was the only factor associated with an increase in Feno (OR: 4.2 [1.1-16.8]) in subjects with a positive SIC. Conclusion An increase in Feno after exposure to agents causing OA seems to occur more consistently in subjects with OA caused by high molecular weight than in those with OA due to LMW.

The increased fraction of exhaled nitric oxide (Feno) values observed in asthmatic patients are thought to reflect increased airway inflammation. However, Feno values can be affected by airway caliber reduction, representing a bias when using Feno values to assess asthma control.We sought to determine the effect of changes in both airway caliber and inflammation on Feno values using the allergen challenge model.FEV1 and Feno values were measured during early airway responses (EARs) and late airway responses after challenge with house dust mite allergens in 15 patients with mild allergic asthma. Helium and sulfur hexafluoride (SF6) phase III expired concentration slopes (SHe and SSF6, respectively) from single-breath washout tests were measured to identify sites of airway constriction.In EARs, FEV1 and Feno value decreases reached 36.8% and 22%, respectively (P.001). ΔSHe was greater than ΔSSF6 (+189.4% vs +82.2%, P = .001). In late airway responses FEV1 and Feno value decreases reached 31.7% and 28.7%, respectively (P.001), with the same ΔSHe and ΔSSF6 pattern (+155.8% vs +76%, P = .001). Eight hours after the EAR, FEV1 was still decreased (P.001), whereas Feno values had returned to baseline. At 24 hours, FEV1 had returned to baseline, with Feno values increased by 38.7% (P = .04).In patients with mild allergic asthma, airway caliber changes modulate changes in Feno values resulting from airway inflammation. Therefore Feno should no longer be considered solely an inflammation biomarker but rather a biomarker that integrates both airway inflammation and lung function changes. Furthermore, early and late phases resulting from allergen exposure were shown to involve similar lung regions.

BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma. C.O. is supported by a NIH grant that supported the Hutterite studies (R01 HL085197). D.E. is supported by UK Medical Research Council Centre (G0600705). G.S. is supported by UK Medical Research Council Centre (G0600705). J.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). L.D. is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 (no. MC 1226- 2009). N.T. is supported by UK Medical Research Council Centre (G0600705). R.V. was partly supported by an unrestricted personal grant from GlaxoSmithKline, NL. V.J. is supported by the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). L. Duijts is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme (FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 [no. MC 1226-2009]). M. T. Salam has received research support from the National Heart, Lung, and Blood Institute (NHLBI; 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048); and the Environmental Protection Agency (EPA; 5P01ES009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25- 1). Evans has received a grant in the form of the MRC New Investigator Award G0600705. B. St Pourcain has received research support with Autism Speaks (7132). O. Fuchs has received research support from the European Commission within Seventh Framework Programme (theme FP7-KBBE-2007- 1) as part of EFRAIM (Impact of exogenous factors in the development of Allergy, contract no. 211911), the European Respiratory Society for a long-term research fellowship (no. 675). F. D. Gilliand has received research support from the NHLBI (5R01HL61768 and 5R01HL76647), Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048), the Children’s Environmental Health Center funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency (5P01Es009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627)

Background Previous studies have identified asthma phenotypes based on small numbers of clinical, physiologic, or inflammatory characteristics. However, no studies have used a wide range of variables using machine learning approaches. Objectives We sought to identify subphenotypes of asthma by using blood, bronchoscopic, exhaled nitric oxide, and clinical data from the Severe Asthma Research Program with unsupervised clustering and then characterize them by using supervised learning approaches. Methods Unsupervised clustering approaches were applied to 112 clinical, physiologic, and inflammatory variables from 378 subjects. Variable selection and supervised learning techniques were used to select relevant and nonredundant variables and address their predictive values, as well as the predictive value of the full variable set. Results Ten variable clusters and 6 subject clusters were identified, which differed and overlapped with previous clusters. Patients with traditionally defined severe asthma were distributed through subject clusters 3 to 6. Cluster 4 identified patients with early-onset allergic asthma with low lung function and eosinophilic inflammation. Patients with later-onset, mostly severe asthma with nasal polyps and eosinophilia characterized cluster 5. Cluster 6 asthmatic patients manifested persistent inflammation in blood and bronchoalveolar lavage fluid and exacerbations despite high systemic corticosteroid use and side effects. Age of asthma onset, quality of life, symptoms, medications, and health care use were some of the 51 nonredundant variables distinguishing subject clusters. These 51 variables classified test cases with 88% accuracy compared with 93% accuracy with all 112 variables. Conclusion The unsupervised machine learning approaches used here provide unique insights into disease, confirming other approaches while revealing novel additional phenotypes.

Background Improved diagnostic tools for predicting future exacerbation frequency in asthmatic patients are required. A sputum gene expression signature of 6 biomarkers (6-gene signature [6GS], including Charcot-Leyden crystal galectin [CLC]; carboxypeptidase 3 [CPA3]; deoxyribonuclease 1-like 3 [DNASE1L3]; alkaline phosphatase, liver/bone/kidney [ALPL]; CXCR2; and IL1B) predicts inflammatory and treatment response phenotypes in patients with stable asthma. Recently, we demonstrated that azithromycin (AZM) add-on treatment in patients with uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial). Objectives We sought to test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES and to test the effect of AZM therapy on 6GS expression and prognostic capacity. Methods One hundred forty-two patients (73 placebo-treated and 69 AZM-treated patients) had sputum stored for quantitative PCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression and receiver operating characteristic and area under the curve (AUC) determination were performed on baseline measures, and in an exploratory analysis the predictive value of the 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes. Results The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for the 6GS were significantly greater than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts, and combined sputum eosinophil and neutrophil counts. 6GS AUCs were also numerically but not significantly greater than those for fractional exhaled nitric oxide values and sputum eosinophil counts. AZM treatment altered neither 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population. Conclusion We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with the greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.

Background The single-center double-blind, randomized controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FENO) in combination with asthma symptoms (FENO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (Australian New Zealand Clinical Trials Registry, no. 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FENO group. However, the effect of FENO-guided management on the development of asthma in the offspring is unknown. Objective We sought to investigate the effect of FENO-guided asthma management during pregnancy on asthma incidence in childhood. Methods A total of 179 mothers consented to participate in the Growing into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FENO-guided asthma management on childhood asthma incidence. Results A total of 140 children (78%) were followed up at 4 to 6 years of age. FENO-guided as compared to symptoms-only approach significantly reduced doctor-diagnosed asthma (25.9% vs 43.2%; odds ratio [OR], 0.46, 95% CI, 0.22-0.96; P = .04). Furthermore, frequent wheeze (OR, 0.27; 95% CI, 0.09-0.87; P = .03), use of short-acting β-agonists (OR, 0.49; 95% CI, 0.25-0.97; P = .04), and emergency department visits for asthma (OR, 0.17; 95% CI, 0.04-0.76; P = .02) in the past 12 months were less common in children born to mothers from the FENO group. Doctor-diagnosed asthma was associated with common risk alleles for early onset asthma at gene locus 17q21 ( P = .01 for rs8069176; P = .03 for rs8076131), and higher airways resistance ( P = .02) and FENO levels ( P = .03). A causal mediation analysis suggested natural indirect effects of FENO-guided asthma management on childhood asthma through "any use" and "time to first change in dose" of inhaled corticosteroids during the MAP trial (OR: 0.83; 95% CI: 0.59-0.99, and OR: 0.90; 95% CI: 0.70-1.03, respectively). Conclusions FENO-guided asthma management during pregnancy prevented doctor-diagnosed asthma in the offspring at preschool age, in part mediated through changes in use and dosing of inhaled corticosteroids during the MAP trial.

Exposure to tobacco smoke is a well-known risk factor for childhood asthma and reduced lung function, but the effect on airway inflammation in preschool-aged children is unclear.To examine the effect of parental smoking on lung function and fractional concentration of exhaled nitric oxide (Feno) in relation to both parental reports and children's urine cotinine concentrations in preschool-aged children with multiple-trigger wheeze.A total of 105 3- to 7-year-old children with multiple-trigger wheeze and lung function abnormalities were recruited. Lung function was assessed by impulse oscillometry, and Feno measurements were performed. Exposure to tobacco smoke was determined by parental reports and measurement of children's urinary cotinine concentrations.Forty-three percent of the children were exposed to environmental tobacco smoke according to parental reports. The Feno level was significantly higher in children with a smoking mother (n = 27) than in children with a nonsmoking mother (23.4 vs 12.5 ppb, P = .006). The Feno level expressed as z score and the cotinine level correlated significantly (P = .03). Respiratory resistance at 5 Hz was higher in children exposed to maternal smoking than in others (0.99 vs 0.88 kPas/L, P = .005). Urinary cotinine concentrations reflected well parental reports on their daily smoking and increased relative to the number of cigarettes smoked in the family (P.01). Atopy was found in 75% of the children, but it was not associated with the Feno value (P = .65).Maternal smoking was associated with increased Feno value and poorer lung function in steroid-naive preschool children with multiple-trigger wheeze. Larger controlled trials are needed to generalize the results.

A biomarker provides a window on underlying disease activity. This is helpful when the pathology, treatment response, or both are heterogeneous or when trying to interpret nonspecific respiratory symptoms in patients with comorbidities. The successful application of a biomarker result is critically dependent on the specific question being addressed and the performance characteristics of the biomarker in relation to that question in the context of pretest probabilities. Negative prediction might be the best way to use a biomarker, such as a D-dimer, pro-brain natriuretic peptide, and exhaled nitric oxide. In this review the role of biomarkers in airways disease (notably induced sputum eosinophils and exhaled nitric oxide) is considered in relation to risk stratification, identification of treatment responders, identification of a clinical phenotype, monitoring of disease, and new drug development.

Background Children with asthma exposed to secondhand smoke (SHS) might be at higher risk for severe exacerbations, but biomarkers of susceptibility to SHS exposure have not been previously reported. Objectives We sought to assess the usefulness of urinary leukotriene E 4 (uLTE 4 ) levels in the prediction of increased risk of severe asthma exacerbations requiring emergency department (ED) or urgent care (UC) visits. Methods Forty-four schoolchildren with moderate-to-severe asthma receiving inhaled corticosteroids were followed for 5 months with repeated measurements of uLTE 4 and monitoring of ED and UC visits. SHS exposure status was determined by using prestudy questionnaires and repeated measurements of urinary cotinine during the study. Results Nine (45%) of 20 children with SHS exposure experienced a severe exacerbation requiring an ED or UC visit compared with 3 (12.5%) of 24 children without significant SHS exposure (relative risk, 3.6; 95% CI, 1.1-11.5; P = .02). The uLTE 4 level was a significant predictor of exacerbation risk in children exposed to SHS (area under the curve, 0.85; P = .003). Other predictors, such as nighttime symptom frequency, prebronchodilator and postbronchodilator lung function, and exhaled nitric oxide levels, were not related to exacerbations in this group. uLTE 4 levels at or greater than 106 pg/mg achieved 67% (6/9) sensitivity and 100% (11/11) specificity for predicting children with SHS exposure who required an ED or UC visit. Conclusions Children exposed to SHS are at increased risk for severe asthma exacerbations, despite use of inhaled corticosteroids. uLTE 4 levels identify children exposed to SHS at high risk for asthma exacerbations.

Dietary fat activates systemic innate immune responses, but the effect on airway responses is unknown.To examine effects of a high-fat versus low-fat meal on systemic and airway inflammation in asthma.Nonobese subjects with asthma were randomized to consume a high-fat (n = 19; 48% [49 g] fat) or low-fat (n = 18; 15% [3 g] fat) meal. Fourteen obese patients with asthma and 21 healthy controls also consumed a high-fat meal. Another group of patients with asthma consumed a high-trans (n = 5; 5.2 g trans fat) or nontrans (n = 5,0.3 g trans fat) fatty acid meal. Lung function was measured at baseline (prebronchodilator) and 2, 3, and 4 hours after bronchodilator. Airway inflammation was assessed by using induced sputum cell counts and Toll-like receptor 4 mRNA expression by real-time PCR. Systemic inflammation was measured by ELISA quantification of plasma TNF-α, high-sensitivity C-reactive protein, and IL-6 concentrations.In patients with asthma, at 4 hours postmeal, increases in sputum % neutrophils and Toll-like receptor 4 mRNA expression were higher and increases in FEV(1)/forced vital capacity (FVC) were lower in the high-fat versus low-fat groups. Changes in plasma fatty acids correlated with changes in sputum % neutrophils and were negatively associated with changes in % FEV(1), % FVC, and FEV(1)/FVC. After the high-trans fatty acid meal, sputum % neutrophils were significantly higher than after the nontrans meal.A high-fat meal augments neutrophilic airway inflammation, with the effect dependent on the type of fat consumed. A high-fat meal also suppresses bronchodilator recovery in asthma. Modifying dietary fat intake may be useful in asthma.

Background Studies of selected patient groups have shown that airway hyperresponsiveness (AHR) to mannitol is more specific than methacholine for the diagnosis of asthma, as well as more closely associated with markers of airway inflammation in asthma. Objective We sought to compare AHR to mannitol and methacholine and exhaled nitric oxide (eNO) levels in a nonselected population sample. Methods In 238 young adults randomly drawn from the nationwide civil registration list in Copenhagen, Denmark, AHR to mannitol and methacholine, as well as levels of eNO, were determined, and the association with asthma was analyzed. Results In diagnosing asthma the specificity of methacholine and mannitol was 80.2% (95% CI, 77.1% to 82.9%) and 98.4% (95% CI, 96.2% to 99.4%), respectively, with a positive predictive value of 48.6% versus 90.4%, whereas the sensitivity was 68.6% (95% CI, 57.1% to 78.4%) and 58.8% (95% CI, 50.7% to 62.6%), respectively. In asthmatic subjects AHR to mannitol was associated with increased eNO levels (positive AHR to mannitol: median, 47 ppb [interquartile range, 35-68 ppb]; negative AHR to mannitol: median, 19 ppb [interquartile range, 13-30 ppb]; P = .001), whereas this was not the case for AHR to methacholine (median of 37 ppb [interquartile range, 26-51 ppb] vs 24 ppb [interquartile range, 15-39 ppb], P = .13). Conclusion In this random population sample, AHR to mannitol was less sensitive but more specific than methacholine in the diagnosis of asthma. Furthermore, AHR to mannitol was more closely associated with ongoing airway inflammation in terms of increased eNO levels.

Background Patients with aspirin-exacerbated respiratory disease have been shown to benefit clinically from aspirin desensitization followed by chronic high-dose aspirin therapy. However, the mechanism of this phenomenon is still unclear. Objective The aim of this study was to characterize the airway inflammatory response to aspirin desensitization and after treatment with high-dose aspirin for 6 months. Methods Twenty-one adult patients with asthma, chronic polypoid sinusitis, and a convincing history of acute respiratory reaction to the ingestion of aspirin or nonsteroidal anti-inflammatory drugs were selected. These patients underwent an oral desensitization to aspirin over a 2-day period, followed by daily ingestion of aspirin 650 mg twice daily. Induced sputum samples and exhaled nitric oxide measurements were taken before the procedure, during the second day of the procedure, and after 6 months of treatment. Results There was a significant elevation in both the exhaled nitric oxide level ( P = .03) and sputum tryptase level ( P = .05) during the desensitization process. After 6 months of aspirin treatment, sputum IL-4 ( P = .0007) and matrix metalloproteinase 9 (MMP-9; P = .05) decreased significantly compared with baseline. Predesensitization to postdesensitization changes in MMP-9 and tissue inhibitors of metalloproteinases 1 were highly correlated ( r = 0.79; P = .0003). Immediately after the desensitization, MMP-9 and tryptase were correlated ( r = 0.82; P = .001), whereas IL-4 was inversely related with FMS-like tyrosine kinase 3 ligand (FLT3-L) ( r = –0.79; P = .0008). There was a significant decrease in the average symptom score at 6 months. Conclusion Consistent with previous reports, acute aspirin desensitization in patients with aspirin-exacerbated respiratory disease involves mast cell degranulation. In contrast, long-term treatment with aspirin involves suppression of IL-4 as well as downregulation of proinflammatory MMP-9 while T h 1 marker FLT3-L increases.

Background Ambient and home exposure to nitrogen dioxide (NO 2 ) causes asthma symptoms and decreased lung function in children with asthma. Little is known about the health effects of school classroom pollution exposure. Objective We aimed to determine the effect of indoor classroom NO 2 on lung function and symptoms in inner-city school children with asthma. Methods Children enrolled in the School Inner-City Asthma Study were followed for 1 academic year. Subjects performed spirometry and had fraction of exhaled nitric oxide values measured twice during the school year at school. Classroom NO 2 was collected by means of passive sampling for 1-week periods twice per year, coinciding with lung function testing. Generalized estimating equation models assessed lung function and symptom relationships with the temporally nearest classroom NO 2 level. Results The mean NO 2 value was 11.1 ppb (range, 4.3-29.7 ppb). In total, exposure data were available for 296 subjects, 188 of whom had complete spirometric data. At greater than a threshold of 8 ppb of NO 2 and after adjusting for race and season (spirometry standardized by age, height, and sex), NO 2 levels were associated highly with airflow obstruction, such that each 10-ppb increase in NO 2 level was associated with a 5% decrease in FEV 1 /forced vital capacity ratio (β = −0.05; 95% CI, −0.08 to −0.02; P = .01). Percent predicted forced expiratory flow between the 25th and 75th percentile of forced vital capacity was also inversely associated with higher NO 2 exposure (β = −22.8; 95% CI, −36.0 to −9.7; P = .01). There was no significant association of NO 2 levels with percent predicted FEV 1 , fraction of exhaled nitric oxide, or asthma symptoms. Additionally, there was no effect modification of atopy on lung function or symptom outcomes. Conclusion In children with asthma, indoor classroom NO 2 levels can be associated with increased airflow obstruction.

Physical activity is essential for young children to develop adequately and for quality of life. It can be lower in children with subclinical asthma, and therefore methods to reveal subclinical reduction in physical activity in young children are warranted.We sought to study an association between physical activity in preschool children and objectively assessed intermediary asthma phenotypes.We studied 253 five-year-old children (127 girls) participating in the Copenhagen Prospective Studies on Asthma in Childhood. The main outcome measure was level of physical activity assessed objectively with accelerometers worn on an ankle for 4 weeks. Objective assessment of asthma intermediary phenotypes included prebronchodilator and postbronchodilator specific airway resistance, bronchial responsiveness to cold dry-air hyperventilation, and exhaled nitric oxide levels. Analyses were performed with generalized linear model and principal component analysis.Physical activity was inversely associated with bronchial responsiveness (relative rate, 0.89; 95% CI, 0.83-0.95; P = .007) and significantly increased in the months of spring and summer (P.001) and in boys (relative rate, 1.16; 95% CI, 1.09-1.25; P.001). Physical activity was independent of asthma diagnosis, age, body mass index, baseline specific airway resistance, reversibility to beta(2)-agonist, sensitization, and exhaled nitric oxide level.Physical activity in preschool children was reduced with increasing bronchial responsiveness. The reduced physical activity was subclinical and not realized by parents or doctors despite daily diary cards and close clinical follow-up since birth. This observation warrants awareness of even very mild asthma symptoms in clinical practice.

For children living in inner cities, asthma tends to be more frequent and severe. To characterize, understand, and treat children with asthma living in the inner city more effectively, the National Institute of Allergy and Infectious Diseases established an Inner-City Asthma Program in 1991. In addition, the revised National Asthma Education and Prevention Program Expert Panel 3 report was introduced with new concepts for asthma management that are now centered on asthma control. The purpose of this review is to highlight features of the National Institute of Allergy and Infectious Diseases Inner-City Asthma Consortium Asthma Control Evaluation study that enhance our knowledge regarding the application of the asthma guidelines and to provide a summary of lessons learned from that important study. We recognized that asthma symptoms and exacerbations are theoretically linked to underlying inflammation of airways but are not direct indicators of inflammation. Based on the observations from the Asthma Control Evaluation study, we were impressed that a systematic guidelines-based approach improved asthma control significantly over the course of the 1-year treatment period.

Background Disturbance in the delicate balance between L-arginine–metabolizing enzymes such as nitric oxide synthase (NOS) and arginase may lead to decreased L-arginine availability to constitutive forms of NOS (endothelial NOS), thereby increasing the nitro-oxidative stress and airway hyperresponsiveness (AHR). Objective In this study, we investigated the effects of high doses of L-arginine on L-arginine–metabolizing enzymes and subsequent biological effects such as cyclic guanosine monophosphate production, lipid peroxidation, peroxynitrite, AHR, and airway inflammation in a murine model of asthma. Methods Different doses of L-arginine were administered to ovalbumin–sensitized and challenged mice. Exhaled nitric oxide, AHR, airway inflammation, T H 2 cytokines, goblet cell metaplasia, nitro-oxidative stress, and expressions of arginase 1, endothelial NOS, and inducible NOS in lung were determined. Results L-arginine significantly reduced AHR and airway inflammation including bronchoalveolar lavage fluid eosinophilia, T H 2 cytokines, TGF-β1, goblet cell metaplasia, and subepithelial fibrosis. Further, L-arginine increased ENO levels and cyclic guanosine monophosphate in lung and reduced the markers of nitro-oxidative stress such as nitrotyrosine, 8-isoprostane, and 8-hydroxy-2′-deoxyguanosine. This was associated with reduced activity and expression of arginase 1, increased expression of endothelial NOS, and reduction of inducible NOS in bronchial epithelia. Conclusion We conclude that L-arginine administration may improve disordered nitric oxide metabolism associated with allergic airway inflammation, and alleviates some features of asthma.

In the past, we viewed lack of response to asthma medications as a rare event. Based on recent studies, we now expect significant variation in treatment response for all asthma medications. However, little information is available about methods to predict favorable treatment response. Research conducted in the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network verified this variability in response to several long-term control medications, specifically inhaled corticosteroids and leukotriene receptor antagonists, in adults and children with mild-to-moderate persistent asthma. The networks also identified potential methods to use patients' characteristics, such as age and allergic status, and biomarkers, such as bronchodilator response, exhaled nitric oxide, and urinary leukotrienes, to help predict response to inhaled corticosteroids and leukotriene receptor antagonists and to determine which of the 2 treatments might be more effective in individual patients. This information now assists the clinician in personalizing asthma treatment at the time of initiating long-term control therapy.

Background Asthma is a leading cause of pediatric hospitalizations across the country, yet no clinical instrument exists that incorporates the child's perception of dyspnea in determining discharge readiness. Objective We sought to develop the Pediatric Dyspnea Scale (PDS) to support discharge decision making in hospitalized asthmatic patients and to compare the performance of the PDS with traditional markers of asthma control in predicting outcomes after discharge. Methods Asthmatic children aged 6 to 18 years hospitalized for an exacerbation were included in the study. The PDS score, demographics, asthma severity, spirometric results, peak expiratory flow rate, and fraction of exhaled nitric oxide were assessed at the time of discharge. A telephone call 14 days after discharge determined relapse, activity limitation, asthma control, and asthma-related quality-of-life outcomes. Results Eighty-nine patients were enrolled, of whom 70 completed the telephone follow-up. Eight patients had a relapse, and 29 complained of limited activity. A PDS score of greater than 2 on the 7-point scale was a significant predictor of these poor outcomes, with each additional point of the PDS doubling the risk. A higher score on the PDS also correlated with worse asthma control and poor asthma-specific quality of life. The PDS performed better than FEV 1 , peak expiratory flow rate, or fraction of exhaled nitric oxide in predicting the outcomes of interest. Conclusion The PDS, which is easy to use in children as young as 6 years of age, might be able to predict adverse outcomes after hospitalization for an asthma exacerbation and should be used as a tool to help guide inpatient discharge decisions.

Occupational asthma (OA) may account for 25% or more of de novo adult asthma. The nomenclature has now better defined categories of OA caused by sensitizing agents and irritants, the latter best typified by the reactive airways dysfunction syndrome. Selecting the most appropriate diagnostic testing and management is driven by assessing whether a sensitizer is involved, and if so, identifying whether the sensitizing agent is a high-molecular-weight agent such as a protein or a low-molecular-weight reactive chemical such as an isocyanate. Increased understanding of the pathogenesis of OA from reactive chemical sensitizers is leading to development of better diagnostic testing and also an understanding of why testing for sensitization to such agents can be problematic. Risk factors for OA including possible genetic factors are being delineated better. Recently published guidelines for the diagnosis and management of occupational asthma are summarized; these reflect an increasingly robust evidence basis for recommendations. The utility of diagnostic tests for OA is being better defined by evidence, including sputum analysis performed in relation to work exposure with suspected sensitizers. Preventive and management approaches are reviewed. Longitudinal studies of patients with OA continue to show that timely removal from exposure leads to the best prognosis.

Background Cysteinyl leukotrienes (CysLTs) are important mediators of asthma in children. Predictors of susceptibility to CysLT effects have not been developed. Objectives To identify susceptibility markers to CysLT effects and montelukast response. Methods Twenty-seven schoolchildren were followed for 5 months with measurements of urinary leukotriene E4 (LTE 4 ), cotinine, fractional exhaled nitric oxide (FENO), and monitoring of albuterol use. After a baseline run-in, children were randomized to receive daily montelukast or placebo without change in their current controller medications. Results At baseline, a significant ( P = .003) positive association was observed between LTE 4 levels and albuterol use 2 days later. LTE 4 -related albuterol usage (ie, change per interquartile increase in LTE 4 ) declined significantly after montelukast treatment (12% decline; P = .0005 for relative difference between intervals) but not placebo (2% increase; P = .80). Declines in LTE 4 -related albuterol usage between intervals tended to be greater in girls ( P = .01 for girls; P = .21 for boys; P = .07 for interaction) and were greater among children with higher cotinine levels ( P = .01 for high cotinine group; P = .17 for low cotinine group; P = .04 for interaction). Children with high LTE 4 levels relative to FENO demonstrated significant ( P = .05) declines in LTE 4 -related albuterol usage between intervals ( P = .89 for low ratio group; P = .25 for interaction). Conclusion Increased individual CysLT levels are associated with subsequent albuterol usage. CysLT–related albuterol usage and montelukast responsiveness are increased in children exposed to tobacco smoke and tend to be greater in girls than boys. Measurement of LTE 4 to FENO ratios may help predict susceptibility to montelukast.

Background Aeroallergen sensitization in adult asthmatic patients from a wide geographic area has not been correlated with patients' characteristics, markers of airways inflammation, and lung function. Objective We assessed data obtained from the Asthma Clinical Research Network trials to determine the relationship of aeroallergen sensitization to age, sex, ethnicity, and markers of inflammation and airways function. Methods Skin testing (14 epicutaneous) was performed on 1338 subjects with objectively diagnosed mild-to-moderate asthma from 11 Asthma Clinical Research Network studies. Skin testing used identical techniques and a quality assurance program to ensure uniformity across centers. Results Ninety-five percent of the subjects had at least 1 positive skin test response. Of these, 14% had positive reactions to 1 or 2 allergens and 81% had positive reactions to 3 or more allergens, and 2% of subjects reacted only to seasonal allergens, 26% only to perennial allergens, and 67% to both. Increasing IgE and exhaled nitric oxide values, decreasing PC 20 values, and minority ethnicity significantly correlated with the number of positive skin test responses. Subjects with late-onset asthma were less likely to be sensitized; nonetheless, 89% of subjects older than 60 years had positive responses. Conclusion Ninety-five percent of patients with mild-to-moderate asthma might have an allergic component. Age does not significantly affect aeroallergen sensitization, but the pattern of allergic sensitization varies with ethnicity and geography. Measures used to characterize asthma, such as IgE, exhaled nitric oxide, and PC 20 values, are correlated with aeroallergen sensitization.

Respiratory symptoms are common in early childhood. The clinical characterization of disease presentation and hence its likely disease progression has so far been proven difficult.To investigate whether exhaled nitric oxide (NO) could be helpful to distinguish between subgroups of nonwheezy and wheezy young children less than 4 years of age.Exhaled NO was measured in 391 children (age 3-47 months) with nonwheezy and wheezy respiratory symptoms. Children were divided into 3 groups: children with recurrent cough but no history of wheeze (group 1), with early recurrent wheeze and a loose index for the prediction of asthma at school age (group 2), and with frequent recurrent wheeze and a stringent index for the prediction of asthma at school age (group 3).Children from group 3 showed significantly higher median (interquartile range) fractional exhaled NO (FeNO) levels (11.7 [11.85]) than children from groups 1 (6.5 [5.5]; P.001) and 2 (6.4 [6.5]; P.001). No difference in FeNO levels was found between children from groups 1 and 2 (P = .91).Wheezy young children less than 4 years of age with a stringent index for the prediction of asthma at school age have elevated levels of FeNO compared with children with recurrent wheeze and a loose index for the prediction of asthma at school age or children with recurrent cough.

Most asthma is mild and moderate and can be well controlled by low-dose inhaled steroid with or without bronchodilators. However, 5% to 10% of patients with asthma have more troublesome disease despite using such medication. Recent reports showed that nitrative stress induced tissue remodeling in vitro, which is associated with a component of refractoriness in asthma. However, there is no report that nitrative stress is involved in refractory asthma.The aim of this study is to evaluate whether patients with refractory asthma have more nitrative stress.Ten healthy subjects, 10 patients with well-controlled asthma, and 8 patients with refractory asthma took part in the current study. Exhaled nitric oxide, xanthine oxidase activity in the supernatant of the sputum, immunostaining for the inducible type of nitric oxide synthase, and 3-nitrotyrosine in induced sputum from the subjects were assessed.All nitrative markers including exhaled nitric oxide (P.01), immunopositivities for inducible nitric oxide synthase (P.01), xanthine oxidase activities (P.01), and 3-nitrotyrosine (P.01) in sputum from the refractory asthma group were enhanced compared with the well-controlled group. All these nitrative markers in the sputum had a significant negative correlation with the %FEV(1) values (P.01).These results suggested that patients with refractory asthma have more nitrative stress in their airways compared with patients with well-controlled asthma.

Because the outcomes experienced in adult asthma often result from pathophysiology that begins in early childhood, this year's summary focuses on recent advances in pediatric asthma. This past year, we have learned that early intervention with inhaled corticosteroids in childhood asthma reduces morbidity but does not alter the natural history of asthma. Theme issues over the last year focused attention on severe asthma and black box warnings. Both of these themes significantly affect the management of childhood asthma. Responsiveness to asthma treatment is heterogeneous even among patients with asthma of similar severity. This heterogeneity calls attention to the importance of assessing control and adjusting treatment accordingly. We are now moving toward an individualized approach to asthma therapy and searching for biomarkers and genetics as a resource to guide treatment. To improve asthma control, we must continue to obtain information on early asthma, severe asthma, asthma exacerbations, and methods to improve asthma control. Evaluation and management of severe asthma in children include verification of the diagnosis, assessment for coexisting illnesses, and identification of effective treatment strategies directed to adherence, medication delivery, and combination therapy. Application of biomarkers and genetics could be useful tools in individualizing our approach to the management of childhood asthma.

Background The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma. Objectives To explore the mechanisms underlying the effect of the reliever dose on exacerbations by examining the effect of combination therapy on the allergen challenge model when given after allergen exposure. Methods In a randomized, double-blind crossover study, single doses of budesonide/formoterol (400/12 μg), formoterol (12 μg), budesonide (400 μg), or placebo were administered during the acute bronchoconstriction response (early airway response) immediately after allergen inhalation in 15 patients with mild asthma. Allergen-induced late airway response (LAR), sputum inflammatory markers, airway hyperresponsiveness, and exhaled nitric oxide were measured. Results All active treatments significantly attenuated the LAR, with budesonide/formoterol significantly better than its monocomponents (maximum FEV 1 fall: placebo, [mean ± SEM] 21.2% ± 3.1%; budesonide/formoterol, 4.2% ± 1.4%; formoterol, 7.5% ± 1.7%; budesonide, 10.4% ± 1.6%). Allergen-induced change in methacholine PC 20 was significantly attenuated by budesonide/formoterol, but not by its monocomponents. Sputum cell counts and exhaled nitric oxide increased significantly after all allergen challenges, with no significant attenuation by any of the treatments. Therapy with combination and formoterol alone, but not budesonide, significantly reduced the early airway response. Conclusion A single dose of budesonide/formoterol was superior to its monocomponents in attenuating the allergen-induced LAR and airway hyperresponsiveness. These effects may represent the contribution of the reliever dose to the budesonide/formoterol maintenance and reliever regimen. Clinical implications The protective effect against allergic airway responses with a single reliever dose of budesonide/formoterol is predominantly related to greater functional antagonism of airway smooth muscles.

Background Statins lower cholesterol and also exhibit anti-inflammatory properties. In vitro and animal studies have suggested they may be useful for the treatment of a number of inflammatory conditions. Objective To evaluate the in vivo therapeutic potential of simvastatin as an anti-inflammatory agent in patients with asthma. Methods Potential signal from treatment effect was optimized by withdrawing all anti-inflammatory treatment for the duration of the study. Participants received 1 month of daily simvastatin and 1 month of daily placebo in a randomized, double-blind crossover trial. A total of 16 patients completed per protocol. Asthmatic inflammation was evaluated by measuring exhaled tidal nitric oxide, alveolar nitric oxide, sputum and peripheral eosinophil count, methacholine hyperresponsiveness, salivary eosinophilic cationic protein, and C-reactive protein. Measurements of dynamic and static lung volumes and of cholesterol were also made. Results After initial withdrawal of usual asthma medication, there was a 1.43 geometric mean fold increase (ie, 43% difference) in fraction of exhaled nitric oxide (95% CI, 1.15 to 1.78; P = .004). Compared with placebo, simvastatin led to a 0.86 geometric mean fold decrease (95% CI, 0.7 to 1.04; P = .15) in exhaled nitric oxide (ie, a 14% difference), and a −0.18 doubling dilution shift (95% CI, −1.90 to 1.55; P = 1.0) in methacholine hyperresponsiveness. There were no significant differences in other inflammatory outcomes, lung volumes, or airway resistance between simvastatin and placebo. Treatment with simvastatin led to a significant reduction ( P Conclusion There is no evidence to suggest simvastatin has anti-inflammatory activity in patients with asthma. Clinical implications Simvastatin is not useful for the treatment of asthma.

Background More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children. Objective The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control. Methods A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV 1 ≥ 80% predicted and methacholine FEV 1 PC 20 ≤ 12.5 mg/mL, were randomized to 1 of 3 double-blind 48-week treatments: fluticasone 100 μg twice daily (fluticasone monotherapy), fluticasone 100 μg/salmeterol 50 μg in the morning and salmeterol 50 μg in the evening (PACT combination), and montelukast 5 mg in the evening. Outcomes included asthma control days (primary outcome), exacerbations, humanistic measurements, and pulmonary function measurements. Results Fluticasone monotherapy and PACT combination were comparable in many patient-measured outcomes, including percent of asthma control days, but fluticasone monotherapy was superior for clinic-measured FEV 1 /forced vital capacity ( P = .015), maximum bronchodilator response ( P = .009), exhaled nitric oxide ( P .001), and PC 20 ( P .001). Fluticasone monotherapy was superior to montelukast for asthma control days (64.2% vs 52.5%; P = .004) and for all other control outcomes. Growth over 48 weeks was not statistically different (fluticasone, 5.3 cm; PACT combination, 5.3 cm; montelukast, 5.7 cm). Conclusion Both fluticasone monotherapy and PACT combination achieved greater improvements in asthma control days than montelukast. However, fluticasone monotherapy was superior to PACT combination in achieving other dimensions of asthma control. Growth was similar in all groups. Clinical implications Therefore, of the regimens tested, the PACT study findings favor fluticasone monotherapy in treating children with mild-moderate persistent asthma with FEV 1 ≥ 80% predicted, confirming current guideline recommendations.