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Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function. We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma. We analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity. Greater baseline wall area percent (β = –0.15 [95% CI = –0.26 to –0.05]; P <.01), hyperinflation percent (β = –0.25 [95% CI = –0.41 to –0.09]; P <.01), and Jacobian gradient measurements (cranial-caudal β = 10.64 [95% CI = 3.79-17.49]; P <.01; posterior-anterior β = –9.14, [95% CI = –15.49 to –2.78]; P <.01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P =.02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P =.03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P <.01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85] ; P =.01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires. Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations. [ABSTRACT FROM AUTHOR]

The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium. We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program. Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed. Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P <.05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB , or gasdermin A (3.1 × 10−9 < P < 1.8 × 10−4). Higher expression levels of GSDMB correlated with asthma and greater number of exacerbations (P <.05). Expression levels of GSDMB correlated with genes involved in IFN signaling, MHC class I antigen presentation, and immune system pathways (false-discovery rate–adjusted P <.05). rs1031458 and rs3902920 in GSDMB colocalized with IFN regulatory factor binding sites and associated with GSDMB expression, asthma severity, and asthma exacerbations (P <.05). By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity. [ABSTRACT FROM AUTHOR]

Tools for quantification of asthma severity are limited. We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted. [ABSTRACT FROM AUTHOR]

Despite advances in asthma care, disparities persist. Black patients are disproportionally affected by asthma and also have poorer outcomes compared with white patients. We sought to determine associations between black and white patients and asthma-related health care use, accounting for complex relationships. This study was completed as part of the National Heart, Lung, and Blood Institute's Severe Asthma Research Program, a prospective observational cohort. Between November 2012 and February 2015, it enrolled 579 participants 6 years and older with 1 year of observation time and complete data. Inverse probability of treatment weighting was used to balance racial groups with respect to community and family socioeconomic variables and environmental exposure variables. The primary outcome was emergency department (ED) use for asthma. Secondary outcomes included inhaled corticosteroid use, outpatient physician's office visits for asthma, and asthma–related hospitalization. Black patients had greater odds of ED use over 1 year (odds ratio, 2.19; 95% CI, 1.43-3.35) but also differed in the majority (>50%) of baseline variables measured. After statistical balancing of the racial groups, the difference between black and white patients with respect to ED use no longer reached the level of significance. Instead, in secondary analyses black patients were less likely to see an outpatient physician for asthma management (adjusted odds ratio, 0.57; 95% CI, 0.38-0.85). The disparity in ED use was eliminated after consideration of multiple variables. Social and environmental policies and interventions tailored to black populations with a high burden of asthma are critical to reduction (or elimination) of these disparities. [ABSTRACT FROM AUTHOR]

Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. Sputum CCL5 expression strongly correlated with T1 chemokines (P <.001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P =.009), blood eosinophils (P <.001), and sputum eosinophils (P =.001) in addition to sputum neutrophils (P =.001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P =.083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia. [ABSTRACT FROM AUTHOR]

Background: PCR studies have demonstrated evidence of Mycoplasma pneumoniae and Chlamydophila pneumoniae in the lower airways of patients with asthma. Objective: To test the hypothesis that clarithromycin would improve asthma control in individuals with mild-to-moderate persistent asthma that was not well controlled despite treatment with low-dose inhaled corticosteroids. Methods: Adults with an Asthma Control Questionnaire score ≥1.5 after a 4-week period of treatment with fluticasone propionate were entered into a PCR-stratified randomized, controlled trial to evaluate the effect of 16 weeks of either clarithromycin or placebo, added to fluticasone, on asthma control in individuals with or without lower airway PCR evidence of M pneumoniae or C pneumoniae. Results: A total of 92 participants were randomized. Twelve (13%) subjects demonstrated PCR evidence of M pneumoniae or C pneumoniae in endobronchial biopsies; 80 were PCR-negative for both organisms. In PCR-positive participants, clarithromycin yielded a 0.4 ± 0.4 unit improvement in the Asthma Control Questionnaire score, with a 0.1 ± 0.3 unit improvement in those allocated to placebo. This between-group difference of 0.3 ± 0.5 (P = .6) was neither clinically nor statistically significant. In PCR-negative participants, a nonsignificant between-group difference of 0.2 ± 0.2 units (P = .3) was observed. Clarithromycin did not improve lung function or airway inflammation but did improve airway hyperresponsiveness, increasing the methacholine PC20 by 1.2 ± 0.5 doubling doses (P = .02) in the study population. Conclusion: Adding clarithromycin to fluticasone in adults with mild-to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control. Although there was an improvement in airway hyperresponsiveness with clarithromycin, this benefit was not accompanied by improvements in other secondary outcomes. [Copyright &y& Elsevier]

Background: Chitinolytic enzymes play important roles in the pathophysiology of allergic airway responses in mouse models of asthma. Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) have chitinolytic activity, but relatively little is known about their expression in human asthma. Objective: We sought to determine the expression and activity of AMCase and CHIT1 in healthy subjects, subjects with asthma, and habitual smokers, taking account of the null 24-bp duplication in the CHIT1 gene. Methods: We measured chitinase activity in bronchoalveolar lavage (BAL) fluid at multiple pHs by using a synthetic chitin substrate. We also determined AMCase and CHIT1 gene expression in epithelial brushings and BAL fluid macrophages by means of real time RT-PCR. Paired DNA samples were genotyped for the CHIT1 duplication. Results: In all subgroups the pH profile of chitinase activity in BAL fluid matched that of CHIT1, but not AMCase, and chitinase activity was absent in subjects genetically deficient in active CHIT1. Although AMCase protein was detectable in lavage fluid, AMCase transcripts in macrophages were consistent with an isoform lacking enzymatic activity. Median chitinase activity in BAL fluid tended to be lower than normal in asthmatic subjects but was increased 7-fold in habitual smokers, where CHIT1 gene expression in macrophages was increased. Conclusions: Chitinase activity in the lung is the result of CHIT1 activity. Although AMCase protein is detectable in the lung, our data indicate that it is inactive. Chitinase activity is not increased in subjects with asthma and in fact tends to be decreased. The high levels of chitinase activity in habitual smokers result from upregulation of CHIT1 gene expression, especially in macrophages. [Copyright &y& Elsevier]

Background: Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with inhaled corticosteroids. Objective: To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and nonresponders to asthma control over a longer interval (16 additional weeks). Methods: Eighty-three subjects with asthma off steroid were enrolled in this multicenter study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a 6-week trial for changes in FEV1 and methacholine PC20. After this, an additional 4-month trial evaluated asthma control. Results: Although multiple baseline predictors had significant correlations with improvements for short-term inhaled steroid success, the only strong correlations (r ≥ ± 0.6) were albuterol reversibility (r = 0.83; P < .001), FEV1/forced vital capacity (r = −0.75; P < .001), and FEV1 % predicted (r = −0.71; P < .001). Dividing the subjects in the short-term inhaled steroid trial into responders (>5% FEV1 improvement) and nonresponders (≤5%) determined the longer-term need for steroids. For the nonresponders, asthma control remained unchanged whether inhaled corticosteroids were continued or were substituted with a placebo (P = .99). The good short-term responders maintained asthma control longer-term only if maintained on inhaled steroids (P = .007). Conclusion: The short-term response to inhaled corticosteroids with regard to FEV1 improvement predicts long-term asthma control. Clinical implications: The decision to use long-term inhaled steroids could be based on a short-term trial. Different therapeutic strategies would need to be established for nonresponders. [Copyright &y& Elsevier]

Background: Asthma functional genomics studies are challenging because it is difficult to relate gene expression changes to specific disease mechanisms or pathophysiologic features. Use of simplified model systems might help to address this problem. One such model is the IL-13/Epi (IL-13–overexpressing transgenic mice with STAT6 expression limited to epithelial cells) focused transgenic mouse, which isolates the effects of a single mediator, IL-13, on a single cell type, the airway epithelial cell. These mice develop airway hyperreactivity and mucus overproduction but not airway inflammation. Objective: To identify how effects of IL-13 on airway epithelial cells contribute to gene expression changes in murine asthma models and determine whether similar changes are seen in people with asthma. Methods: We analyzed gene expression in ovalbumin allergic mice, IL-13–overexpressing mice, and IL-13/Epi mice with microarrays. We analyzed the expression of human orthologues of genes identified in the mouse studies in airway epithelial cells from subjects with asthma and control subjects. Results: In comparison with the other 2 models, IL-13/Epi mice had a remarkably small subset of gene expression changes. Human orthologues of some genes identified as increased in the mouse models were more highly expressed in airway epithelial cells from subjects with asthma than in controls. These included calcium-activated chloride channel 1, 15-lipoxygenase, trefoil factor 2, and intelectin. Conclusion: The combination of focused transgenic models, DNA microarray analyses, and translational studies provides a powerful approach for analyzing the contributions of specific mediators and cell types and for focusing attention on a limited number of genes associated with specific pathophysiologic aspects of asthma. [Copyright &y& Elsevier]

Background: Although inhaled corticosteroids (ICSs) are effective in preventing deterioration in asthma control, at least half of subjects with mild-to-moderate asthma will remain stable when these agents are discontinued. Objective: We sought to determine whether noninvasive markers of inflammation predict which individuals maintain asthma control after discontinuation of ICSs. Methods: We analyzed data obtained from 164 subjects with mild-to-moderate asthma who participated in a 16-week trial comparing the effects of continued ICS use with the effects of a switch to salmeterol or placebo. Results: In comparison with continued ICS use, a switch to salmeterol or placebo was associated with increased rates of asthma deterioration over 16 weeks (9.3% vs 24.1% and 37.5%, respectively; P =.04 and P < .001, respectively). We found that neither exhaled nitric oxide nor methacholine PC20, when measured at randomization or 2 weeks after randomization, were significant predictors of subsequent asthma control in subjects who discontinued ICSs. However, both induced sputum eosinophil counts measured 2 weeks after a switch from ICS to placebo and changes in sputum eosinophil counts from before cessation of ICSs to after a switch to placebo predicted subsequent asthma deterioration (area under the receiver-operating characteristic curve, 0.771 [P < .001] and 0.825 [P < .001], respectively). Conclusion: On the basis of a model treatment strategy, we estimate that allocating subjects to ICS therapy on the basis of changes in sputum eosinophil counts after a trial discontinuation could allow 48% of subjects with mild-to-moderate asthma to discontinue ICS therapy without an increased risk of asthma deterioration over a period of at least 14 weeks. [ABSTRACT FROM AUTHOR]

Morbidity and mortality associated with childhood asthma are driven disproportionately by children with severe asthma. However, it is not known from longitudinal studies whether children outgrow severe asthma. We sought to study prospectively whether well-characterized children with severe asthma outgrow their asthma during adolescence. Children with asthma were assessed at baseline with detailed questionnaires, allergy tests, and lung function tests and were reassessed annually for 3 years. The population was enriched for children with severe asthma, as assessed by the American Thoracic Society/European Respiratory Society guidelines, and subject classification was reassessed annually. At baseline, 111 (59%) children had severe asthma. Year to year, there was a decrease in the proportion meeting the criteria for severe asthma. After 3 years, only 30% of subjects met the criteria for severe asthma (P <.001 compared with enrollment). Subjects experienced improvements in most indices of severity, including symptom scores, exacerbations, and controller medication requirements, but not lung function. Surprisingly, boys and girls were equally likely to has resolved asthma (33% vs 29%). The odds ratio in favor of resolution of severe asthma was 2.75 (95% CI, 1.02-7.43) for those with a peripheral eosinophil count of greater than 436 cells/μL. In longitudinal analysis of this well-characterized cohort, half of the children with severe asthma no longer had severe asthma after 3 years; there was a stepwise decrease in the proportion meeting severe asthma criteria. Surprisingly, asthma severity decreased equally in male and female subjects. Peripheral eosinophilia predicted resolution. These data will be important for planning clinical trials in this population. [ABSTRACT FROM AUTHOR]

Omalizumab is an mAb that binds free IgE and ultimately reduces the density of IgE-loaded receptors on IgE effector cells. Because IgE effector cells, such as mast cells and basophils, are a source of proinflammatory chemokines, cytokines, and proteases, it is not surprising that omalizumab has anti-inflammatory effects, most notably large effects in reducing airway eosinophilia. What has been surprising is the nature of the clinical effects of omalizumab. Rates of exacerbation in omalizumab-treated patients are approximately half those in placebo-treated patients. This important clinical effect has occurred despite the fact that omalizumab does not improve nonspecific bronchial hyperesponsiveness and does not have large effects on airflow. The unsuspected dissociations among asthma outcomes uncovered during clinical trials of omalizumab remind us that mysteries remain for how inflammation, remodeling, and airway function are linked in asthma. [Copyright &y& Elsevier]

Background Airway type 2 inflammation is usually corticosteroid sensitive, but the role of type 2 inflammation as a mechanism of asthma in patients receiving high-dose inhaled corticosteroids (ICSs) is uncertain. Objective We sought to determine whether airway type 2 inflammation persists in patients treated with ICSs and to evaluate the clinical features of patients with steroid-resistant airway type 2 inflammation. Methods We used quantitative PCR to generate a composite metric of type 2 cytokine gene expression (type 2 gene mean [T2GM]) in induced sputum cells from healthy control subjects, patients with severe asthma receiving ICSs (n = 174), and patients with nonsevere asthma receiving ICSs (n = 85). We explored relationships between asthma outcomes and T2GM values and the utility of noninvasive biomarkers of airway T2GM. Results Sputum cell T2GM values in asthmatic patients were significantly increased and remained high after treatment with intramuscular triamcinolone. We used the median T2GM value as a cutoff to classify steroid-treated type 2–low and steroid-resistant type 2–high (srT2-high) subgroups. Compared with patients with steroid-treated type 2–low asthma, those with srT2-high asthma were older and had more severe asthma. Blood eosinophil cell counts predicted srT2-high asthma when body mass index was less than 40 kg/m2 but not when it was 40 kg/m2 or greater, whereas blood IgE levels strongly predicted srT2-high asthma when age was less than 34 years but not when it was 34 years or greater. Conclusion Despite ICS therapy, many asthmatic patients have persistent airway type 2 inflammation (srT2-high asthma), and these patients are older and have more severe disease. Body weight and age modify the performance of blood-based biomarkers of airway type 2 inflammation. [ABSTRACT FROM AUTHOR]

Background Epithelial barrier dysfunction and increased permeability may contribute to antigen sensitization and disease progression in asthma. Claudin-18.1 is the only known lung-specific tight junction protein, but its contribution to airway barrier function or asthma is unclear. Objectives We sought to test the hypotheses that claudin-18 is a determinant of airway epithelial barrier function that is downregulated by IL-13 and that claudin-18 deficiency results in increased aeroantigen sensitization and airway hyperresponsiveness. Methods Claudin-18.1 mRNA levels were measured in airway epithelial brushings from healthy controls and patients with asthma. In patients with asthma, claudin-18 levels were compared with a three-gene-mean marker of T H 2 inflammation. Airway epithelial permeability changes due to claudin-18 deficiency were measured in 16HBE cells and claudin-18 null mice. The effect of IL-13 on claudin expression was determined in primary human airway epithelial cells and in mice. Airway hyperresponsiveness and serum IgE levels were compared in claudin-18 null and wild-type mice following aspergillus sensitization. Results Epithelial brushings from patients with asthma (n = 67) had significantly lower claudin-18 mRNA levels than did those from healthy controls (n = 42). Claudin-18 levels were lowest among T H 2-high patients with asthma. Loss of claudin-18 was sufficient to impair epithelial barrier function in 16HBE cells and in mouse airways. IL-13 decreased claudin-18 expression in primary human cells and in mice. Claudin-18 null mice had significantly higher serum IgE levels and increased airway responsiveness following intranasal aspergillus sensitization. Conclusions These data support the hypothesis that claudin-18 is an essential contributor to the airway epithelial barrier to aeroantigens. Furthermore, T H 2 inflammation suppresses claudin-18 expression, potentially promoting sensitization and airway hyperresponsiveness. [ABSTRACT FROM AUTHOR]

Background: The 3-gene signature of periostin, chloride channel accessory 1 (CLCA1), and Serpin β2 (SERPINB2) in airway epithelial brushings is used to classify asthma into TH2-high and TH2-low endotypes. Little is known about the utility of gene profiling in sputum as a molecular phenotyping method. Objective: We sought to determine whether gene profiling in sputum cells can identify TH2-high and TH2-low subtypes of asthma. Methods: In induced sputum cell pellets from 37 asthmatic patients and 15 healthy control subjects, PCR was used to profile gene expression of the epithelial cell signature of IL-13 activation (periostin, CLCA1, and SERPINB2), TH2 genes (IL4, IL5, and IL13), and other genes associated with airway TH2 inflammation. Results: Gene expression levels of CLCA1 and periostin, but not SerpinB2, were significantly higher than normal in sputum cells from asthmatic subjects. Expression levels of IL-4, IL-5, and IL-13 were also significantly increased in asthmatic patients and highly correlated within individual subjects. By combining the expression levels of IL-4, IL-5, and IL-13 in a single quantitative metric (“TH2 gene mean”), 26 (70%) of the 37 asthmatic patients had TH2-high asthma, which was characterized by more severe measures of asthma and increased blood and sputum eosinophilia. TH2 gene mean values tended to be stable when initial values were very high or very low but fluctuated above or below the TH2-high cutoff when initial values were intermediate. Conclusion: IL-4, IL-5, and IL-13 transcripts are easily detected in sputum cells from asthmatic patients, and their expression levels can be used to classify asthma into TH2-high and TH2-low endotypes. [Copyright &y& Elsevier]

Background: Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by TH2 cytokines in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective: We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods: We measured fraction of exhaled nitric oxide (Feno), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results: We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV1, 60% of predicted value; mean Asthma Control Questionnaire [ACQ] score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, Feno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia (P = .007). Conclusion: Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting TH2 inflammation. [Copyright &y& Elsevier]

Background: Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. Objective: National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. Methods: We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011. Results: Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. Conclusion: The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories. [ABSTRACT FROM AUTHOR]

Background: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives: We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur. Methods: Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP. Results: Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20-fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (χ2 = 26.8, P < .001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A americanum (rs  = 0.75, P < .001). Conclusion: The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy. [ABSTRACT FROM AUTHOR]

Background: Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups (“TH2 high” and “TH2 low” asthma) based on epithelial cell gene signatures for the activity of TH2 cytokines. Objectives: We sought to characterize intraepithelial mast cells (IEMCs) in asthma. Methods: We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells. Results: By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with TH2-high asthma compared with that seen in subjects with TH2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13–activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression. Conclusion: IEMC numbers are increased in subjects with TH2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13–stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in TH2-high asthmatic epithelium. [Copyright &y& Elsevier]