Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: ...Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines' impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
Background Identification of patients at risk for asthma exacerbations can assist physicians in addressing disease management and improve asthma-related health outcomes. Objective We sought to ...evaluate whether level of impairment, as defined by the 2007 asthma guidelines, predicts risk for future asthma exacerbations. Methods The study included children aged 6 to 11 years (n = 82) and adolescent/adult patients aged 12 years and older (n = 725) from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study with data representing all components of the impairment domain of the asthma guidelines at baseline, month 12, and month 24. Patients were categorized into 2 cohorts: (1) consistently very poorly controlled (VPC) asthma from baseline through 2 years of follow-up and (2) improved from VPC asthma at baseline (including patients who improved to not well-controlled or well-controlled asthma), with improvement maintained through 2 years of follow-up. Odds ratios (ORs) and 95% CIs for risk of asthma exacerbations at month 30 were generated by using multivariable logistic regression by age group. Results After adjustment, children with consistently VPC asthma over the 2-year period demonstrated a 6-fold increased risk of hospitalization, emergency department visit, or corticosteroid burst (OR, 6.4; 95% CI, 1.2-34.5) compared with the improved group. Adolescent/adult patients with consistently VPC asthma were more likely to have a corticosteroid burst (OR, 2.8; 95% CI, 1.7-4.8) or have a hospitalization, emergency department visit, or corticosteroid burst (OR, 3.2; 95% CI, 1.9-5.3). Conclusions Consistently VPC asthma, as defined by the impairment domain of the 2007 asthma guidelines, is strongly predictive of future asthma exacerbations.
Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts ...responsiveness to current treatments, but new treatment approaches will require a better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation, which arises in subgroups of obese and older patients, increases the severity of asthma. Interleukin-6 (IL-6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the association between IL-6 concentrations, metabolic dysfunction, and asthma severity.
In this cross-sectional analysis, patients were recruited from two cohorts: mainly non-severe asthmatics from the University of California San Francisco (UCSF) and mainly severe asthmatics from the Severe Asthma Research Program (SARP). We generated a reference range for plasma IL-6 in a cohort of healthy control patients. We compared the clinical characteristics of asthmatics with plasma IL-6 concentrations above (IL-6 high) and below (IL-6 low) the upper 95% centile value for plasma IL-6 concentration in the healthy cohort. We also compared how pulmonary function, frequency of asthma exacerbations, and frequency of severe asthma differed between IL-6 low and IL-6 high asthma populations in the two asthma cohorts.
Between Jan 1, 2005, and Dec 31, 2014, we recruited 249 patients from UCSF and between Nov 1, 2012, and Oct 1, 2014, we recruited 387 patients from SARP. The upper 95th centile value for plasma IL-6 concentration in the healthy cohort (n=93) was 3·1 pg/mL, and 14% (36/249) of UCSF cohort and 26% (102/387) of the SARP cohort had plasma IL-6 concentrations above this upper limit. The IL-6 high patients in both asthma cohorts had a significantly higher average BMI (p<0·0001) and a higher prevalence of hypertension (p<0·0001) and diabetes (p=0·04) than the IL-6 low patients. IL-6 high patients also had significantly worse lung function and more frequent asthma exacerbations than IL-6 low patients (all p values <0·0001). Although 80% (111/138) of IL-6 high asthmatic patients were obese, 62% (178/289) of obese asthmatic patients were IL-6 low. Among obese patients, the forced expiratory volume in 1 s (FEV1) was significantly lower in IL-6 high than in IL-6 low patients (mean percent predicted FEV1=70·8% SD 19·5 vs 78·3% 19·7; p=0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL-6 high than in IL-6 low patients (66% 73/111 vs 48% 85/178; p=0·003). Among non-obese asthmatics, FEV1 values and the frequency of asthma exacerbations within the past 1-2 years were also significantly worse in IL-6 high than in IL-6 low patients (mean FEV1 66·4% SD 23·1 vs 83·2% 20·4 predicted; p<0·0001; 59% 16/27 vs 34% 108/320; p=0·01).
Systemic IL-6 inflammation and clinical features of metabolic dysfunction, which occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, are associated with more severe asthma. These data provide strong rationale to undertake clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma. Plasma IL-6 is a biomarker that could guide patient stratification in these trials.
NIH and the Parker B Francis Foundation.
Background Studies of asthma phenotypes have identified obesity as a component of a group characterized by a high proportion of subjects with adult-onset asthma. However, whether age of asthma onset ...modifies the association between obesity and asthma is unknown. Objectives We sought to compare the associations between body mass index (BMI) categories with physiological, inflammatory, and clinical parameters across age of asthma onset phenotypes; and to compare the rate of BMI change in relation to asthma duration, by age of onset asthma phenotypes. Methods From the Severe Asthma Research Program, we defined age of asthma onset as early (<12 years of age) and late (≥12 years of age). Comparisons of BMI categories were done within age-of-onset groups, and obesity was also compared across these groups. Multivariable logistic regression analysis was done to evaluate the association between BMI categories with health care use and respiratory symptoms and multivariable linear regression for the association between duration of asthma and weight gain (BMI change per year). An interaction between obesity and age of asthma onset was included in the multivariable analyses. Results The study population consisted of 1049 subjects, and the median age for asthma onset was 10 years (interquartile range, 4-25 years); 48% had late-onset asthma (≥12 years of age), and 52% had early-onset asthma (<12 years of age). Compared with obese subjects with late-onset asthma, obese subjects with early-onset asthma had more airway obstruction, bronchial hyperresponsiveness, and higher odds ratios of ever having 3 or more previous oral steroid tapers per year or intensive care unit admissions for asthma per preceding year (interactions between obesity and age of asthma onset were P = .055 and P = .02, respectively). In subjects with early-onset asthma but not in subjects with late-onset asthma, there was a significant association between increasing BMI and duration of asthma after adjusting for confounders. The interaction between asthma duration and age of asthma onset was a P value of less than .01. Conclusion Asthmatic subjects are differentially affected by obesity based on whether they had asthma early (<12 years of age) or later in life. These results highlight the need to understand obesity as a comorbidity that affects specific clinical phenotypes and not all asthma subjects alike.
Background Clinical cluster analysis from the Severe Asthma Research Program (SARP) identified 5 asthma subphenotypes that represent the severity spectrum of early-onset allergic asthma, late-onset ...severe asthma, and severe asthma with chronic obstructive pulmonary disease characteristics. Analysis of induced sputum from a subset of SARP subjects showed 4 sputum inflammatory cellular patterns. Subjects with concurrent increases in eosinophil (≥2%) and neutrophil (≥40%) percentages had characteristics of very severe asthma. Objective To better understand interactions between inflammation and clinical subphenotypes, we integrated inflammatory cellular measures and clinical variables in a new cluster analysis. Methods Participants in SARP who underwent sputum induction at 3 clinical sites were included in this analysis (n = 423). Fifteen variables, including clinical characteristics and blood and sputum inflammatory cell assessments, were selected using factor analysis for unsupervised cluster analysis. Results Four phenotypic clusters were identified. Cluster A (n = 132) and B (n = 127) subjects had mild-to-moderate early-onset allergic asthma with paucigranulocytic or eosinophilic sputum inflammatory cell patterns. In contrast, these inflammatory patterns were present in only 7% of cluster C (n = 117) and D (n = 47) subjects who had moderate-to-severe asthma with frequent health care use despite treatment with high doses of inhaled or oral corticosteroids and, in cluster D, reduced lung function. The majority of these subjects (>83%) had sputum neutrophilia either alone or with concurrent sputum eosinophilia. Baseline lung function and sputum neutrophil percentages were the most important variables determining cluster assignment. Conclusion This multivariate approach identified 4 asthma subphenotypes representing the severity spectrum from mild-to-moderate allergic asthma with minimal or eosinophil-predominant sputum inflammation to moderate-to-severe asthma with neutrophil-predominant or mixed granulocytic inflammation.
Background Asthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to ...school-age children with persistent asthma across a wide range of severities. Objectives This study determined how children with severe asthma are distributed across a cluster analysis and how well these clusters conform to current definitions of asthma severity. Methods Cluster analysis was applied to 12 continuous and composite variables from 161 children at 5 centers enrolled in the Severe Asthma Research Program. Results Four clusters of asthma were identified. Children in cluster 1 (n = 48) had relatively normal lung function and less atopy. Children in cluster 2 (n = 52) had slightly lower lung function, more atopy, and increased symptoms and medication use. Cluster 3 (n = 32) had greater comorbidity, increased bronchial responsiveness, and lower lung function. Cluster 4 (n = 29) had the lowest lung function and the greatest symptoms and medication use. Predictors of cluster assignment were asthma duration, the number of asthma controller medications, and baseline lung function. Children with severe asthma were present in all clusters, and no cluster corresponded to definitions of asthma severity provided in asthma treatment guidelines. Conclusion Severe asthma in children is highly heterogeneous. Unique phenotypic clusters previously identified in adults can also be identified in children, but with important differences. Larger validation and longitudinal studies are needed to determine the baseline and predictive validity of these phenotypic clusters in the larger clinical setting.
Background Asthma is a heterogeneous clinical disorder. Methods for objective identification of disease subtypes will focus on clinical interventions and help identify causative pathways. Few studies ...have explored phenotypes at a molecular level. Objective We sought to discriminate asthma phenotypes on the basis of cytokine profiles in bronchoalveolar lavage (BAL) samples from patients with mild-moderate and severe asthma. Methods Twenty-five cytokines were measured in BAL samples of 84 patients (41 severe, 43 mild-moderate) using bead-based multiplex immunoassays. The normalized data were subjected to statistical and informatics analysis. Results Four groups of asthmatic profiles could be identified on the basis of unsupervised analysis (hierarchical clustering) that were independent of treatment. One group, enriched in patients with severe asthma, showed differences in BAL cellular content, reductions in baseline pulmonary function, and enhanced response to methacholine provocation. Ten cytokines were identified that accurately predicted this group. Classification methods for predicting methacholine sensitivity were developed. The best model analysis predicted hyperresponders with 88% accuracy in 10 trials by using a 10-fold cross-validation. The cytokines that contributed to this model were IL-2, IL-4, and IL-5. On the basis of this classifier, 3 distinct hyperresponder classes were identified that varied in BAL eosinophil count and PC20 methacholine. Conclusion Cytokine expression patterns in BAL can be used to identify distinct types of asthma and identify distinct subsets of methacholine hyperresponders. Further biomarker discovery in BAL may be informative.
Background Sputum eosinophil percentages are a strong predictor of airway inflammation and exacerbations and aid asthma management, whereas sputum neutrophil percentages indicate a different severe ...asthma phenotype that is potentially less responsive to TH 2-targeted therapy. Variables, such as blood eosinophil counts, total IgE levels, fraction of exhaled nitric oxide (F eno ) levels, or FEV1 percent predicted, might predict airway eosinophil percentages, whereas age, FEV1 percent predicted, or blood neutrophil counts might predict sputum neutrophil percentages. Availability and ease of measurement are useful characteristics, but accuracy in predicting airway eosinophil and neutrophil percentages either individually or combined is not established. Objectives We sought to determine whether blood eosinophil counts, F eno levels, and IgE levels accurately predict sputum eosinophil percentages and whether age, FEV1 percent predicted, and blood neutrophil counts accurately predict sputum neutrophil percentages. Methods Subjects in the Wake Forest Severe Asthma Research Program (n = 328) were characterized by blood and sputum cell counts, health care use, lung function, F eno levels, and IgE levels. Multiple analytic techniques were used. Results Despite significant association with sputum eosinophil percentages, blood eosinophil counts, F eno levels, and total IgE levels did not accurately predict sputum eosinophil percentages, and combinations of these variables did not improve prediction. Age, FEV1 percent predicted, and blood neutrophil counts were similarly unsatisfactory for the prediction of sputum neutrophil percentages. Factor analysis and stepwise selection found F eno levels, IgE levels, and FEV1 percent predicted, but not blood eosinophil counts, correctly predicted 69% of sputum eosinophil percentages of less than 2% or 2% and greater. Likewise, age, asthma duration, and blood neutrophil counts correctly predicted 64% of sputum neutrophil percentages of less than 40% or 40% and greater. A model to predict both sputum eosinophil and neutrophil percentages accurately assigned only 41% of samples. Conclusion Despite statistically significant associations, F eno levels, IgE levels, blood eosinophil and neutrophil counts, FEV1 percent predicted, and age are poor surrogates, both separately and combined, for accurately predicting sputum eosinophil and neutrophil percentages.
Background Asthma is a heterogeneous disease that is caused by the interaction of genetic susceptibility with environmental influences. Genome-wide association studies (GWASs) represent a powerful ...approach to investigate the association of DNA variants with disease susceptibility. To date, few GWASs for asthma have been reported. Objectives A GWAS was performed on a population of patients with severe or difficult-to-treat asthma to identify genes that are involved in the pathogenesis of asthma. Methods A total of 292,443 single nucleotide polymorphisms (SNPs) were tested for association with asthma in 473 The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) cases and 1892 Illumina general population controls. Asthma-related quantitative traits (total serum IgE, FEV1 , forced vital capacity, and FEV1 /forced vital capacity) were also tested in identified candidate regions in 473 TENOR cases and 363 phenotyped controls without a history of asthma to analyze GWAS results further. Imputation was performed in identified candidate regions for analysis with denser SNP coverage. Results Multiple SNPs in the RAD50-IL13 region on chromosome 5q31.1 were associated with asthma: rs2244012 in intron 2 of RAD50 ( P = 3.04E-07). The HLA-DR/DQ region on chromosome 6p21.3 was also associated with asthma: rs1063355 in the 3′ untranslated region of HLA-DQB1 ( P = 9.55E-06). Imputation identified several significant SNPs in the TH 2 locus control region 3′ of RAD50 . Imputation also identified a more significant SNP, rs3998159 ( P = 1.45E-06), between HLA-DQB1 and HLA-DQA2. Conclusion This GWAS confirmed the important role of TH 2 cytokine and antigen presentation genes in asthma at a genome-wide level and the importance of additional investigation of these 2 regions to delineate their structural complexity and biologic function in the development of asthma.
Background Patients with severe asthma have increased granulocytes in their sputum compared with patients with mild to moderate asthma. Objective We hypothesized that inflammatory granulocytes in ...sputum may identify specific asthma severity phenotypes and are associated with different patterns of inflammatory proteins in sputum supernatants. Methods This hypothesis was tested in 242 patients with asthma enrolled in the Severe Asthma Research Program who provided sputum samples for cell count, differential cell determinations, cell lysates for Western blot, and supernatant analyses by inflammatory protein microarrays and ELISAs. ANOVA and multiple linear regression models tested mediator associations. Results Stratified by sputum granulocytes, <2% or ≥2% eosinophils and <40% or ≥40% neutrophils, subjects with both increased eosinophils and neutrophils had the lowest lung function and increased symptoms and health care use. Subjects with elevated eosinophils with or without increased neutrophils had significantly increased fraction exhaled nitric oxide (FeNO) and serum eosinophils and greater frequency of daily β-agonist use. Microarray data stratified by granulocytes revealed 25 to 28 inflammatory proteins increased >2-fold in sputa with ≥40% neutrophils. Microarray analyses stratified by severity of asthma identified 6 to 9 proteins increased >2-fold in sputa in subjects with severe asthma compared with nonsevere asthma. ELISA data stratified by sputum granulocytes showed significant increases in brain-derived neurotrophic factor, IL-1β, and macrophage inflammatory protein 3α/CCL20 for those with ≥40% neutrophils; these mediators demonstrated positive associations with neutrophil counts. Conclusion Combined increased sputum eosinophils and neutrophils identified patients with asthma with the lowest lung function, worse asthma control, and increased symptoms and health care requirements. Inflammatory protein analyses of sputum supernatants found novel mediators increased in patients with asthma, predominantly associated with increased sputum neutrophils.
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