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Background: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study demonstrated high morbidity in patients with severe or difficult-to-treat asthma despite standard-of-care treatment., Objective: We sought to determine the long-term natural history of disease and outcomes in patients in TENOR I after more than a decade., Methods: TENOR I was a multicenter observational study (2001-2004) of 4756 patients with severe or difficult-to-treat asthma. TENOR II was a follow-up study of TENOR I patients using a single cross-sectional visit in 2013/2014. Overall, the sites participating in TENOR II originally enrolled 1230 patients in TENOR I. Clinical and patient-reported outcomes were assessed, including very poorly controlled asthma based on National Heart, Lung, and Blood Institute guidelines., Results: A total of 341 (27.7%) patients were enrolled in TENOR II and were representative of the TENOR I cohort. The most frequent comorbidities were rhinitis (84.0%), sinusitis (47.8%), and gastroesophageal reflux disease (46.3%). Mean percent predicted prebronchodilator and postbronchodilator FEV 1 were 72.7% (SD, 21.4%) and 78.2% (SD, 20.7%), respectively. A total of 231 (72.9%) of 317 patients had positive test responses to 1 or more allergen-specific IgEs. The mean blood eosinophil count was 200/μL (SD, 144/μL). Eighty-eight (25.8%) patients experienced an asthma exacerbation in the prior 3 months requiring hospital attention, oral corticosteroids, or both. More than half (197/339 [58.1%]) had very poorly controlled asthma. Medication use suggested undertreatment., Conclusion: TENOR II provides longitudinal data to characterize disease progression, heterogeneity, and severity in patients with severe or difficult-to-treat asthma. Findings show continued morbidity, including a high degree of comorbid conditions, allergic sensitization, exacerbations, and very poorly controlled asthma, including reduced lung function., (Copyright © 2017. Published by Elsevier Inc.)

Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma phenotyping can facilitate understanding of disease pathogenesis and potential targeted therapies., Objective: To further characterize the distinguishing features of phenotypic groups in difficult-to-treat asthma., Methods: Children ages 6-11 years (n = 518) and adolescents and adults ages ≥12 years (n = 3612) with severe or difficult-to-treat asthma from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study were evaluated in this post hoc cluster analysis. Analyzed variables included sex, race, atopy, age of asthma onset, smoking (adolescents and adults), passive smoke exposure (children), obesity, and aspirin sensitivity. Cluster analysis used the hierarchical clustering algorithm with the Ward minimum variance method. The results were compared among clusters by χ(2) analysis; variables with significant (P < .05) differences among clusters were considered as distinguishing feature candidates. Associations among clusters and asthma-related health outcomes were assessed in multivariable analyses by adjusting for socioeconomic status, environmental exposures, and intensity of therapy., Results: Five clusters were identified in each age stratum. Sex, atopic status, and nonwhite race were distinguishing variables in both strata; passive smoke exposure was distinguishing in children and aspirin sensitivity in adolescents and adults. Clusters were not related to outcomes in children, but 2 adult and adolescent clusters distinguished by nonwhite race and aspirin sensitivity manifested poorer quality of life (P < .0001), and the aspirin-sensitive cluster experienced more frequent asthma exacerbations (P < .0001)., Conclusion: Distinct phenotypes appear to exist in patients with severe or difficult-to-treat asthma, which is related to outcomes in adolescents and adults but not in children. The study of the therapeutic implications of these phenotypes is warranted., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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, FEV(1), forced vital capacity, and FEV(1)/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 T(H)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 T(H)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., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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.

Background: Children with severe/difficult-to-treat asthma experience high morbidity including frequent severe exacerbations. More knowledge is required to identify predictors of these exacerbations to reduce their occurrence., Objective: To investigate the risk of future severe exacerbations (FSEs) in children with severe/difficult-to-treat asthma and recent severe exacerbations (RSEs)., Methods: We analyzed the occurrence and association of RSE (defined as 1 or more corticosteroid bursts during the 3 months before each of 3 annual visits) and FSE (defined as 1 or more corticosteroid bursts 6 or 12 months later) in children age 6 to 11 years in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens 3-year observational study. Repeated measures logistic regression analysis assessed the risk of FSE adjusted for demographics and clinical variables., Results: In a multivariable model, FSE at 6 months was most strongly predicted by RSE (odds ratio [OR], 3.08; 95% CI, 2.21-4.28) and having 3 to 4 allergic triggers (OR, 2.05; 95% CI, 1.31-3.20). Race (OR, 1.77; 95% CI, 1.25-2.51) and being very poorly controlled according to the impairment component of the National Heart, Lung, and Blood Institute guidelines (OR, 1.59; 95% CI, 1.14-2.23) also significantly predicted FSE., Conclusion: Recent severe asthma exacerbations are an important independent predictor of FSE in children with severe/difficult-to-treat asthma and should be considered when establishing asthma management plans.

Background: Despite health initiatives for advancing the management of asthma, evidence suggests that many asthmatic subjects have uncontrolled disease. However, the prevalence of uncontrolled asthma in the United States is not known and has not been fully characterized., Objective: We sought to assess the prevalence, morbidity, and factors associated with uncontrolled asthma in a nationally representative sample of patients with moderate-to-severe asthma using standard asthma medications., Methods: A Web-based survey was administered to patients with diagnoses of asthma for at least 1 year who were receiving multiple controller medications. The Asthma Control Test score was used to stratify respondents into controlled and uncontrolled cohorts., Results: A total of 1812 patients were assessed; 809 (45%) had controlled asthma, and 1003 (55%) had uncontrolled asthma. Most patients had health care coverage and received care from a general practitioner; a large proportion of patients with controlled asthma (74%) and patients with uncontrolled asthma (65%) reported never receiving an asthma action plan. Inhaled corticosteroid plus long-acting beta-agonist was the most common medication regimen in patients with controlled asthma (60%) and patients with uncontrolled asthma (48%) patients. Patients with uncontrolled asthma reported significantly higher rates of health care use. Several comorbidities were predictive of uncontrolled asthma., Conclusion: Uncontrolled asthma is highly prevalent (55%) in patients using standard asthma medications. There is need for improved asthma care in patients with moderate-to-severe asthma, including a global evaluation of asthma control, implementation of treatment plans and asthma control tests, and addressing comorbid conditions., Clinical Implications: Improved asthma care requires broader assessments of asthma control, including asthma-related health care and medication use, comorbidities, and the implementation of treatment plans and formal asthma control tests.

Background: Young patients with severe or difficult-to-treat asthma are an understudied population., Objective: To assess age-associated and gender-associated differences in children and adolescents in the observational study, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens., Methods: Cross-sectional baseline data for patients greater than or equal to 6 years and less than or equal to 17 years (n = 1261) were stratified by age group (6-8, 9-11, 12-14, and 15-17 years). The chi(2) test for categorical variables and analysis of variance for continuous variables were used to identify differences among age groups, stratified by gender., Results: Most patients had moderate (55%) or severe (41%) asthma by physician assessment. Of those using greater than or equal to 3 long-term controllers (62%), 53% of children (6-11 years) and 44% of adolescents (12-17 years) reported an oral corticosteroid burst and 25% and 19%, respectively, had an emergency department visit in the previous 3 months; 10% and 15%, respectively, reported past intubation. In females, weight for age ranged between the 67th and 70th percentiles; height for age was between the 42nd and 54th percentiles (P < .01 among age groups). Lung function was lower in adolescents than children: prebronchodilator percent predicted forced expiratory volume in 1 second (FEV(1))/forced vital capacity was 0.92 (6-8 years) and 0.83 (15-17 years), P less than .05, in males; and 0.94 (6-8 years) and 0.87 (15-17 years), P less than .05, in females., Conclusions: Children and adolescents demonstrated high rates of health care use and loss of lung function, despite using multiple long-term controllers., Clinical Implications: Asthma treatments that prevent loss of lung function and reduce health care resource use are needed in young patients with severe or difficult-to-treat asthma.

Background: Patients with aspirin sensitivity experience hyperplastic sinusitis and nasal polyposis. We speculated that similar mechanisms could be acting in the lower airway and that these individuals would demonstrate more severe asthma and irreversible loss of lung function., Objective: We sought to investigate the role of aspirin-exacerbated respiratory disease (AERD) as a risk factor for the development of irreversible airway obstruction., Methods: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is a multicenter observational study of subjects with severe or difficult-to-treat asthma. Data were compared between subjects who reported asthma exacerbation after aspirin ingestion and those who did not. The primary measure of bronchodilator-resistant obstruction (possible remodeling) was the maximally achieved postbronchodilator spirometry averaged over the 3-year duration of the study., Results: Adult subjects (>/=18 years) with AERD (n = 459) were compared with subjects with non-aspirin-sensitive asthma (n = 2848). Subjects with AERD had significantly lower mean postbronchodilator percent predicted FEV(1) compared with subjects with non-aspirin-sensitive asthma (75.3% vs 79.9%, P < .001). Differences in spirometry between the 2 cohorts persisted after controlling for potential confounding variables. In addition, subjects with AERD were more likely to have severe asthma by means of physician assessment (66% vs 49%, P < .001), to have been intubated (20% vs 11%, P < .001), to have a steroid burst in the previous 3 months (56% vs 46%, P < .001), and to have required high-dose inhaled corticosteroids (34% vs 26%, P < .001)., Conclusions: These data suggest that aspirin sensitivity is associated with increased asthma severity and possible remodeling of both the upper and lower airways.