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Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study

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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.

Section snippets

Burden of illness and asthma-related QoL

High rates of health care use (HCU) and medication use were observed in the TENOR cohort. In the 3 months before enrollment, 5% and 15% of adults, 10% and 17% of adolescents, and 9% and 22% of children had at least 1 asthma hospitalization or emergency department (ED) visit, respectively, and in addition, almost half the adults and children and approximately 40% of adolescents reported oral corticosteroid (OCS) bursts and unscheduled visits for asthma.4 Approximately 10% of patients across all

Lung function

Because optimal control of asthma remains elusive in many children, TENOR compared the rates of asthma exacerbations by lung function in children versus adolescents/adults who were taking recommended long-term controller asthma medications.15 Zeiger et al15 showed that approximately 30% to 40% of all patients with abnormal lung function (FEV1 ≤80%) had a course of OCSs in the 3 months before the 12- and 18-month follow-up visits (Table II). By the 24-month follow-up visit, more than half (52%)

Asthma control and exacerbations: TENOR main outcomes

TENOR analyses have consistently shown that a recent asthma exacerbation is the strongest predictor for a future exacerbation.28, 29 In multivariate analyses conducted in children (n = 563), a future severe asthma exacerbation at 6 months was most strongly predicted by a recent severe exacerbation (odds ratio [OR], 3.08; 95% CI, 2.21-4.28), followed by having 3 to 4 allergic triggers (OR, 2.05; 95% CI, 1.31-3.20). Other significant predictors of future severe asthma exacerbation were

IgE and allergen sensitization

It is estimated that the population-based proportion of asthma cases attributable to atopy is between 50%-60%.32, 33 IgE plays a key role in mediating the allergic response in asthma,34 and populations of patients with asthma have increased total IgE levels compared with nonasthmatic populations. In TENOR male subjects, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset asthma had higher IgE levels compared with nonasthmatic or nonallergic populations; total IgE

Special populations examined within TENOR

The TENOR study is unique largely because it identified important subgroups and possible asthma phenotypes within the study population, which may help improve asthma care in these groups.

Clinical tools

Developing reliable and predictive clinical tools may help physicians identify those patients at increased risk for hospitalization/ED visits and loss of productivity/activity. An innovative TENOR-derived risk score was developed that could reliably predict asthma-related hospitalizations/ED visits in adults with severe or difficult-to-treat asthma.50 In an analysis of 2821 adults, 239 (8.5%) reported asthma-related hospitalizations/ED visits at follow-up. Variables that predicted increased

Genetic studies

In the first genome-wide association analysis in patients with severe or difficult-to-treat asthma to uncover the association of DNA variants with asthma susceptibility, 473 TENOR patients and 1892 population control subjects were studied for 292,443 single nucleotide polymorphisms (SNPs) for association with asthma.48 Total serum IgE levels, FEV1 and FVC values, and FEV1/FVC ratios in identified candidate regions in 473 TENOR patients and 363 control subjects without a history of asthma were

Conclusions

Since its launch in 2001, TENOR has provided the scientific and clinical community with important lessons in understanding the natural history, asthma morbidity and burden, and unmet needs in patients with severe or difficult-to-treat asthma for the purpose of improving asthma-related health outcomes in this understudied population. The key observations and clinical implications from TENOR have potentially important clinical implications for health care providers (Table IV).

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      An estimated 5% to 10% of adults with asthma have severe asthma (SA), a heterogeneous disease requiring “high-dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy.”1,2 Compared with nonsevere asthma, SA is associated with a greater risk of exacerbations, reduced quality of life, reduced work productivity, and disproportionately high health care resource use.3-5 The development and approval of monoclonal antibody therapies (ie, biologics) that target specific inflammatory pathways has transformed the management of uncontrolled SA.6,7

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    Genentech, Inc (South San Francisco, Calif), and Novartis Pharmaceuticals (East Hanover, NJ) provided support for the preparation of this manuscript.

    Disclosure of potential conflict of interest: B. E. Chipps has consultant arrangements with Alcon, Genentech, AstraZeneca, GlaxoSmithKline, Meda, Novartis, Sunovion, Merck-Schering, ISTA, Quintiles, and Dey; is on the speakers' bureau for Alcon, Genentech, AstraZeneca, GlaxoSmithKline, Meda, Novartis, Sunovion, Merck-Schering, ISTA, and Dey; has received grants for clinical research from Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Sunovion, and Merck-Schering; and has received grants for education activities from Alcon, Genentech, AstraZeneca, GlaxoSmithKline, and Novartis. R. S. Zeiger has consultant arrangements with AstraZeneca, Aerocrine, Genentech, GlaxoSmithKline, Novartis, Sunovion, Schering-Plough, and MedImmune and has received research support from Aerocrine, Genentech, GlaxoSmithKline, and Merck and Co. L. Borish has received honoraria from Merck; has consultant arrangements with Genentech, Endo Pharmaceuticals, Regeneron, Cephalon, Pfizer, and Hoffman-LaRoche; has received research support from Merck and Genentech; is on committees for the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology; and is a volunteer for the Charlottesville Free Clinic. M. L. Hayden has received speaker's honoraria from TEVA, Merck and Co, and Dey Labs and has consultant arrangements with Sunovion. D. P. Miller's employer has Genentech as a client. E. R. Bleecker has consultant arrangements with Genentech and has received research support from Genentech. F. E. R. Simons has received research support from the Canadian Institutes of Health Research. S. J. Szefler has consultant arrangements with GlaxoSmithKline, Genentech, Merck, Boehringer-Ingelheim, Novartis, and Schering-Plough and has received research support from the National Institutes of Health/National Heart, Lung, and Blood Institute's Childhood Management Program (CAMP); the National Heart, Lung, and Blood Institute's Childhood Asthma Research and Education (CARE); the National Institutes of Health/National Heart, Lung, and Blood Institute's Asthma Clinical Research Network (ACRN); the National Institutes of Health/National Institutes of Allergy and Infectious Disease's Inner City Asthma Consortium (ICAC); GlaxoSmithKline; the National Institutes of Health/National Heart, Lung, and Blood Institute's Asthma Net; and a National Institute of Environmental Health Sciences/Environmental Protection Agency's Childhood Environmental Health Center grant. T. Haselkorn has been a paid consultant to Genentech, Inc since 2002. The rest of the authors declare that they have no relevant conflicts of interest.

    Dr Yegin is currently affiliated with Actelion Pharmaceuticals.

    For a complete list of TENOR Study Group members, please contact Genentech, Inc.

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