Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort
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- Chipps, B.E., Zeiger, R.S., Dorenbaum, A. et al. Curr Respir Care Rep (2012) 1: 259. doi:10.1007/s13665-012-0025-x
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Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.
KeywordsSevere asthma Difficult-to-treat asthma Asthma control Exacerbation
According to World Health Organization (WHO) estimates, 235 million people worldwide currently have asthma . Although patients with severe or difficult-to-treat asthma comprise only a small proportion (<15 %) of the total asthma population, they account for substantial asthma morbidity, mortality, and healthcare costs [2, 3, 4, 5, 6]. As for all patients with asthma, the primary objective of treatment for patients with severe disease is to achieve and maintain clinical control [7••]. To improve outcomes among these patients, it is necessary to understand the extent to which this objective is being met, identify barriers that may hinder achievement of asthma control, and ascertain whether specific subgroups of patients are at increased risk of poor control.
Large registries that accumulate data from “real-world” settings are a valuable tool with which to evaluate treatment outcome. In 2001, a multicenter, observational, prospective cohort study, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR), was initiated to study patients described by their physicians as having severe or difficult-to-treat asthma [8, 9]. Data from TENOR have been reported in more than 25 publications, and provide insight into asthma-related health outcome and barriers to optimum asthma care for these patients. Analyses of TENOR data have also provided the opportunity to characterize patients with severe or difficult-to-treat asthma with regard to atopy. For example, in TENOR most patients were found to have high immunoglobulin (IgE) levels, particularly males, children, smokers, non-white racial or ethnic group, and adults with childhood-onset disease . In young patients, IgE levels were found to be associated with asthma severity , and high frequencies of comorbid allergic diseases and allergen sensitization were seen .
In this review, we summarize the findings from TENOR in relation to asthma control and asthma exacerbations in patients with severe or difficult-to-treat disease and further examine specific patient subgroups within this population.
Defining asthma severity and control
When TENOR was initiated in 2001, asthma severity was defined in the National Heart Lung and Blood Institute (NHLBI) guidelines according to symptoms, activity limitation, rescue medication use, and exacerbation frequency . In 2007, these guidelines were updated, recommending that physicians assess asthma severity using two domains: current impairment (day-to-day symptoms and limitation of activity) and future risk (likely outcome if patient remains on current treatment, based on asthma severity, history, and probability of exacerbation) [13, 14]. Similarly, current Global Initiative for Asthma (GINA) guidelines note that asthma severity encompasses both the underlying nature of the disease and the response to treatment [7••]. Consequently, the GINA guidelines classify asthma as severe if it requires high intensity treatment or if control is not achieved despite such treatment. Both NHLBI and GINA guidelines also recognize the importance of evaluating future risk of exacerbation, on the basis of current clinical control, lung function, and exacerbation history [7••, 13].
Data from the TENOR registry have proved extremely useful for identifying patients at high-risk of poor asthma control and frequent asthma exacerbations. This review summarizes the analyses and findings related to asthma control and exacerbations in TENOR through the evolution of these terms and definitions.
The TENOR registry
Objectives and design
The primary objective of TENOR was to collect prospective data to improve our understanding of the natural history of asthma in patients with severe or difficult-to-treat disease . Secondary objectives were to examine the relationship between features of asthma treatment and outcome, to observe the frequency of pre-defined comorbid conditions, and to describe the relationship between IgE levels and disease.
TENOR baseline demographics and clinical characteristics 
Adults (≥18 years)
Adolescents (13–17 years)
Children (6–12 years)
Patients, n (%)
Age, mean ± SD, years
38.9 ± 20.92
48.9 ± 14.85
14.5 ± 1.34
9.5 ± 1.88
Weight, mean ± SD, kg
75.2 ± 26.53
83.9 ± 2.22
66.9 ± 21.03
41.1 ± 16.64
BMI, mean ± SD, kg/m2
28.3 ± 8.59
30.4 ± 7.73
25.4 ± 9.86
20.7 ± 6.17
IgE, geometric mean, IU/mL
Sex, n (%)
Race or ethnicity, n (%)
Asian or Pacific Islander
Physician assessment of severity, n (%)
Smoking history, n (%)
Predicted pre-bronchodilator FEV1, n (%)
>60 % to <80 %
Pre-bronchodilator FEV1, (% predicted), mean ± SD
77.2 ± 23.28
74.2 ± 23.45
84.0 ± 21.63
87.0 ± 19.57
Post-bronchodilator FEV1 (% predicted), mean ± SD
82.5 ± 23.04
79.0 ± 23.08
91.1 ± 21.03
93.9 ± 18.50
QoL scorea, mean
At baseline, at least one asthma hospitalization or emergency department (ED) visit in the previous three months occurred in 5 % and 15 % of adults, 10 % and 17 % of adolescents, and 9 % and 22 % of children, respectively. Almost half of adults and children, and ~40 % of adolescents reported OCS courses and unscheduled visits for asthma in the previous three months . Across all age groups, approximately 10 % of patients reported a history of intubation for asthma. This high healthcare utilization was observed despite the use of multiple long-term controller medications [8, 9]. Notably, of those using at least three long-term controllers, 15 % of adults, 19 % of adolescents, and approximately 25 % of children had visited an ED in the three months before baseline [15•].
Recent and future asthma exacerbation
Predictors of future exacerbations in children aged 6–11 years [17•]
Stepwise model where future exacerbation includes 6-month and 12-month time frames
Additional stepwise reduction of model including only 6-month events
95 % CI
95 % CI
Non-white vs. white
1 or 2 allergic triggers
3 or 4 allergic triggers
NHLBI guidelines control impairment domaine
VPC vs. NWC
WC vs. NWC
Duration of asthma (per year)
Non-allergic triggersf, 1–2 vs. 0
This analysis for adults, adolescents, and children reveal that a recent severe exacerbation (within the previous three months) is an important independent predictor of a future severe exacerbations in severe or difficult-to-treat asthma.
Asthma control and asthma exacerbations
The NHLBI asthma guidelines were further investigated by assessing the affect of individual components of the impairment domain on the classification of asthma control and prediction of asthma exacerbations. It was found that omission of individual components of the impairment domain resulted in asthma control being wrongly classified in 11–39 % of patients [20•]. The strongest predictor of an asthma exacerbation at 12 months was a previous exacerbation at baseline (in adults and adolescents: OR = 2.93; 95 % CI 2.38, 3.61 and in children: OR = 2.94; 95 % CI 1.71, 5.07). In addition, very poorly controlled asthma, classified on the basis of use of short-acting β2-agonists (SABAs), was associated with a twofold higher exacerbation risk in children (OR = 2.03; 95 % CI 1.17, 3.52). In adults and adolescents, significant predictors of exacerbations at Month 12 were very poorly controlled asthma on the basis of lung function (OR = 1.66; 95 % CI 1.34, 2.06) and very poorly controlled asthma on the basis of the ATAQ control score (OR = 1.94; 95 % CI 1.56, 2.40). In addition, for adults and adolescents, very poorly controlled asthma and not well controlled asthma, classified on the basis of the use of SABAs, was also associated with increased exacerbation risk (OR = 1.49; 95 % CI 1.19, 1.85). This study reaffirmed that a recent asthma exacerbation is the strongest predictor of a future exacerbation and that, although specific components of the NHLBI impairment domain may be more important than others in predicting asthma exacerbations, the combined use of the components is essential for improving the identification of patients at high-risk of future exacerbations [20•].
Asthma control and asthma exacerbations in high-risk patient subgroups
The TENOR registry has provided a valuable opportunity to evaluate asthma control and exacerbations in several patient subgroups, including older patients (≥65 years) who are often excluded from clinical trials. Characterization of these subgroups can assist physicians in addressing individual disease-management needs, and may help to improve asthma-related health outcome.
Compared with younger patients (18–64 years) in TENOR, lower healthcare resource utilization, better asthma-related quality of life (QoL), and fewer asthma control problems were observed for older patients, despite their poorer lung function . These findings may be related to more intensive treatment (as evidenced by greater use of ICS and OCS) and higher medication adherence among older TENOR patients. Also, although older patients reported fewer problems controlling their asthma (p < 0.001), they reported worse communication with their physicians (p = 0.02) than younger patients.
Body mass index (BMI) and weight have both been positively correlated with asthma incidence and severity, and negatively associated with response to ICS [22, 23, 24]. For adult TENOR patients (aged ≥18 years), body weight changes were found to affect asthma control and exacerbation . Patients who gained at least 5 lb (2.27 kg) during a 12-month interval reported poorer asthma control (adjusted OR = 1.22; 95 % CI 1.01, 1.49), worse QoL, and a greater number of OCS courses (OR = 1.31; 95 % CI 1.04, 1.66), than patients who maintained or lost weight.
Studies have shown that African–Americans with asthma are more likely to experience treatment failure than white patients, despite having fewer asthma symptoms and using less rescue medication . It has also been shown that African–Americans tend to have more severe acute asthma episodes than white patients, and have greater utilization of emergency healthcare [26, 27, 28]. The underlying reasons for increased asthma morbidity among black patients compared with those from other racial/ethnic groups, have not been fully elucidated. To improve understanding, a TENOR analysis of adult patients (≥18 years) compared 243 black patients with 1,885 white patients. One year after enrollment, black patients were more likely to have a higher frequency of ED visits, more problems with asthma control, poorer QoL, and greater requirement for three or more long-term controllers (among those with physician-assessed severe asthma) . These racial differences were not explained by adjustment for broad sets of confounding variables, including socioeconomics, disease severity, BMI, sensitization to allergens, medication adherence, or treatment setting. Asthma-related behavioral and knowledge factors, which are understudied aspects of current racial disparity research, did not differ between black and white patients. These findings suggest the need to evaluate genetic and pharmacogenetic factors to help explain these racial differences.
Although treatment reverses airway obstruction in patients with asthma, it has been noted that some patients have persistent airflow limitation (PAFL) which is characterized by a lack of reversal of obstruction, despite treatment, and is associated with a high risk of morbidity and mortality [13, 30, 31, 32]. A 2007 analysis from the TENOR registry showed that PAFL was highly prevalent in adult (≥18 years) patients with severe or difficult-to-treat asthma, and can be associated with identifiable clinical and demographic characteristics . Of the 1,017 TENOR patients included in this analysis, evidence of PAFL (defined as post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio ≤70 % at two annual consecutive visits) was observed for 612 (60 %). Patients with chronic obstructive pulmonary disease (COPD), obesity with a restrictive respiratory pattern, or a ≥30 pack-year history of smoking were excluded. Risk factors for PAFL were old age (OR per 10 years = 1.4; 95 % CI 1.3, 1.6), male gender (OR = 4.5; 95 % CI 2.3, 8.5), black ethnicity (OR = 2.2; 95 % CI 1.3, 2.8), current or past smoking (OR = 3.9; 95 % CI 1.8, 8.6 and 1.6; 95 % CI, 1.2, 2.3, respectively), aspirin sensitivity (OR = 1.5; 95 % CI 1.0, 2.4), and longer asthma duration (OR per 10 years = 1.6; 95 % CI 1.4, 1.8). Factors that appeared to protect against PAFL were Hispanic ethnicity, being better educated, having a history of atopic dermatitis, having pet(s) in the home, and dust sensitivity. Importantly, however, no evidence of PAFL was found for 40 % of patients analyzed, suggesting PAFL may be a distinct asthma phenotype which does not develop in all severe or difficult-to-treat patients with asthma.
It has been noted that patients with aspirin-exacerbated respiratory disease (AERD), which is characterized by aspirin sensitivity, severe persistent asthma, extensive chronic hyperplastic eosinophilic sinusitis, and nasal polyp formation, are at particularly high risk of asthma exacerbations [34, 35]. Aspirin sensitivity as a risk factor for the development of irreversible airway obstruction was evaluated for adult patients (aged ≥18 years) in the TENOR registry . Compared with patients with non-aspirin-sensitive asthma, patients with AERD had significantly lower mean post-bronchodilator percent predicted FEV1 (75.3 % vs. 79.9 %), were more likely to have physician-assessed severe asthma (66 % vs. 49 %), to have been intubated for asthma (20 % vs. 11 %), to require OCS courses (56 % vs. 46 %), or require higher doses of ICS (34 % vs. 25 %). These findings suggest that aspirin sensitivity is associated with increased asthma severity, and possible remodeling of the upper and lower airways .
Since its initiation in 2001, the TENOR registry has provided clinicians with unique and important information that can be used to help guide effective management of patients with severe asthma by improved understanding of factors associated with poor asthma control and high levels of healthcare resource use. Analysis of data from the TENOR cohort have revealed that patients with severe or difficult-to-treat asthma should be assessed to determine their recent exacerbation history (previous 3 months). In addition, analyses of data from the TENOR cohort provide strong support for assessment of current asthma control to estimate future exacerbation risk and guide management decisions [19•, 20•]. The most recent NHLBI and GINA guidelines for the management of asthma [7••, 13] both recognize the importance of evaluating future risk of exacerbations on the basis of assessment of exacerbations history and current asthma control.
Summary table of important findings from TENOR and applications to patient care
Important findings from the TENOR cohort: Asthma control and exacerbations in patients with severe or difficult-to-treat asthma
Patients with severe or difficult-to-treat asthma have poor asthma control and high rates of asthma-related healthcare utilization, despite use of multiple long-term controller medications
Poor asthma control, whether defined by self-reported validated instruments, for example the ATAQ, or by use of NHLBI 2007 guideline classifications, is strongly associated with an increased risk of future asthma exacerbations
Patients are at significant risk of a future asthma exacerbations if they have had a recent exacerbations in the preceding 3 months
Asthma control and exacerbations in high-risk patient subgroups with severe or difficult-to-treat asthma
Adult (≥18 years) patients who gain weight (≥5 lb during a 12-month period) are more likely to have poorer asthma control, worse QoL, and a greater number of OCS courses compared with patients who maintain or lose weight
Adult (≥18 years) black patients are at an increased risk of asthma exacerbations, poorer asthma control, and compromised responsiveness to some medications
PAFL is highly prevalent among adult (≥18 years) patients, particularly those of older age, male sex, black race, who are current or past smokers, aspirin sensitive, or have a long asthma duration
Adult (≥18 years) patients with aspirin sensitivity are more likely to have severe asthma and possible remodeling of the upper and lower airways
Applications to patient care
Recent exacerbations history (preceding 3 months) and an evaluation of the level of asthma control should be included as a component of asthma assessment and management
Future exacerbations for individual patients can be predicted by use of asthma control, defined by the impairment domain of the NHLBI 2007 asthma guidelines
Validated, self-assessed measures of asthma control, for example the ATAQ, are effective tools for identifying and managing patients at greatest risk of future health impairment and severe asthma-related incidents
Physicians should be aware of the importance of good communication with patients, particularly old patients, and ensure appropriate use of ICS and patient adherence to prescribed regimens
Strategies to prevent weight gain may help patients achieve better asthma control and improve asthma-related QoL
Increased awareness of patient subgroups that are particularly at risk of poor asthma control and future exacerbations can help in the design of asthma-management strategies for individual patients. These include patients with weight gain, black patients, patients with PAFL, and patients with aspirin-sensitive asthma
We gratefully acknowledge all participants in the TENOR Study Group, including the dedicated investigators and study coordinators who enrolled and collected the extensive data, ultimately enabling all research projects to be possible, and the invaluable collaborators and contributors to the research projects summarized in this article (in alphabetical order): H. Barron, MD; P. D. Blanc, MD, MSPH; B. W. Bresnahan, PhD; J. D. Campbell, PhD; H. Chen, MD, MPH; Y. Deniz, MD; C. M. Dolan, PhD; A. Dorenbaum, MD; J. E. Fish, MD; K. E. Fraher, MS; L. C. Grammer, MD; E. Israel, MD; C. A. Johnson, MD; T. V. Kamath, PhD; J. H. Lee, MD; X. Li, PhD; K. Mascia, PhD; D. A. Meyers, PhD; M. K. Miller, MS; D. R. Mink, MS; D. J. Pasta, MS; A. T. Peters, MD; M. Pritchard, MS; L. Rasouliyan, MS; R. G. Slavin, MD; S. D. Sullivan, PhD; E. H. Warren, MBA; D. A. Wong, MD, and B. Zheng, PhD.
Editorial support was provided by professional medical writers Lisa Quinn (CircleScience) and Paul Hutchin PhD (contracted to CircleScience), funded by Genentech Inc.
Declaration of source of funding
Genentech, Inc, South San Francisco, CA, USA, and Novartis Pharmaceuticals, East Hanover, NJ, USA, provided support for the preparation of this manuscript.
B.E. Chipps: consultant arrangements with Genentech and Novartis, is on the speakers’ bureau for Genentech and Novartis, and has received grants for clinical research and education activity from Genentech and Novartis; R.S. Zeiger: consultant arrangements with Genentech and Novartis, and has received research support from Genentech; L. Borish: consultant arrangements with Genentech and has received research support from Genentech; D.P. Miller: employer has Genentech as a client; M.L. Hayden: speakers’ bureau for Genentech and Novartis; E.R. Bleecker: consultant arrangements with Genentech and has received research support from Genentech; S. Szefler: consultant arrangements with Genentech and Novartis; T. Haselkorn: paid consultant of Genentech, Inc.; A. Dorenbaum: an employee of Genentech, Inc. and holds Roche stock options; S.E. Wenzel, E.R. Simons, and S.T. Weiss: no relevant conflicts of interest.
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