Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort

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 [8]. 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.

The TENOR study design has been described in detail elsewhere [8] and is shown in Fig. 1. TENOR is a large, observational study of severe or difficult-to-treat asthma which enrolled 4,756 patients (3,489 adults ≥18 years, 497 adolescents 13–17 years, and 770 children 6–12 years) with diverse racial and ethnic backgrounds, and from different geographic areas [8]. Patients were enrolled from specialized asthma care settings in the USA, including managed care organizations, community physicians, group practices, and academic centers.

Patients were included in the TENOR registry if they had severe or difficult-to-treat asthma, with asthma severity being determined by their physician. Patients with mild or moderate asthma were therefore eligible for enrollment if their asthma was considered difficult-to-treat. Patients were assessed as having “difficult-to-treat” asthma on the basis of pre-specified criteria, including the need for multiple drugs, occurrence of frequent exacerbations, severe exacerbations, inability to avoid asthma triggers, and use of a complex treatment regimen [8]. Patients were also required to have high use of the healthcare system (≥2 unscheduled care visits for asthma or ≥2 oral corticosteroid (OCS) courses) or high medication use (requiring ≥3 medications to control asthma or requiring long-term daily high-doses of inhaled corticosteroids (ICS)) in the previous 12 months. At enrollment, 48 % of patients had severe asthma, 48 % moderate asthma, 3 % mild asthma, and 96 % difficult-to-treat asthma. After enrollment, patients completed seven study visits over three years, during which a range of demographic, clinical, standard laboratory, and patient self-reported assessments was completed. Baseline demographics and clinical characteristics of the TENOR population are presented in Table 1.

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 [8]. 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•].

Given the high rates of healthcare utilization in the TENOR cohort, subsequent analysis has focused on identifying specific predictors for future asthma exacerbations. In adults, adolescents, and children, after assessing a broad range of variables, recent asthma exacerbation was the strongest predictor of future asthma exacerbation [16]. In patients aged ≥12 years, those who reported an asthma-related ED visit or overnight hospitalization in the three months before baseline were more than sixfold more likely (odds ratio (OR) = 6.33; 95 % confidence interval (CI) 4.57, 8.76), to experience a future severe asthma exacerbation (defined as an asthma-related ED visit, overnight hospitalization, or an asthma-related death) at the 18-month follow-up (Fig. 2) [16]. After adjusting for demographic and clinical factors, the risk of future severe exacerbation remained high (OR = 3.77; 95 % CI 2.62, 5.43). When analysis was individually adjusted for various asthma severity measures, the increased risk was consistently more than fivefold (physician-assessed: OR = 5.62; 95 % CI 4.03, 7.83; National Asthma Education and Prevention Program guideline assessed: OR = 5.07; 95 % CI 3.62, 7.11; GINA guideline assessed: OR = 5.32; 95 % CI 3.80, 7.47). When adjusted for asthma control (using the asthma therapy assessment questionnaire; ATAQ), the risk of future severe exacerbation was nearly fourfold (OR = 3.90; 95 % CI 2.77, 5.50). An increased risk of future exacerbation requiring an OCS course was also seen if patients had a recent exacerbation requiring an OCS course in the three months before baseline (Fig. 2) [16].

Similarly, separate analysis for children (aged 6–11 years) assessed the occurrence and association of a recent severe exacerbation defined as one or more OCS courses during the three months before each of three annual visits (baseline, Month 12, and Month 24), and a future severe exacerbation, defined as one or more OCS courses six or twelve months later. A future severe exacerbation at six months was most strongly predicted by a recent severe exacerbation (OR = 3.08; 95 % CI 2.21, 4.28) and having 3 or 4 allergic triggers (OR = 2.05; 95 % CI 1.31, 3.20) [17•] (Table 2, Model II). Other predictors of a future severe exacerbation at six months included non-white race (OR = 1.77; 95 % CI 1.25, 2.51) and very poorly controlled asthma, as defined by the NHLBI guidelines (OR = 1.59; 95 % CI 1.14, 2.23).

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.

We also examined the relationship between asthma control and asthma exacerbations. The findings consistently revealed that poor asthma control, whether defined by the patient (using self-reported, validated instruments) or by national asthma guideline classifications, was strongly associated with an increased risk of asthma exacerbations. In an early analysis, TENOR used the ATAQ in patients ≥18 years to assess the association between baseline asthma control, and subsequent severe asthma-related healthcare events within the first year of follow-up. After adjustment for covariates, patients with poor asthma control at baseline (three or four control problems) were found to be at increased risk of: unscheduled office visits (relative risk (RR) = 2.8; 95 % CI 2.4, 3.2), requiring a course of OCS (RR = 2.9; 95 % CI 2.5, 3.3), ED visits (RR = 4.1; 95 % CI 2.7, 6.2), and hospitalization (RR = 13.6; 95 % CI 7.4, 24.9) within the first year of follow-up, compared with patients with no asthma control problems [18] (Fig. 3).

After the 2007 update to the NHLBI asthma guidelines [13], we evaluated the classification scheme for asthma control based on the impairment domain of the guidelines for identifying patients at risk of future asthma exacerbation [19•]. Using data representing all components of the impairment domain at baseline, Month 12, and Month 24, patients were categorized into two groups: those whose asthma was consistently very poorly controlled from baseline through two years of follow-up, and those whose asthma improved from very poorly controlled at baseline with improvement maintained throughout two years of follow-up. In multivariate analysis, pediatric patients whose asthma was consistently very poorly controlled were at sixfold increased risk of hospitalization, ED visit, or OCS burst (OR = 6.4; 95 % CI 1.2, 34.5) at the Month 30 visit, compared with those who improved over the two-year period. Adult and adolescent patients who were consistently very poorly controlled were more likely to require an OCS course (OR = 2.8; 95 % CI 1.7, 4.8), or have a hospitalization, ED visit, or OCS course when these outcomes were assessed as a composite measure (OR = 3.2; 95 % CI 1.9, 5.3; Fig. 4). These data from TENOR provided validation for the impairment domain of the 2007 NHLBI guidelines as an effective tool for classifying and managing patients with severe or difficult-to-treat asthma.

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•].

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 [21]. 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 [22‐24]. For adult TENOR patients (aged ≥18 years), body weight changes were found to affect asthma control and exacerbation [25]. 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 [26]. 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 [26‐28]. 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) [29]. 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, 30‐32]. 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 [33]. 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 [36]. 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 [36].