Recent asthma exacerbations predict future exacerbations in children with severe or difficult-to-treat asthma

Article Outline

• Abstract
• Methods
  • Study design
  • Inclusion and exclusion criteria
  • Data collection
  • Asthma control
  • Predictors and outcome measures
  • Statistical analyses
• Results
  • Baseline demographics and RSE
  • Asthma impairment and RSE
  • Predictors of future exacerbations
  • Predicted probabilities of a future exacerbation
• Discussion
• Acknowledgment
• References
• Copyright

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.

Key words: Severe asthma, pediatric asthma, exacerbation, predictor of exacerbation, corticosteroid burst, long-term control

Abbreviations used: ATAQ, Asthma Therapy Assessment Questionnaire, FSE, Future severe exacerbation, HCU, Health care use, NHLBI, National Heart, Lung, and Blood Institute, OR, Odds ratio, PACT, Pediatric Asthma Controller Trial, PAQLQ(S), Pediatric Asthma Quality of Life Questionnaire With Standardized Activities, RSE, Recent severe exacerbation, TENOR, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens

Asthma is a major health problem that affects nearly 300 million people¹ or as many as an estimated 20% of children and 8% of adults worldwide.² In 2005, more than 9 million children in the United States under 18 years of age (13%) had ever been diagnosed with asthma, and about 6.5 million (8.9%) still had the disease.³ Severe or difficult-to-treat asthma, broadly defined as asthma that is refractory to treatment and poorly controlled over time,⁴ affects only 5% to 10% of the patient population, but it accounts for a disproportionate share of health care costs and morbidity associated with the disease.⁵, ⁶, ⁷, ⁸, ⁹

Studies have documented the high cost of asthma-related medication and health care use (HCU) in children and how these costs relate to morbidity and symptom control.⁸, ¹⁰, ¹¹, ¹² As with adults, annual per capita health care costs for children increase significantly with severity; the annual cost for severe asthma is $1840 compared with $390 and $682 for mild and moderate asthma, respectively.¹⁰ Among children with severe or difficult-to-treat asthma, rates of HCU are high despite use of multiple medications; of patients using 3 or more long-term controllers, 53% of children reported an oral corticosteroid burst and 25% had an emergency department visit within a 3-month period.⁸

The ability to identify patients at greatest risk for future severe exacerbation (FSE) is important for developing effective prevention strategies, reducing health care costs, and achieving the goals of asthma management.¹³, ¹⁴ A previous analysis of adult patient data from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study, the largest prospective, 3-year, multicenter observational study of patients with severe or difficult-to-treat asthma,⁸, ¹⁵ showed that a recent severe exacerbation (RSE) or recent corticosteroid burst is a strong independent predictor of FSE in this patient population.¹⁶ Given the burden of asthma in children and the lack of available data in this age group, particularly in children with severe asthma, we performed an additional analysis focusing on young patients, age 6 to 11 years, in the TENOR study. The objective was to evaluate RSE as a potential predictor of FSE after adjustments for asthma impairment domain of asthma control and other risk factors.

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Methods 

Study design 

The methods and baseline cohort characteristics of the TENOR study have been previously described.⁸, ¹⁵ Briefly, TENOR was a prospective, observational, 3-year study (2001-2004) conducted in the United States in patients with severe difficult-to-treat asthma followed by asthma specialists. Patients were recruited from diverse geographic areas to represent typical patient care settings, including managed care organizations, community physicians/practices, and academic centers. No experimental intervention was involved; patients continued to receive asthma medications and treatments as recommended by their allergists or pulmonologists. At baseline, 4756 patients were enrolled at 283 study sites, of whom 637 (13.4%) were children age 6 to 11 years.

Inclusion and exclusion criteria 

Children were included in the TENOR study if they were diagnosed with severe asthma or with mild/moderate asthma considered difficult-to-treat by the study site asthma specialist, had received health care from their current provider for ≥1 year, could read and understand English, and satisfied at least 1 of the following conditions of high medication or HCU:

Patients were excluded from the study if they had a primary diagnosis of cystic fibrosis, severe cardiovascular disease (New York Heart Association class II or higher), cancer (not including nonmelanoma skin cancer or cancer in remission for ≥5 years), severe psychiatric disorder (not including anxiety or depression), or significant systemic disease (<2-3 years of life expectancy).

Data collection 

Data were collected at semiannual visits. Demographic and clinical data were collected by study coordinator interview and evaluation. In addition, patients completed a self-administered questionnaire. For children younger than 12 years of age, the parent or guardian was present to help answer interview questions and complete the questionnaires. At study entry and at each 6-month visit during the 3-year follow-up, patients reported asthma-related HCU during the previous 3 months. Patients brought their medications, including long-term controllers and quick-relief medications, to the coordinator interview to record current use. Histories of allergic rhinitis and atopic dermatitis, as well as asthma trigger information, were self-reported.

Asthma control 

Asthma control was assessed by using the NHLBI guidelines impairment domain.¹⁸ The impairment metrics (symptoms, nighttime awakenings, interference with normal activity, short-acting β₂-agonist use, and lung function) were obtained from data collected in the TENOR study at baseline and annual visits. Information regarding symptoms, nighttime awakenings, and interference with normal activity was obtained from the Pediatric Asthma Quality of Life Questionnaire With Standardized Activities (PAQLQ[S]).¹⁹ The PAQLQ(S), a validated questionnaire developed for patients with asthma age 7 to 17 years, was administered and yielded data on the basis of recall of the previous 1-week period. Although the age range of subjects for whom the instrument was developed does not include 6-year-olds, who are included in the present analysis, the individual items evaluated provided the requisite data for mapping the responses accurately to the guidelines. Detailed information describing the data collected with the PAQLQ(S) and their correspondence to the NHLBI guideline criteria has been reported previously.²⁰ The use of short-acting β₂-agonists for symptom control was captured as part of medication use data, and lung function—prebronchodilator FEV₁—was assessed by spirometry. Medication use and spirometry were measured on the date of assessment. At each time point, patients were grouped by their asthma impairment status into 1 of 3 cohorts defined by the impairment domain of the NHLBI guidelines:¹⁸ very poorly controlled, not well controlled, and well controlled.

Predictors and outcome measures 

An RSE was defined as 1 or more corticosteroid bursts within the 3 months before baseline, month 12, and month 24 of the study period. For consistency with a previously reported analysis of adult patients,¹⁶ a similar set of additional candidate predictor variables was considered: age at baseline, duration of asthma at baseline, sex, race/ethnicity (white/nonwhite), body mass index for age-assessed obesity, number of allergic triggers (animals, dust, mold, pollen), and number of nonallergic triggers (emotional stress, sinus infection). Four additional candidate variables (passive smoking exposure, number of long-term controllers used at baseline, the NHLBI guidelines control impairment domain, and median income within zip code) were added for the current pediatric analysis.

As the key outcome, FSE was defined as 1 or more corticosteroid bursts reported 6 months and 12 months after an RSE.

Statistical analyses 

Categorical data and continuous data are reported by using percentages or means and SDs, respectively. The Pearson χ² test for categorical data and the 2-sample t test for continuous data are used to describe the differences between patients with RSE and those without RSE. Both proportions and means are reported as a function of nonmissing data. Missing data were uncommon and occurred typically in less than 1% of study patients, except for spirometry (13.7%) and responses to the Asthma Therapy Assessment Questionnaire (ATAQ; 25.4%). Assessments with missing covariate data were excluded from the final models if any of the significant covariates were missing. Exacerbation outcomes for the preceding 3 months were measured in 6-month intervals. These repeated dichotomous outcomes were analyzed by using a repeated measures logistic regression with generalized estimating equations. All patients with data for at least 1 follow-up outcome contributed to the regression models.

To arrive at a final model, backward selection was used starting with the prespecified set of candidate variables. An entry criterion of P < .05 was used for statistical significance during this process.

Two models were considered for this analysis. Model I (Fig 1) used the first 3 annual visits to define the candidate predictor variables and the 2 subsequent semiannual follow-ups to define the outcome variable. Patients with complete 3-year data could contribute as many as 6 assessments to the model. Backward selection proceeded as described until a list of significant predictor variables was achieved. Model II (Fig 2) started with this list of candidate variables but only considered FSE in the 3 months before the subsequent semiannual visit as the outcome. Thus, each patient could only contribute a maximum of 3 assessments to the model, and the interpretation could be more tightly focused on near-term events. Additional backward selection was then conducted, resulting in a reduced set of predictors, which was used to compute the predicted probabilities of FSE.

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• Fig 1. 

  Model I diagram. ^∗Many covariates were collected annually and not semiannually, requiring that the covariates be defined only at baseline (BL), 12 months, and 24 months.

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• Fig 2. 

  Model II diagram. ^∗Many covariates were collected annually and not semiannually, requiring that the covariates be defined only at baseline (BL), 12 months, and 24 months.

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Results 

Baseline demographics and RSE 

Of the 637 children age 6 to 11 years in the TENOR database, 68 did not have any follow-up data, and 6 others did not have follow-up visits during which HCU data were recorded, leaving data from 563 children available for analysis. Children excluded from the analysis were not appreciably different from those included in terms of age, physician-assessed asthma severity, and number of asthma control problems, but they were more likely to be girls (44.4% vs 31.3%; P = .025) and black (35.1% vs 23.4%; P < .001).

Approximately half of all children in the analysis had experienced RSE within 3 months before study enrollment (Table I). Compared with children without RSE, those with RSE had a slightly longer mean duration of asthma (P = .011) and also had poorer lung function than the non-RSE cohort, as assessed by prebronchodilator percent predicted FEV₁ (P = .012).

Table I. Baseline patient demographics and clinical characteristics: stratification by RSE

Characteristic	No RSE	With RSE	P value
Total no. of children	282	281
Age, n (%)
6-8 y	91 (32.3)	111 (39.5)	.074
9-11 y	191 (67.7)	170 (60.5)
Sex, n (%)
Female	87 (30.9)	89 (31.7)	.83
Male	195 (69.1)	192 (68.3)
Race/ethnicity, n (%)
Nonwhite∗	96 (34.0)	117 (41.6)	.063
White	186 (66.0)	164 (58.4)
BMI for age obesity, n (%)
Not obese	235 (83.3)	220 (78.6)	.15
Obese	47 (16.7)	60 (21.4)
Median income in zip code, mean ± SD	$52,012 ± $19,263	$50,752 ± $19,894	.45
Duration of asthma (y), mean ± SD	5.8 ± 2.7	6.4 ± 2.4	.011
Long-term controllers, n (%)
0-1	28 (9.9)	24 (8.5)	.15
2	98 (34.8)	79 (28.1)
3+	156 (55.3)	178 (63.3)
At least 1 smoker at home, n (%)
No	206 (73.6)	212 (76.3)	.46
Yes	74 (26.4)	66 (23.7)
Allergic triggers,† n (%)
0	40 (14.3)	36 (12.9)	.66
1-2	128 (45.7)	121 (43.4)
3-4	112 (40.0)	122 (43.7)
Nonallergic triggers,‡ n (%)
0	37 (13.2)	25 (9.0)	.11
1-2	243 (86.8)	254 (91.0)
NHLBI guidelines control impairment domain, n (%)
Well controlled	13 ( 5.3)	8 (3.3)	.001
Not well controlled	98 (40.3)	63 (26.1)
Very poorly controlled	132 (54.3)	170 (70.5)
No. of asthma control problems (ATAQ index score), n (%)
0 problems	27 (12.7)	8 (3.9)	<.001
1 problem	47 (22.1)	21 (10.1)
≥2 problems	139 (65.3)	178 (86.0)
Prebronchodilator percent predicted FEV1, mean ± SD	90.1 ± 18.5	85.7 ± 20.4	.012

BMI, Body mass index; GL, Guidelines.

Asthma impairment and RSE 

At baseline, compared with children without RSE, those who had RSE were more likely to have very poorly controlled asthma as measured by the NHLBI guidelines impairment domain (70.5% vs 54.3%; P = .001) and to have reported 2 or more asthma control problems by the ATAQ (86.0% vs 65.3%; P < .001; Table I).

Predictors of future exacerbations 

When analyzed in a multivariable model that included 6-month and 12-month events, children with a recent exacerbation had a 2-fold greater risk of FSE (odds ratio [OR], 1.99; 95% CI, 1.51-2.61; Table II). Reporting 3 or more allergic triggers (OR, 2.01; P < .001), having at least 1 nonallergic trigger (OR, 1.52; P = .019), and being nonwhite (OR, 1.76; P < .001) were also strong independent predictors of FSE for children. In addition, having very poorly controlled asthma as measured by the NHLBI guidelines impairment domain (OR, 1.40; P = .010) and duration of asthma (OR, 1.06; P = .021) also significantly increased the risk of FSE in children. Age, sex, obesity, income, number of long-term controllers, and passive smoking were not significant predictors of FSE.

Table II. Predictors of future exacerbations in children age 6 to 11 years: model results

	Model I∗			Model II†
	Stepwise model where future exacerbations include 6-mo and 12-mo time frame			Additional stepwise reduction of model B including only 6-mo events
Predictors‡	OR	95% CI	P value	OR	95% CI	P value
Recent exacerbation	1.99	(1.51-2.61)	<.001	3.08	(2.21-4.28)	<.001
Nonwhite vs white	1.76	(1.34-2.32)	<.001	1.77	(1.25-2.51)	.001
Allergic triggers§
1-2 allergic triggers	1.39	(0.99-1.95)	.059	1.26	(0.82-1.93)	.29
3-4 allergic triggers	2.01	(1.40-2.89)	<.001	2.05	(1.31-3.20)	.002
NHLBI guidelines control impairment domain ||
VPC vs NWC	1.40	(1.08-1.80)	.010	1.59	(1.14-2.23)	.007
WC vs NWC	0.89	(0.45-1.75)	.73	0.85	(0.37-1.92)	.69
Duration of asthma (per year)	1.06	(1.01-1.12)	.021	—	—	—
Nonallergic triggers,¶ 1-2 vs 0	1.52	(1.07-2.16)	.019	—	—	—

NWC, Not well controlled; VPC, very poorly controlled; WC, well controlled.

When analyzed in a multivariable model including only 6-month events, children with a recent exacerbation had more than a 3-fold greater risk of FSE (OR, 3.08; 95% CI, 2.21-4.28; Table II). Reporting 3 or more allergic triggers (OR, 2.05; P = .002), having very poorly controlled asthma by the impairment domain (OR, 1.59; P = .007), and being nonwhite (OR, 1.77; P < .001) were again strong independent predictors of FSE for children. Duration of asthma and nonallergic triggers were no longer significant predictors of FSE.

Predicted probabilities of a future exacerbation 

Using the 6-month model to examine predicted probabilities of FSE, we found that white children with no RSE, well controlled asthma by the impairment domain, and no allergic triggers had a low (8.7%) risk of FSE, whereas nonwhite children with an RSE, very poorly controlled asthma by the impairment domain, and 3 to 4 allergic triggers had a high (63.4%) risk of FSE (Fig 3). The lowest probability of FSE for a child with an RSE and 3 to 4 allergic triggers was 37.7% (white, well controlled asthma by the impairment domain).

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• Fig 3. 

  Predictors of future exacerbations.

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Discussion 

This study demonstrates a strong association between recent and future severe exacerbations in a large cohort of children with severe or difficult-to-treat asthma. This association persisted and remained strong (ORs ranged from 1.99 to 3.08) after adjusting for demographic and clinical variables, asthma control by the impairment domain, and allergic and nonallergic triggers, demonstrating that regardless of these other factors, RSE is the main driver of FSE in children with severe or difficult-to-treat asthma. In the adjusted regression models, asthma control as measured by the NHLBI guidelines impairment domain was an independent predictor of FSE, whereas the number of long-term controllers were not found to be associated with FSE, which suggests that even maximally treated patients can be at high risk. Race/ethnicity, allergic triggers, and nonallergic triggers were also independent predictors of FSE.

The TENOR data set, derived from a multicenter, prospective study of the largest available pediatric cohort with severe or difficult-to-treat asthma, made it possible to investigate several potential prognostic factors for severe exacerbations. To our knowledge, this is the first study to evaluate RSE history and asthma control as 2 separate, independent risk factors for FSE in children with severe or difficult-to-treat asthma. RSE was the strongest predictor of FSE, which supports the recent NHLBI Expert Panel Report 3 thesis suggesting that recent exacerbation history is important in the overall clinical assessment of a patient.¹⁸ This is especially true for children and adolescents with severe or difficult-to-treat asthma, who have more frequent and more severe exacerbations than adults.²¹

The most striking findings in these analyses are that children with RSE, compared with those without, are 3 times more likely to have an exacerbation 6 months later even after adjustment for asthma control by impairment domain and other risk factors. Our findings are similar to those reported in the children with mild to moderate asthma participating in the Pediatric Asthma Controller Trial (PACT) study, in which only recent exacerbation history (exacerbations requiring prednisone in the previous year) was identified as a predictor for future exacerbations (OR, 2.1; P < .001) despite administration of long-term controllers, including inhaled corticosteroids.²² Moreover, in the PACT study, recent exacerbation history remained an independent predictor of subsequent exacerbations after adjusting for other variables, such as treatment.

Prebronchodilator FEV₁ differed significantly between children with RSE and those without RSE in the univariate analysis. The NHLBI guidelines control impairment domain definition, which incorporates this spirometry measure, was associated with FSE in the multivariable analyses. Our findings are consistent with studies in children with mild to moderate asthma, in which prebronchodilator percent FEV₁,²³ or a baseline peak flow or FEV₁ predicted <65%²⁴ was a significant risk factor for exacerbations. Our findings also support the approach of the guidelines that both impairment and risk, as measured by exacerbations, must be considered.

Allergic triggers and race/ethnicity were also independent predictors for FSE in this study. Evaluation of triggers and related phenotypic characteristics may be necessary to supplement the approach proposed by the guidelines. Exposure to inhaled allergens and indoor mold has been associated with increased exacerbations in young children with severe asthma.²⁵, ²⁶ More than 50% of a large (N = 937) sample of inner-city children with severe asthma had positive skin tests to multiple aeroallergens and higher exacerbation frequencies (83%) despite high-dose inhaled corticosteroid treatment compared with children with mild to moderate asthma (43%).²⁷ Approaches to prevent or alleviate allergen-induced asthma morbidity include immunotherapy, anti-IgE antibody therapy, and environmental interventions that reduce allergen exposure.¹⁸, ²⁸, ²⁹

Nonwhite (black or other) race/ethnicity was associated with a significantly increased risk of future exacerbations compared with white subjects (Model I: OR, 1.76, P < .001; Model II: OR, 1.77, P = .001; Table II). In adult TENOR patients, nonwhite race/ethnicity was similarly associated with a higher risk of FSE (OR, 1.59; P = .008) and future corticosteroid burst (OR, 1.30; P = .025; based on data from Miller et al¹⁶). Other studies evaluating the likelihood of exacerbations in black (African American) children²⁴, ³⁰, ³¹ and adults¹⁶, ³² have shown similar results. Factors related to this association include suboptimal use of preventive services for asthma, poor adherence and access to care, ineffective asthma management, and a greater likelihood of steroid insensitivity.³⁰, ³¹, ³³ A limitation of our study is that these potential confounding effects were not collected. Further investigations of factors associated with race/ethnicity and exacerbations may be warranted. Like allergic triggers, these factors may be helpful in supplementing the approach recommended by the guidelines.

There are several additional limitations of this analysis. Recall bias may have been introduced by the self-report of exacerbations from patients, and gaps in data collection prevented a full assessment of exacerbations over the past year as proposed by the guidelines. Nonetheless, limiting recall to 3 months was deemed necessary to maximize the quality of the patient-reported data. In addition, the risk of FSE found in this study is only directly generalizable to a severe or difficult-to-treat patient population and may be higher than in the general asthma population. However, as Robertson et al³⁴ reported, a substantial percentage of asthma mortality can be attributed to individuals who are not considered high-risk. Therefore, a comprehensive evaluation of risk factors and identification of new risk factors may also be important in the general asthma population. Differences between patients with complete data and those lost to follow-up also reduce the generalizability of our study, but the repeated-measures approach in which all available data are used for each patient reduces that bias.

In summary, RSE is the most powerful independent predictor of FSE in children with severe or difficult-to-treat asthma regardless of lung function or use of long-term controllers. As such, RSE should be considered during the clinical assessment of asthma and establishment of asthma management plans to prevent FSE. Whereas inhaled corticosteroid therapy in the PACT study³⁵ and multiple controller therapy in the TENOR cohort did not reduce the rate of FSE or improve asthma control, identification and more aggressive treatment of children who are at increased risk for FSE may help to reduce the rate of FSE and improve asthma control.

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We acknowledge Dave P. Miller for his statistical consultation.

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