Use of the Asthma Control Questionnaire to predict futurerisk of asthma exacerbation

Eli O. Meltzer, MD,a WilliamW. Busse, MD,b Sally E. Wenzel, MD,c Vasily Belozeroff, PhD,d Haoling H. Weng, MD, MHS,d

JingYuan Feng, MS,d Yun Chon, PhD,d Chiun-Fang Chiou, PhD,d Denise Globe, PhD,d and Shao-Lee Lin, MD, PhDd San

Diego and Thousand Oaks, Calif, Madison, Wis, and Pittsburgh, Pa

Background: Direct correlation of assessments of a validatedcomposite measure such as the Asthma Control Questionnaire(ACQ) and risk of exacerbation has not been previouslydemonstrated in a randomized controlled trial.Objective: To evaluate the ability of the ACQ score over time topredict risk of a future asthma exacerbation.Methods: This analysis included data from a 12-week placebo-controlled trial (N 5 292) of AMG 317, an IL-4 receptor aantagonist, in patients with moderate to severe atopic asthma.At baseline, patients had an ACQ score >_1.5. Exacerbationswere defined as requirement for systemic corticosteroids. A Coxproportional hazards model was used, with ACQ score as thetime-dependent covariate. The analysis was repeated forindividual components of the ACQ.Results: Each 1-point increase in ACQ was associated with a50% increased risk of exacerbation (hazard ratio, 1.50; 95%CI, 1.03-2.20) for the following 2-week period. Evaluation ofindividual ACQ components also demonstrated a similar

From athe Allergy andAsthmaMedical Group and Research Center, SanDiego; btheUni-

versity of Wisconsin; cthe University of Pittsburgh Medical Center; and dAmgen Inc,

Thousand Oaks.

Supported by Amgen Inc.

Trial registration: This study is registered with ClinicalTrials.gov with the identifier NCT

00436670.

Disclosure of potential conflict of interest: E. O. Meltzer has received research support

from UCB, Alcon, Alexza, Amgen, Antigen Labs, Apotex, Astellas, AstraZeneca,

Boehringer Ingelheim, Capnia, Critical Therapeutics, GlaxoSmithKline, MAP,

MEDA, Merck, Novartis, Proctor & Gamble, Schering-Plough, and Teva; has served

as a consultant or on an advisory board for Schering Plough, Alcon, Alexza Pharma-

ceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Capnia, Dainippon Sumitomo

Pharma, Dey, ISTA, Johnson& Johnson, Kalypsys, MAP,Meda,Merck, National Jew-

ish Health, Rady Children’s Hospital San Diego, Sandoz, Sepracor, SRxA, Teva, Ven-

tiRx, Wockhardt, and Wyeth; is a speaker for GlaxoSmithKline, MEDA, Merck,

Sanofi-Aventis, Schering-Plough, Sepracor, and SRxA; has served as an expert in legal

matters on the topics of desloratadine, fexofenadine, montelukast, and levocetirizine;

and is a fellow for the AAAAI and the American College of Allergy, Asthma and Im-

munology. W. W. Busse is on the advisory board for Altair, GlaxoSmithKline, Merck,

Wyeth, Pfizer Centocor, Amgen, and Johnson & Johnson; is a speaker for Merck; is a

consultant for Novartis, Astra Zeneca, TEVA, Boehringer Ingelhim, and GlaxoSmith-

Kline; and has received research support from NIH-NIAID, NIH-NHLBI, Novartis,

AstraZeneca, GlazoSmithKline, MedImmune, and Ception. S. E. Wenzel is a consul-

tant for GlaxoSmithKline, Merck, Amgen, and Pearl Therapeutics; is on the advisory

board for Amira, Altair, and Epigenesis; and has received research support from

GlaxoSmithKline, Amgen, and MedImmune. V. Belozeroff, H. H. Weng, D. Globe,

and S.-L. Lin are employed by Amgen. Y. Chon holds stock in Amgen. The rest of

the authors have declared that they have no conflict of interest.

Received for publication June 21, 2010; revised August 20, 2010; accepted for publica-

tion August 23, 2010.

Available online November 18, 2010.

Reprint requests: Eli O. Meltzer, MD, Allergy and Asthma Medical Group and Research

Center, 9610Granite Ridge Drive, Suite B, SanDiego, CA 92123. E-mail: eomeltzer@

aol.com.

0091-6749/$36.00

� 2010 American Academy of Allergy, Asthma & Immunology

doi:10.1016/j.jaci.2010.08.042

trend, though each to a lesser degree than the full compositeACQ.Conclusion: Although based on a retrospective analysis, withsmall number of exacerbations, these findings support the utilityof the composite ACQ score measurement to predict risk offuture exacerbation in clinical trials and clinical practice.The composite ACQ score measurement was found to be abetter predictor of future risk than individual ACQcomponents. (J Allergy Clin Immunol 2011;127:167-72.)

Key words: Asthma exacerbation, ACQ score, asthma control,prediction, IL-4 receptor a, antagonist

Asthma is a chronic inflammatory disorder of the airways thataffects over 300 million people worldwide.1 Many patients withasthma experience ongoing symptoms that interrupt daily activi-ties, cause overall poor quality of life, and may subsequently leadto lower productivity and greater health care costs.2 In a recentlypublished cross-section survey of 2500 patients with asthma, thepercentage who needed acute care for asthma in the past 12months has not changed significantly in 2009 versus 1998 (34%vs 36%).3,4 Several large community-based asthma surveyshave also shown that the majority of patients have a high rate ofsymptoms and impairment from their disease.4-6 Recentcommunity-based surveys have shown that 51% to 59% of pa-tients have uncontrolled asthma even with the use of standardasthma medications.7-9 The Gaining Optimal Asthma Control(GOAL) clinical trial found that <45% of patients achieved totalasthma control (ie, no daytime symptoms, use of bronchodilators,or exacerbations, and morning peak expiratory flow >_80% in 7 of8 weeks) despite intensive therapy and dose escalation based onexisting treatment guidelines.10

The importance of asthma control has been emphasized by therecent disease management guidelines, including the GlobalInitiative for Asthma guidelines and the National AsthmaEducation and Prevention Program.11,12 Control of asthma ismonitored by level of current control (impairment) and risk forlong-term effects on exacerbations, progressive impairment oflung function, and medication side effects.11,12 Achieving ade-quate asthma control and minimizing future risk of exacerbationsare the primary goals in the management of the disease.Level of asthma control may be examined by a single clinical

feature of asthma such as FEV1. However, the American ThoracicSociety/European Respiratory Society statement on endpoints forasthma clinical trials recommends considering use of a validatedcomposite measure, such as the Asthma Control Questionnaire(ACQ), in clinical trials to assess asthma control.13 The utilityof composite measures to predict long-term risk, particularly ex-acerbations, remains poorly studied. Although measurementssuch as variation in peak expiratory flow rate (PEFR) and low

167

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168 MELTZER ET AL

Abbreviations used

ACQ: A

sthma Control Questionnaire

HR: H

azard ratio

MID: M

inimal important difference

PEFR: P

eak expiratory flow rate

FEV1 have been associated with risk of exacerbations,14 it is con-

ceivable that a composite measure such as the ACQ,15 which as-sesses the adequacy of asthma control by using symptoms,activity limitation, use of rescue medications, and lung function,may better capture different aspects of asthma control and predic-tion of risk.Direct correlation of sequential measurements of asthma

control over time and risk of exacerbation has not been previouslyreported in a randomized clinical trial. The purpose of this studywas to examine the association between the ACQ score and therisk of future exacerbation within a randomized controlled trial ofpatients with moderate to severe asthma. Individual componentsof the ACQ aswell as the ACQ6-item (ACQ-6) and 5-item (ACQ-5) versions were also examined for their association with the riskof exacerbation.

METHODS

PatientsA post hoc analysis of data from a 12-week multicenter, double-blind,

randomized, placebo-controlled clinical trial16 was conducted to assess the

association between the ACQ and asthma exacerbation. Patients with

moderate to severe atopic asthma were enrolled in a dose-ranging phase 2

study to assess the safety and efficacy of AMG 317, an IL-4 receptor a

antagonist. Patients were randomly assigned in a 1:1:1:1 ratio to receive

1 of 3 doses of the IL-4 receptor a antagonist or placebo administered once

weekly for 12 weeks.

To be eligible for the study, patients had to meet the following inclusion

criteria: (1) age 18 to 65 years, (2) FEV1% predicted >_50% to <_80%, (3) at

least 12% reversibility over baseline FEV1 with b-agonist inhalation, (4) in-

haled corticosteroid >_200 and <_1000 mg/d fluticasone propionate or equiva-

lent, (5) positive to skin prick test or RAST to at least 2 allergens, and (6)

ongoing asthma symptoms with ACQ score at screening and baseline >_1.5.

Subjects who received oral or parenteral corticosteroids within 6 weeks before

the first run-in visit were excluded from the study. Details for this clinical trial

have been previously published.16

Before enrollment into the study, the institutional review board for each site

provided written approval of the protocol, and patients provided informed

consent to participate in the study.

ACQEligible patients completed the ACQ weekly for 2 weeks before treatment

initiation and every 2 weeks for 16 weeks after treatment initiation. The ACQ

is a validated 7-item questionnaire that measures asthma control and is

increasingly being used in clinical practice and research.15,17,18 Patients are

asked to recall their symptoms during the previous week and to respond to

the first 6 questions (nighttime waking, symptoms on waking, activity limita-

tion, shortness of breath, wheeze, and rescue short-actingmedication use) on a

7-point scale from 0 (no impairment) to 6 (maximum impairment). Clinicians

score the percent predicted prebronchodilator FEV1 (the seventh question) on

a similar 7-point scale as the other ACQ questions. The items are equally

weighted, and the ACQ score is the mean of the 7 items, with scores between

0 (totally controlled) and 6 (severely uncontrolled). The minimal important

difference (MID) is 0.5, representing the smallest change that is considered

clinically meaningful.17 An ACQ score of 1.5 has been identified as the best

discriminator between patients with asthma who are well controlled and those

who are not well controlled.19

Shorter versions of the ACQ have been validated, including the ACQ-6,

which excludes lung function, and ACQ-5, which excludes lung function and

rescue medication use.17,18

Asthma exacerbationAsthma exacerbation was defined as ‘‘requirement for systemic cortico-

steroids.’’ An alternative definition, ‘‘requirement for systemic corticoste-

roids or doubling of inhaled corticosteroid dose,’’ was also separately

evaluated. Both definitions were prespecified in the study protocol and

analysis plan.

Time to event for asthma exacerbation was defined as the time to the

first exacerbation after treatment initiation for patients with at least

1 exacerbation. For patients with no exacerbations through 12 weeks of

study, the time to event was considered censored and was thus observed

from randomization to either week 12 or their last follow-up date,

whichever date occurred first.

Other assessmentsSpirometry assessments were performed at screening and every 2weeks for

16 weeks. Rescue medication use was defined as the number of puffs per day

of short-acting b-agonist use and was recorded daily in an electronic diary

(eDiary). Patients recorded daily peak flows and asthma symptoms in the

morning and evening using the eDiary. The nighttime symptom score was

rated on a 0 to 3 scale with 0 meaning ‘‘no symptoms,’’ 1 meaning ‘‘mild,

awoke wheezing at least once but returned to sleep,’’ 2 meaning ‘‘moderate,

awakened more than once and remained awake for >1 hour,’’ and 3 meaning

‘‘severe, awake most of the night.’’

Statistical analysisThe association between baseline ACQ score and exacerbation was

assessed by using a Cox proportional hazards model adjusting for treatment

assignment. A second Cox proportional hazards model used all ACQ scores

before exacerbation as time-dependent covariates.20 The time-dependent

model was selected to enable the use of all the ACQ scores over time before

the exacerbation occurred, rather than the single baseline or the last ACQ

score. The association between the last ACQ score before exacerbation and

the risk of exacerbationwas also assessed by using a logistic regressionmodel.

The linearity assumption between ACQ and odds of asthma exacerbation was

assessed by plotting the log of the odds and mean ACQ in 5 ACQ categories

(&1, >1 and <_2, >2 and <_3, >3 and <_4, >4).

To identify a threshold ACQ score that would predict future asthma

exacerbation, the sensitivity and specificity for the prediction at a given ACQ

score were calculated for all ACQ scores measured immediately before

exacerbation.

Individual components of ACQ, ACQ-6, and ACQ-5 were also evaluated

for their association with risk of exacerbation.

The eDiary measures were recorded daily and summarized weekly as an

independent measure from the ACQ. Effects of asthma measures, such as

night-time symptom score from eDiary and lung function on the risk of

exacerbation, were assessed to evaluate whether the effects of these asthma

measures were similar to the effects of those components in ACQ.

RESULTS

PatientsA total of 292 patients with moderate to severe asthma were

included in the analysis. The study population was 71%white, 18% black, 58% women, and had a mean age of 41 years(Table I). At baseline, patients had a mean FEV1 of 68.3% andmean ACQ score of 2.54. Baseline characteristics were similarbetween patients with and without an exacerbation. All baseline

TABLE I. Characteristics of the study population at baseline

Characteristics All patients (N 5 292)

Patients without asthma

exacerbation (N 5 261)

Patients with asthma

exacerbationy (N 5 31)

Age (y), mean (SD) 41.3 (11.0) 41.4 (11.3) 40.8 (8.1)

Women, n (%) 168 (57.5) 150 (57.5) 18 (58.1)

Race, n (%)

White 208 (71.2) 184 (70.5) 24 (77.4)

Black 52 (17.8) 50 (19.2) 2 (6.5)

Hispanic/Latino 27 (9.2) 22 (8.4) 5 (16.1)

Body mass index (kg/m2), mean (SD) 31.0 (8.0) 31.0 (8.1) 30.5 (7.3)

Asthma duration (y), mean (SD) 26.0 (13.7) 26.3 (13.8) 23.2 (12.5)

%FEV1, mean (SD) 68.3 (12.0) 68.3 (12.0) 68.1 (11.5)

Rescue medication use (puffs/d),* mean (SD) 3.68 (3.64) 3.63 (3.68) 4.06 (3.30)

Inhaled corticosteroid dose (mg),� mean (SD) 440 (223) 436 (224) 472 (219)

ACQ score, mean (SD) 2.54 (0.70) 2.53 (0.70) 2.58 (0.70)

For FEV1, comparisons of patients with and without exacerbation had P values >.10.

*No. of puffs per day of short-acting b-agonist use.

�Exacerbation defined as requirement for systemic corticosteroids.

�Fluticasone equivalent.

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characteristics were considered for the final model; nonewere de-termined as potential confounders relative to exacerbations.

ACQ and exacerbationsAsthma Control Questionnaire scores observed in this study

ranged from 0 to 5.71. Thirty-one patients each experienced1 exacerbation in the study. The mean (SD) time between theACQ assessment immediately before an exacerbation and theactual onset of the exacerbation was 9.9 (4.5) days.A time-dependent covariate model demonstrated that the ACQ

score was significantly associated with risk of asthma exacerba-tion. For each 1-point increase in ACQ score, the risk ofexacerbation increased by 1.5-fold or 50% (hazard ratio [HR],1.50; 95% CI, 1.03-2.2; P 5 .035). Using the MID for the ACQ(0.5), an increase of 0.5 in ACQ score was associated with a23% increased risk of exacerbation. Because ACQ scores weremeasured every 2 weeks, statements of relative risk of asthma ex-acerbation correspond to the 2-week period after a given ACQmeasurement. The current analysis did not demonstrate a signif-icant association between the baseline ACQ score and asthma ex-acerbation (HR, 1.13; 95% CI, 0.69-1.87).A logistic regression model was also used to determine whether

the closest ACQ score before the exacerbation was a predictor ofexacerbation. Results demonstrated that a higher ACQ scoreincreased the odds of asthma exacerbation, and the associationrevealed a linear relationship. This relationship was examinedwithin the range (0-4.85) of the last ACQ score measured beforeexacerbation for those patients having exacerbation events, or thelast ACQ score measured before week 12 or last follow-up,whichever camefirst, for patientswhodidnot have anexacerbation.In addition, assessment of cutpoints in ACQ score to determine

whether a threshold existed above which most individuals wouldbe at risk of an exacerbation within the following 2 weeks did notyield any specific threshold of ACQ score with meaningfulsensitivity or specificity to allow for definitive association.

Components of ACQAnalysis of individual components of the ACQ revealed

similar trends for association with the risk of asthma exacerba-tion. The HRs for exacerbation with every ACQ component

ranged from 1.1 to 1.3 (Fig 1). Use of rescue medication (HR,1.34) demonstrated a significant association with risk of exacer-bation (P < .05).

ACQ-6 and ACQ-5Using the time-dependent covariate model, the association of

ACQ-6 with risk of exacerbation demonstrated a trend towardsignificance (HR, 1.41; 95% CI, 0.99-2.02; P 5 .056). Althoughnot significant, the point estimate for the HR also suggested an as-sociation of higher ACQ-5 with increased risk of exacerbation(HR, 1.35; 95% CI, 0.95-1.92; P 5 .10). Baseline ACQ-6 (HR,1.14; 95% CI, 0.73-1.78; P 5 .56) and ACQ-5 (HR, 1.04; 95%CI, 0.67-1.62; P 5 .86) scores were not significantly associatedwith exacerbation risk.The full composite ACQ demonstrated a stronger association

with the risk of exacerbation than ACQ-6, with ACQ-5 having theleast strong association.

Asthma measures from eDiary and spirometryThe analysis of independent measures from the eDiary showed

that nighttime symptoms and use of rescue medications weresignificantly associated with risk of exacerbations. The HR usingthe time-dependent model was 3.10 (95%CI, 1.70-5.64; P <.001)for nighttime symptoms and 1.08 (95%CI, 1.01-1.15;P5.02) foruse of rescue medication.FEV1 and PEFR were also evaluated. Using the time-

dependent model where all values up to the exacerbation are in-cluded, percent predicted FEV1 and FEV1 were not significantlyassociated with risk of exacerbation (HR, 0.98; 95% CI,0.95-1.01; P 5 .10; and HR, 0.52; 95% CI, 0.23-1.19; P 5 .12,respectively). Although not significant, the point estimates forHR demonstrated a trend suggesting that higher FEV1 valuesare associated with decreased risk of exacerbation.The AM peak flow and diurnal variation of peak flow (reported

as 10 L/min unit change) were significantly associated withthe risk of asthma exacerbation (HR, 0.96; 95% CI, 0.92-1.00;P 5 .049; and HR, 1.14; 95% CI, 1.02-1.29; P 5 .026, respec-tively; Table II). Higher AM peak flow and decreased diurnalvariation were each associated with a lower risk of asthmaexacerbation.

FIG 1. Association of individual ACQ components with asthma exacerbations. The HR estimates were

obtained from Cox proportional hazard models on asthma exacerbation by using total ACQ score or each

component of ACQ as time-dependent covariates.

TABLE II. Association of independent measures of eDiary and

FEV1 with risk of asthma exacerbation

HR (95% CI) P value*

Night-time symptom score 3.10 (1.70-5.64) <.001

Rescue medication (puffs/d) 1.08 (1.01-1.15) .017

Peak flow AM (10 L/min)* 0.96 (0.92-1.00) .049

Peak flow PM (10 L/min)* 0.96 (0.91-1.00) .068

Diurnal variation (10 L/min)* 1.14 (1.02-1.29) .026

FEV1% predicted 0.98 (0.95-1.01) .103

FEV1 (L)* 0.52 (0.23-1.19) .121

Asthma exacerbation defined as requirement for systemic corticosteroids.

*The model included age, race, sex, and height in addition to treatment assignment.

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170 MELTZER ET AL

Other analysesSimilar results were observed for association of ACQ and its

individual components with risk of exacerbation by using theexacerbation definition of ‘‘requirement of systemic corticoste-roids or doubling of ICS dose’’ (data not shown).

DISCUSSIONIn this retrospective analysis of data from a randomized clinical

trial, asthma control as measured by the ACQ composite scorewas found to be significantly associated with the risk of futureexacerbation. This finding was confirmed with the analysisdemonstrating consistently higher odds of having an exacerbationwith an increase in the proximate ACQ score. A direct correlationbetween sequential measurements of ACQ, an indicator of asthmaimpairment, and the risk of future exacerbation, as observed inthis study, has not been previously demonstrated in a randomizedclinical trial.Thirty-one exacerbations were observed among 292 patients

over a 12-week period (exposure-adjusted rate, 0.61; 95% CI,0.43-0.85). The rate of exacerbation was comparable to the rateseen in other studies with similar patient populations.21

The time-dependent model used all ACQ scores before anexacerbation. At any given point in time, each 1-point increase inACQ score increased the risk of asthma exacerbation within thefollowing 2-week period by 50%. Expressed in terms of thevalidated MID for the ACQ measure, each 0.5-point increase inACQ score increased the risk of exacerbation within the following2-week period by 23%.Among the individual ACQ components, use of rescue med-

ication showed a significant association with risk of exacerbation.However, the point estimates for the HRs for exacerbation witheach individual ACQ component were less than that found for theoverall ACQ score. Similarly, the associations of ACQ-6 andACQ-5 with risk of exacerbation demonstrated trends towardsignificance but to a lesser degree than the full ACQ compositescore. Overall, these findings suggest that composite ACQ is abetter predictor of exacerbation than individual ACQcomponents.Among other parameters from this study including the eDiary

and spirometry measurements, a statistically significant associa-tion was observed between rescue medication use, AM peak flow,diurnal variation, and nighttime symptoms, and the risk of exac-erbation (Table II).

Significance levels found within the analyses of rescue med-ication use and variation in PEFR were similar to that of ACQ.Overall, the night-time symptom score was best correlated withexacerbation. The implications for clinical practice from theseanalyses are that some individual signs and symptoms or thevariation in PEFR are comparable to ACQ in their ability topredict risk of asthma exacerbation. However, from a practicalperspective, adherence to daily diary records as was required bythis study is generally untenable long-term. The ACQ can bemeasured at clinic visits, thereby providing an accurate andreliable method of measurement. Shorter versions of the ACQsuch as the ACQ-6 and ACQ-5 could be potentially assessed bythe patient outside the clinic setting to assess asthma control andrisk for asthma exacerbation.

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Other studies have shown that low FEV1 at baseline is associ-ated with asthma exacerbation.14,22-25 The current study found asimilar trend between FEV1 and exacerbation using all theFEV1 measurements up to the time of exacerbation, but the asso-ciation was not significant.The time-dependent model performed in this analysis used

ACQ scores collected frequently across the study period, whereasother published studies have been limited in their analyses bydatasets with only baseline asthma control scores or scorescollected at intervals farther apart than every other week.26,27

A recently published retrospective pooled analysis26 of 5 studiesexamined the relationship between current control (defined perthe Global Initiative for Asthma guideline-derived classificationor the ACQ-5) and future risk of exacerbation. Patients were clas-sified into 2 groups by their baseline ACQ-5 score. The studydemonstrated that patients with a baseline ACQ-5 score >_1.5 ver-sus an ACQ score <0.5 had a significantly higher exacerbationrate over a 12-month period (0.36 events/patient/12 mo vs 0.13events/patient/12 mo). The current study evaluated the ACQ 7-item version and included a comparison to understand the predic-tive value of ACQ-6 and ACQ-5. Frequent evaluation of the ACQin the current study revealed a linear association between ACQand asthma exacerbation. In addition, this study allowed the quan-tification of risk of asthma exacerbation for a given individualwithin the near-term period of 2 weeks, suggesting that measure-ment of the ACQ at clinic visits may have clinical utility in asthmamanagement andmay not only assess current control but also pre-dict future loss of control.Limitations of this study include the post hoc nature of analysis

with a small number of exacerbation events. The small number ofexacerbation events in this study may have limited the ability todetect ACQ patterns in terms of characterizing the progressionto exacerbation and to identify any specific threshold ACQ scorewith meaningful sensitivity or specificity to predict future exacer-bation. Additional datasets may provide further insight into po-tential relationships with future evaluations. A secondlimitation was that the patient population may differ from otherasthma patient populations, especially with regard to asthma con-trol (inclusion criterion baseline ACQ score >_1.5). Although base-line ACQ scores in this study were >_1.5, they ranged from 0 to5.71 during the study, demonstrating a range of asthma controlwithin this dataset.In conclusion, the ability to predict an exacerbation could have

a significant impact on asthma management and control, includ-ing increased vigilance at patient visits and an action plan reviewto facilitate proactive adjustments in treatment regimen. In thisstudy, a significant correlation was found between the measure-ments of the ACQ composite score over time and the risk of futureasthma exacerbation. The results with the ACQ compositemeasure were superior to those with the individual ACQ compo-nents, thereby supporting the utility of composite ACQ scoremeasurement in clinical trials and clinical practice.

We acknowledge Meera Kodukulla, PhD, of Amgen Inc and Kathy Fox,

PhD, on behalf of Amgen Inc, for writing and editorial support.

Clinical implications: A quantitative evaluation of the risk of fu-ture exacerbations using the ACQ may allow for better treat-ment of patients in clinical practice and supports using ACQas an endpoint in asthma clinical trials.

REFERENCES

1. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive

summary of the GINA Dissemination Committee report. Allergy 2004;59:

469-78.

2. Weiss KB, Sullivan SD, Lyttle CS. Trends in the cost of illness for asthma in the

United States, 1985-1994. J Allergy Clin Immunol 2000;106:493-9.

3. Asthma insight and management. 2009. Available at: http://www.takingaimatasthma.

com/survey-results.html. Accessed March 9, 2010.

4. Fuhlbrigge AL, Adams RJ, Guilbert TW, Grant E, Lozano P, Janson SL, et al. The

burden of asthma in the United States: level and distribution are dependent on in-

terpretation of the national asthma education and prevention program guidelines.

Am J Respir Crit Care Med 2002;166:1044-9.

5. Lai CK, De Guia TS, Kim YY, Kuo SH, Mukhopadhyay A, Soriano JB, et al.

Asthma control in the Asia-Pacific region: the Asthma Insights and Reality in

Asia-Pacific Study. J Allergy Clin Immunol 2003;111:263-8.

6. Rabe KF, Vermeire PA, Soriano JB, Maier WC. Clinical management of asthma in

1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 2000;

16:802-7.

7. Chapman KR, Boulet LP, Rea RM, Franssen E. Suboptimal asthma control: prev-

alence, detection and consequences in general practice. Eur Respir J 2008;31:

320-5.

8. Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of

asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm

Med 2006;6:13.

9. Peters SP, Jones CA, Haselkorn T, Mink DR, Valacer DJ, Weiss ST. Real-world

Evaluation of Asthma Control and Treatment (REACT): findings from a national

Web-based survey. J Allergy Clin Immunol 2007;119:1454-61.

10. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al.

Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma

ControL study. Am J Respir Crit Care Med 2004;170:836-44.

11. Global Initiative for Asthma (GINA). GINA report: global strategy for asthma man-

agement and prevention. 2009. Available at: http://www.ginasthma.org. Accessed

February 17, 2010.

12. National Heart, Lung, and Blood Institute. National Asthma Education and Prevention

Program. Expert Panel report 3: guidelines for the diagnosis andmanagement of asthma.

2007. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed

August 28, 2007.

13. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al.

An official American Thoracic Society/European Respiratory Society statement:

asthma control and exacerbations: standardizing endpoints for clinical asthma trials

and clinical practice. Am J Respir Crit Care Med 2009;180:59-99.

14. Kitch BT, Paltiel AD, Kuntz KM, Dockery DW, Schouten JP, Weiss ST, et al. A

single measure of FEV1 is associated with risk of asthma attacks in long-term

follow-up. Chest 2004;126:1875-82.

15. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and

validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:

902-7.

16. Corren J, Busse W, Meltzer EO, Mansfield L, Bensch G, Fahrenholz J, et al. A ran-

domized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in pa-

tients with asthma. Am J Respir Crit Care Med 2010;181:788-96.

17. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpre-

tation of three shortened versions of the asthma control questionnaire. Respir Med

2005;99:553-8.

18. Svensson K, Mork A-C, Juniper EF. ACQ—is five out of seven items acceptable in

large clinical studies? [Abstract]. Qual Life Res 2003;12:771.

19. Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘‘well-controlled’’ and

‘‘not well-controlled’’ asthma using the Asthma Control Questionnaire. Respir Med

2006;100:616-21.

20. Allison PD. Survival analysis using the SAS system: a practical guide. Cary (NC):

SAS Institute Inc; 1995. p. 138-54.

21. Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of

omalizumab as add-on therapy in patients with severe persistent asthma who are

inadequately controlled despite best available therapy (GINA 2002 step 4 treat-

ment): INNOVATE. Allergy 2005;60:309-16.

22. Fuhlbrigge AL, Kitch BT, Paltiel AD, Kuntz KM, Neumann PJ, Dockery DW, et al.

FEV(1) is associated with risk of asthma attacks in a pediatric population. J Allergy

Clin Immunol 2001;107:61-7.

23. Fuhlbrigge AL, Weiss ST, Kuntz KM, Paltiel AD. Forced expiratory volume in

1 second percentage improves the classification of severity among children with

asthma. Pediatrics 2006;118:e347-55.

24. Osborne ML, Pedula KL, O’Hollaren M, Ettinger KM, Stibolt T, Buist AS, et al.

Assessing future need for acute care in adult asthmatics: the Profile of Asthma

Risk Study: a prospective health maintenance organization-based study. Chest

2007;132:1151-61.

J ALLERGY CLIN IMMUNOL

JANUARY 2011

172 MELTZER ET AL

25. Sato R, Tomita K, Sano H, Ichihashi H, Yamagata S, Sano A, et al. The strategy for

predicting future exacerbation of asthma using a combination of the Asthma Con-

trol Test and lung function test. J Asthma 2009;46:677-82.

26. Bateman ED, Reddel HK, Eriksson G, Peterson S, Ostlund O, Sears MR, et al.

Overall asthma control: the relationship between current control and future risk.

J Allergy Clin Immunol 2010;125:600-8.

27. Haselkorn T, Fish JE, Zeiger RS, Szefler SJ, Miller DP, Chipps BE, et al. Consis-

tently very poorly controlled asthma, as defined by the impairment domain of the

Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerba-

tions in The Epidemiology and Natural History of Asthma: Outcomes and Treat-

ment Regimens (TENOR) study. J Allergy Clin Immunol 2009;124:895-902,

e1-e4.