Validation and psychometric properties of the Asthma Control Questionnaire among children.

BACKGROUND: The Asthma Control Questionnaire (ACQ) is a patient-centered tool for evaluating asthma control. It has been validated in adults, but not well-validated among children. OBJECTIVE: We evaluated the reliability, validity, and responsiveness to change of the ACQ for assessing asthma control in children ages 6 to 17 years. A threshold value for poor disease control and a minimally important difference were also determined. METHODS: Data from 305 asthmatic children enrolled in a clinical trial were examined. The ACQ was administered at 8 visits. We analyzed results for the combined age group and for the 6- to 11-year-old and 12- to 17-year-old age groups separately. RESULTS: Overall, the Cronbach α value (internal consistency) for the ACQ was 0.74 at baseline, and the intraclass correlation coefficient (test-retest reliability) for repeated questionnaires among stable patients was 0.53. The Pearson correlations between the ACQ and other asthma questionnaires were moderate to strong (-0.64 to -0.73). Mean ACQ scores were higher (worse) in patients whose peak flow decreased, who used more rescue medications, or who sought medical care for asthma than in patients who were stable (P < .0001 for all measures). Changes in ACQ scores were significantly different among patients with deteriorating, improving, or stable asthma symptoms (P ≤ .01). The optimal threshold indicating poor asthma control was 1.25 or greater. The minimally important difference was established to be 0.40. Results for the separate age groups were similar. CONCLUSION: The ACQ is a moderately reliable, valid, and responsive tool with adequate psychometric properties for assessing recent asthma control among children.

Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma.

BACKGROUND: The methacholine challenge test quantifies airway hyper-responsiveness, which is measured by the provocative concentration of methacholine causing a 20% decrease in forced expiration volume in 1 second (PC20). The dose-response effect of inhaled corticosteroids (ICS) on PC20 has been inconsistent and within-patient variability of PC20 is not well established. OBJECTIVE: To determine the effect of high- vs low-dose ICS on PC20 and within-patient variability in those with repeated measurements of PC20. METHODS: A randomized, double-masked, crossover trial was conducted in patients with asthma on controller medications with PC20 of 8 mg/mL or lower (n = 64) to evaluate the effect of high-dose (1,000 µg/d) vs low-dose (250 µg/d) fluticasone for 4 weeks on PC20. In addition, the variability of PC20 was assessed in participants who underwent 2 or 3 PC20 measurements on the same dose of ICS (n = 27) over a 4-week interval. RESULTS: Because there was a significant period effect, dose comparison of the change in PC20 was assessed in the first treatment period. There was no significant difference in the change in PC20 for high- vs low-dose ICS (39% vs 30% increase, respectively; P = .87). The within- and between-participant variances for log PC20 were 0.84 and 0.96, respectively, with an intra-class correlation of 0.53, and 37% of participants had more than 2 doubling dose changes in PC20 in those with repeated measurements. CONCLUSION: The effect of ICS on PC20 is not dose dependent at fluticasone levels of 250 and 1,000 µg/d. Interpersonal variability for PC20 is large. A lack of precise measurements should be taken into account when interpreting any change in PC20.

Asthma symptom utility index: reliability, validity, responsiveness, and the minimal important difference in adult asthmatic patients.

BACKGROUND: The evaluation of asthma symptoms is a core outcome measure in asthma clinical research. The Asthma Symptom Utility Index (ASUI) was developed to assess the frequency and severity of asthma symptoms. The psychometric properties of the ASUI are not well characterized, and a minimal important difference (MID) is not established. OBJECTIVES: We assessed the reliability, validity, and responsiveness to change of the ASUI in a population of adult asthmatic patients. We also sought to determine the MID for the ASUI. METHODS: Adult asthmatic patients (n = 1648) from 2 previously completed multicenter randomized trials were included. Demographic information, spirometric results, ASUI scores, and other asthma questionnaire scores were obtained at baseline and during follow-up visits. Participants also kept a daily asthma diary. RESULTS: The internal consistency reliability of the ASUI was 0.74 (Cronbach α). Test-retest reliability was 0.76 (intraclass correlation). Construct validity was demonstrated by significant correlations between ASUI scores and Asthma Control Questionnaire scores (Spearman correlation r = -0.79; 95% CI, -0.85 to -0.75; P < .001) and Mini Asthma Quality of Life Questionnaire scores (r = 0.59; 95% CI, 0.51-0.61; P < .001). Responsiveness to change was demonstrated, with significant differences between mean changes in ASUI scores across groups of participants differing by 10% in percent predicted FEV(1) (P < .001) and by 0.5 points in Asthma Control Questionnaire scores (P < .001). Anchor-based and statistical methods support an MID for the ASUI of 0.09 points. CONCLUSIONS: The ASUI is reliable, valid, and responsive to changes in asthma control over time. The MID of the ASUI (range of scores, 0-1) is 0.09.

Methacholine challenge test: diagnostic characteristics in asthmatic patients receiving controller medications.

BACKGROUND: The methacholine challenge test (MCT) is commonly used to assess airway hyperresponsiveness, but the diagnostic characteristics have not been well studied in asthmatic patients receiving controller medications after the use of high-potency inhaled corticosteroids became common. OBJECTIVES: We investigated the ability of the MCT to differentiate participants with a physician's diagnosis of asthma from nonasthmatic participants. METHODS: We conducted a cohort-control study in asthmatic participants (n= 126) who were receiving regular controller medications and nonasthmatic control participants (n= 93) to evaluate the sensitivity and specificity of the MCT. RESULTS: The overall sensitivity was 77% and the specificity was 96% with a threshold PC(20) (the provocative concentration of methacholine that results in a 20% drop in FEV(1)) of 8 mg/mL. The sensitivity was significantly lower in white than in African American participants (69% vs 95%, P= .015) and higher in atopic compared with nonatopic (82% vs 52%, P= .005). Increasing the PC(20) threshold from 8 to 16 mg/mL did not noticeably improve the performance characteristics of the test. African American race, presence of atopy, and lower percent predicted FEV(1) were associated with a positive test result. CONCLUSIONS: The utility of the MCT to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma.

Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial.

BACKGROUND: Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations. AIMS: To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospective multicentre clinical trial to replicate this association. METHODS: A total of 300 study participants were included in the analysis. Dietary soy genistein intake was measured using the Block Soy Foods Screener. The level of soy genistein intake (little or no intake, moderate intake, or high intake) was compared with baseline lung function (pre-bronchodilator forced expiratory volume in 1 second (FEV(1))) and asthma control (proportion of participants with an episode of poor asthma control (EPAC) and annualised rates of EPACs over a 6-month follow-up period. RESULTS: Participants with little or no genistein intake had a lower baseline FEV(1) than those with a moderate or high intake (2.26 L vs. 2.53 L and 2.47 L, respectively; p=0.01). EPACs were more common among those with no genistein intake than in those with a moderate or high intake (54% vs. 35% vs. 40%, respectively; p<0.001). These findings remained significant after adjustment for patient demographics and body mass index. CONCLUSIONS: In patients with asthma, consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control.

Measurement characteristics of the childhood Asthma-Control Test and a shortened, child-only version.

The childhood Asthma-Control Test (C-ACT) is validated for assessing asthma control in paediatric asthma. Among children aged 4-11 years, the C-ACT requires the simultaneous presence of both parent and child. There is an unmet need for a tool that can be used to assess asthma control in children when parents or caregivers are not present such as in the school setting. We assessed the psychometric properties and estimated the minimally important difference (MID) of the C-ACT and a modified version, comprising only the child responses (C-ACTc). Asthma patients aged 6-11 years (n=161) from a previously completed multicenter randomised trial were included. Demographic information, spirometry and questionnaire scores were obtained at baseline and during follow-up. Participants or their guardians kept a daily asthma diary. Internal consistency reliabilities of the C-ACT and C-ACTc were 0.76 and 0.67 (Cronbach's α), respectively. Test-retest reliabilities of the C-ACT and C-ACTc were 0.72 and 0.66 (intra-class correlation), respectively. Significant correlations were noted between C-ACT scores and ACQ scores (Spearman's correlation r=-0.56, 95% CI (-0.66, -0.44), P<0.001). The strength of the correlation between C-ACTc scores and ACQ scores was weaker (Spearman's correlation r=-0.46, 95% CI (-0.58, -0.33), P<0.001). We estimated the MID for the C-ACT and C-ACTc to be 2 points and 1 point, respectively. Among asthma patients aged 6-11 years, the C-ACT had good psychometric properties. The psychometric properties of a shortened child-only version (C-ACTc), although acceptable, are not as strong.

Albuterol Overuse: A Marker of Psychological Distress?

BACKGROUND: Albuterol overuse, 3 or more canisters per year, is associated with poor asthma control and frequent exacerbations. OBJECTIVE: To describe albuterol use on symptom and symptom-free days and identify predictors of albuterol overuse and controller medication underuse. METHODS: Secondary analyses of data from adults with mild asthma from the Trial of Asthma Patient Education were carried out. Based on albuterol use of 80% or more on symptom days and less than 20% on symptom-free days, participants were characterized as expected users, overusers, or underusers of albuterol. Good controller medication adherence was defined as 80% or more of prescribed doses. Data included demographic characteristics, diary data, spirometry, and scores from standardized questionnaires. Bivariate associations were examined between categorization of medication use and measured characteristics. RESULTS: Of the 416 participants, 212 (51%) were expected users, 114 (27%) were overusers, and 90 (22%) were underusers of albuterol. No differences were observed among the user groups by demographic characteristics or lung function. Expected users demonstrated the highest asthma-related knowledge, attitudes, and efficacy. Overusers reported the greatest symptom burden, worst asthma control, and highest frequency of symptom days. Overusers also had the highest burden of depression symptoms. More frequent symptom days accounted for 15% of overuse, greater use on symptom days accounted for 31%, and greater use on symptom free days accounted for 54% of overuse. Mean controller adherence was high across all groups, and there were no differences between the groups. CONCLUSIONS: Although overusers experienced more frequent symptom days and used more albuterol on those days, most overuse was attributable to unexpected use on symptom-free days. High levels of comorbid depression were observed, particularly among overusers and among those nonadherent to controller medication.

Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype.

RATIONALE: Gastric acid blockade in children with asymptomatic acid reflux has not improved asthma control in published studies. There is substantial population variability regarding metabolism of and response to proton pump inhibitors based on metabolizer phenotype. How metabolizer phenotype affects asthma responses to acid blockage is not known. OBJECTIVES: To determine how metabolizer phenotype based on genetic analysis of CYP2C19 affects asthma control among children treated with a proton pump inhibitor. METHODS: Asthma control as measured by the Asthma Control Questionnaire (ACQ) and other questionnaires from a 6-month clinical trial of lansoprazole in children with asthma was analyzed for associations with surrogates of lansoprazole exposure (based on treatment assignment and metabolizer phenotype). Groups included placebo-treated children; lansoprazole-treated extensive metabolizers (EMs); and lansoprazole-treated poor metabolizers (PMs). Metabolizer phenotypes were based on CYP2C19 haplotypes. Carriers of the CYP2C19*2, *3, *8, *9, or *10 allele were PMs; carriers of two wild-type alleles were extensive metabolizers (EMs). MEASUREMENTS AND MAIN RESULTS: Asthma control through most of the treatment period was unaffected by lansoprazole exposure or metabolizer phenotype. At 6 months, PMs displayed significantly worsened asthma control compared with EMs (+0.16 vs. -0.13; P = 0.02) and placebo-treated children (+0.16 vs. -0.23; P < 0.01). Differences in asthma control were not associated with changes in gastroesophageal reflux symptoms. Recent upper respiratory infection worsened asthma control, and this upper respiratory infection effect may be more pronounced among lansoprazole-treated PMs. CONCLUSIONS: Children with the PM phenotype developed worse asthma control after 6 months of lansoprazole treatment for poorly controlled asthma. Increased exposure to proton pump inhibitor may worsen asthma control by altering responses to respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00604851).

Exhaled breath condensate pH does not discriminate asymptomatic gastroesophageal reflux or the response to lansoprazole treatment in children with poorly controlled asthma.

BACKGROUND: Although exhaled breath condensate (EBC) pH has been identified as an "emerging" biomarker of interest for asthma clinical trials, the clinical determinants of EBC pH remain poorly understood. Other studies have associated acid reflux-induced respiratory symptoms, for example, cough, with transient acidification of EBC. OBJECTIVE: We sought to determine the clinical and physiologic correlates of EBC acidification in a highly characterized sample of children with poorly controlled asthma. We hypothesized that (1) children with asymptomatic gastroesophageal reflux determined by 24-hour esophageal pH monitoring would have a lower EBC pH than children without gastroesophageal reflux, (2) treatment with lansoprazole would alter EBC pH in those children, and (3) EBC acidification would be associated with increased asthma symptoms, poorer asthma control and quality of life, and increased formation of breath nitrogen oxides (NOx). METHODS: A total of 110 children, age range 6 to 17 years, with poor asthma control and esophageal pH data enrolled in the Study of Acid Reflux in Children with Asthma (NCT00442013) were included. Children submitted EBC samples for pH and NOx measurement at randomization and at study weeks 8, 16, and 24. RESULTS: Serial EBC pH measurements failed to distinguish asymptomatic gastroesophageal reflux and was not associated with breath NOx formation. EBC pH also did not discriminate asthma characteristics such as medication and health care utilization, pulmonary function, and asthma control and quality of life both at baseline and across the study period. CONCLUSION: Despite the relative ease of EBC collection, EBC pH as a biomarker does not provide useful information of children with asthma who were enrolled in asthma clinical trials.

Biologic mechanisms of environmental tobacco smoke in children with poorly controlled asthma: results from a multicenter clinical trial.

BACKGROUND: Environmental tobacco smoke (ETS) negatively affects children with asthma. The prevalence of ETS exposure among children with poor asthma control may be changing. Importantly, the mechanisms by which ETS worsens asthma control are poorly understood. OBJECTIVE: We describe how ETS affects gastroesophageal reflux (GER), respiratory infections, and leukotriene production among children with poor asthma control. METHODS: We analyzed data from 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month clinical trial. We evaluated prevalence and determinants of ETS exposure by interview, questionnaire, and urinary cotinine and the association of ETS exposure on leukotriene production, respiratory infections, GER, lung function, and asthma control. We used multivariable linear, logistic, and Poisson regressions to assess outcomes. RESULTS: ETS prevalence estimates ranged from 6% to 30%. Children with domestic indoor exposure had worse asthma control (c-Asthma Control Test, 17.8 vs 21.5; P = .04), worse FEV1 % predicted (84.1 vs 90.7; P = .02), and a trend for increased mean urinary leukotriene E4. ETS from any setting was associated with increased symptomatic respiratory infections (adjusted incidence rate ratio: 1.30; P = .02). However, children exposed to ETS did not have symptoms or pH probe results, suggestive of heightened GER. CONCLUSIONS: Domestic smoking exposure was associated with both higher rates of symptomatic respiratory infection and poorer asthma control despite generally intensive controller therapy. ETS exposure is common among asthmatic children with poor control and may worsen asthma control by promoting respiratory infections. Further investigation is required to elucidate ETS mechanisms in poor asthma control.

Sex differences in asthma symptom profiles and control in the American Lung Association Asthma Clinical Research Centers.

OBJECTIVE: Important differences between men and women with asthma have been demonstrated, with women describing more symptoms and worse asthma-related quality of life (QOL) despite having similar or better pulmonary function. While current guidelines focus heavily on assessing asthma control, they lack information about whether sex-specific approaches to asthma assessment should be considered. We sought to determine if sex differences in asthma control or symptom profiles exist in the well-characterized population of participants in the American Lung Association Asthma Clinical Research Centers (ALA-ACRC) trials. METHODS: We reviewed baseline data from four trials published by the ALA-ACRC to evaluate individual item responses to three standardized asthma questionnaires: the Juniper Asthma Control Questionnaire (ACQ), the multi-attribute Asthma Symptom Utility Index (ASUI), and Juniper Mini Asthma Quality of Life Questionnaire (mini-AQLQ). RESULTS: In the poorly-controlled population, women reported similar overall asthma control (mean ACQ 1.9 vs. 1.8; p = 0.54), but were more likely to report specific symptoms such as nocturnal awakenings, activity limitations, and shortness of breath on individual item responses. Women reported worse asthma-related QOL on the mini-AQLQ (mean 4.5 vs. 4.9; p < 0.001) and more asthma-related symptoms with a lower mean score on the ASUI (0.73 vs. 0.77; p ≤ 0.0001) and were more likely to report feeling bothered by particular symptoms such as coughing, or environmental triggers. CONCLUSIONS: In participants with poorly-controlled asthma, women had outwardly similar asthma control, but had unique symptom profiles on detailed item analyses which were evident on evaluation of three standardized asthma questionnaires.

Obesity in children with poorly controlled asthma: Sex differences.

BACKGROUND: Obesity increases asthma risk, and may alter asthma severity. In adults, sex appears to modify the effect of obesity on asthma. Among children, the effect of sex on the relationship between obesity and asthma severity remains less clear, particularly when considering race. OBJECTIVE: To determine how obesity affects disease characteristics in a diverse cohort of children with poorly controlled asthma, and if obesity effects are altered by sex. DESIGN: We analyzed 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month trial assessing lansoprazole for asthma control. In this secondary analysis, we determined associations between obesity and symptom severity, spirometry, exacerbation risk, airway biomarkers, bronchial reactivity, and airflow perception. We used both a multivariate linear regression and longitudinal mixed-effect model to determine if obesity interacted with sex to affect asthma severity. RESULTS: Regardless of sex, BMI >95th percentile did not affect asthma control, exacerbation risk or airway biomarkers. Sex changed the effect of obesity on lung function (sex × obesity FEV1%, interaction P-value < 0.01, sex × obesity FEV1/FVC, interaction P-value = 0.03). Obese males had significantly worse airflow obstruction compared to non-obese males, while in females there was no obesity effect on airflow obstruction. In females, obesity was associated with significantly greater FEV1 and FVC, and a trend toward reduced airway reactivity. CONCLUSIONS: Obesity did not affect asthma control, airway markers or disease stability; however obesity did affect lung function in a sex-dependent manner. In males, obesity associated with reduced FEV1/FVC, and in females, obesity associated with substantially improved lung function.

Association between depression and intima-media thickness of carotid bulb in asymptomatic young adults.

OBJECTIVE: Although there is growing evidence that symptoms of depression influence the development of coronary artery disease, information on the underlying subclinical atherosclerotic process is scant in young adults. The study examined the association between symptoms of depression and subclinical atherosclerosis, determined by carotid intima-media thickness in asymptomatic young individuals. METHODS: A cross-sectional study was performed in Bogalusa, Louisiana, a semi-rural biracial (black-white) community. A sample of 996 individuals aged 24 to 44 years (71% were white and 43% were male) enrolled in the Bogalusa Heart Study. The variables included symptoms of depression measured by the Center for Epidemiological Studies-Depression Scale; intima-media thickness of different segments of carotid artery by B-mode ultrasonography; measures of adiposity and glucose homeostasis, lipoproteins, and blood pressure; and cigarette smoking status. RESULTS: Both the adjusted and the unadjusted associations between depression score and carotid bulb intima-media thickness were significant, whereas similar associations with internal carotid and common carotid thickness were nonsignificant. In the multivariable regression model, after adjusting for all covariates, a positive effect of depression scores (Center for Epidemiological Studies-Depression score) and a negative effect of interaction between depression score ratio of total cholesterol (TC)/high-density lipoprotein (HDL) were significant. In a subgroup analysis (among individuals with a ratio of TC/HDL < or = 5) a positive effect of depression on carotid bulb intima-media thickness was significant, whereas the interaction between depression and ratio of TC/HDL was nonsignificant. In subsequent analysis, if individuals with a higher ratio of TC/HDL were included, both depression and negative interaction term were significant. CONCLUSION: The observations show the detrimental effect of depression on subclinical vascular changes in asymptomatic young individuals. The findings underscore the need for considering depression in risk factor profiling. Further study is recommended to investigate the basis of a lower carotid bulb intima-media thickness among subjects with a high depression score and a high ratio of TC/HDL.

Utility of waist-to-height ratio in detecting central obesity and related adverse cardiovascular risk profile among normal weight younger adults (from the Bogalusa Heart Study).

Data on the utility of the waist-to-height ratio in detecting central obesity and related cardiovascular risk among normal weight younger adults are scant. This aspect was examined in 639 normal weight (body mass index 18.5 to 24.9 kg/m(2)) black and white adults (75% white and 36% men) 20 to 44 years old. The subjects with a waist-to-height ratio > or =0.5 were grouped as having central obesity normal weight, with the rest considered the control group. The subjects with central obesity, compared to the controls, after adjusting for age, race, and gender, had significantly greater diastolic blood pressure, mean arterial pressure, low-density lipoprotein cholesterol level, triglycerides, triglycerides/high-density lipoprotein cholesterol ratio, insulin, homeostasis model assessment of insulin resistance, uric acid, C-reactive protein, and liver function enzymes (alanine aminotransferase and gamma-glutamyl transferase). On multivariate analysis, the central obesity group compared to the control group was 1.9, 2.2, 2.9, and 2.5 times more likely to have significantly adverse levels (top tertile vs the rest) of mean arterial pressure, triglycerides/high-density lipoprotein cholesterol ratio, homeostasis model assessment of insulin resistance, and C-reactive protein, respectively. The central obesity group also had a greater prevalence of dyslipidemia, hypertension, insulin resistance, hyperuricemia, and elevated C-reactive protein. The age-, race-, and gender-adjusted mean value of the common carotid intima-media thickness, a measure of subclinical atherosclerosis, was greater in the central obesity group compared to the control group (0.76 vs 0.71 mm, p = 0.009). In conclusion, these findings underscore the utility of the waist-to-height ratio in detecting central obesity and related adverse cardiovascular risk among normal weight younger adults.