Risk Of Future Asthma Exacerbations Research Articles

Clinical Subtypes of Neutrophilic Asthma: A Cluster Analysis From Australasian Severe Asthma Network

Clinical heterogeneity may exist within asthma subtypes defined by inflammatory markers. However, the heterogeneity of neutrophilic asthma (NA) remains largely unexplored. To explore potential clusters and the stability of NA. Participants with NA from the Australasian Severe Asthma Network underwent a multidimensional assessment. They were then asked to participate in a 12-month longitudinal cohort study. We explored potential clusters using a hierarchical cluster analysis and validated the differential future risk of asthma exacerbations in the identified clusters. A decision tree analysis was developed to predict cluster assignments. Finally, the stability of prespecified clusters was examined within 1 month. Three clusters were identified in 149 patients with NA. Cluster 1 (n= 99; 66.4%) was characterized by female-predominant nonsmokers with well-controlled NA, cluster 2 (n= 16; 10.7%) by individuals with comorbid anxiety/depressive symptoms with poorly controlled NA, and cluster 3 by older male smokers with late-onset NA. Cluster 2 had a greater proportion of participants with severe exacerbations (P= .005), hospitalization (P= .010), and unscheduled visits (P= .013) and a higher number of emergency room visits (P= .039) than that of the other two clusters. The decision tree assigned 92.6% of participants correctly. Most participants (87.5%; n= 7) in cluster 2 had a stable NA phenotype, whereas participants of clusters 1 and 3 had variable phenotypes. We identified three clinical clusters of NA, in which cluster 2 represents an uncontrolled and stable NA subtype with an elevated risk of exacerbations. These findings have clinical implications for the management of NA.

Association of eosinophil-derived neurotoxin levels with asthma control status in patients with aspirin-exacerbated respiratory disease.

The long-term goals of asthma treatment are to achieve well control of symptoms and to minimize the future risk of asthma exacerbation. Identifying biomarkers for uncontrolled asthma is important for improving the asthma outcome. This study aimed to investigate the association of the levels of eosinophil-derived neurotoxin (EDN) with asthma control status in specific asthma phenotype, aspirin-exacerbated respiratory disease (AERD), and aspirin-tolerant asthma (ATA). A total of 136 adult asthmatics, including 47 asthmatics with AERD and 89 asthmatics with ATA, were enrolled. Plasma, sputum, and urine were collected at enrollment and the levels of EDN were measured by the K-EDN ELISA kit. Urinary leukotriene E4 (LTE4 ) level was measured using liquid chromatography-mass spectrometry (LC-MS)/MS methods. Asthma control status was evaluated according to the GINA guideline, asthma control test and asthma control questionnaire scores. In the total study subjects, sputum levels of EDN as well as of urine and plasma EDN showed significantly higher levels in patients with uncontrolled asthma than in those with well-controlled or partly-controlled asthma (ANOVA, p<0.001); in patients with AERD, the sputum EDN levels showed significant correlations with ACT, ACQ, and AQLQ scores (p=0.010, r=-0.536, p=0.001, r=0.665, and p<0.001, r=-0.691, respectively), while no differences were noted in patients with ATA. Sputum EDN level was the only significant factor for ACT, ACQ, and AQLQ scores in patients with AERD (p=0.001, p<0.001, and p<0.001, respectively) in the multivariate analysis adjusting for age, sex, peripheral eosinophil count, and urine LTE4 . The ROC curve analysis demonstrated that sputum EDN can predict uncontrolled asthma with 80% sensitivity and 88.2% specificity for ACT≤19 (area under the ROC curve [AUC]=0.824, p=0.019); 71.4% sensitivity and 86.7% specificity for ACQ≥1.5 (AUC=0.752, p=0.049) only in AERD patients. The level of sputum EDN may be a potential biomarker for identifying the asthma control status in patients with AERD.

Proactive Risk Management: A Novel Approach to Embedding Oral Corticosteroid Stewardship into Asthma Care

The continued inclusion of oral corticosteroids (OCS) in treatment guidelines, as well as the accessibility, familiarity, and relatively low cost of this therapeutic option compared with newer alternatives, has contributed to an ongoing overreliance on OCS treatments in severe asthma. This overuse continues despite accumulating evidence to demonstrate the detrimental long-term effects associated with even a short-term, low-dose course of OCS in this patient population. OCS Stewardship is a collaborative, systematic effort designed to protect patients with asthma from inappropriate OCS use through a series of patient- and physician-focused initiatives. Ultimately, OCS Stewardship aims to reduce OCS-related morbidity, lower the risk of OCS-related adverse events (AE), increase health-related quality of life, and reduce healthcare resource utilisation. This article summarises data that were exhibited as part of the European Respiratory Society (ERS) International Congress held in Barcelona, Spain, describing a novel proactive risk-management approach to embedding OCS Stewardship into asthma care. The objectives of this meeting were to highlight the latest data demonstrating the need for OCS Stewardship in asthma; discuss approaches to assessing OCS exposure and OCS-related toxicities, and the rationale for systematic assessment of OCS toxicity in individual patients; and to consider practical tools to evaluate future risk of asthma exacerbations and OCS-related adverse effects. Also described in this article are three posters, which were presented during the same meeting, and provide further data to support OCS-sparing activities in severe asthma by AstraZeneca.

Determinants of asthma control and exacerbations in moderate to severe asthma

Determinants of asthma control and exacerbations in moderate to severe asthma

Detecting asthma control level using feature-based time series classification

Asthma symptom control is the best method for asthma treatment. Early detection of asthma control status can provide the time required for presenting preventive treatment programs to reduce the future risk of asthma exacerbation and episodes of poor asthma control. Accordingly, the current study aims to outline a novel model for classifying asthma control status using a time series/time sequence-based classification approach. Few researchers have addressed the problem of classifying asthma control level in the context of the time series/time sequences dynamics-based approach. It is a significant defect in chronic disease management such as asthma that requires continuous monitoring of symptoms. As a result, it is needed to examine the effect of the time-series/time-sequences of the stimuli affecting asthma status in classifying the control level of this disease. We have designed a daily asthma self-monitoring form and collected a total of 2870 daily assessments of asthma control on 96 asthmatics patients older than five years for 9 months. Using a 7-day window of time, we created the asthma control dataset with clinical variables, the patient’s medical history, and environmental parameters, to detect asthma control level using a time series/time sequence-based classification model. Our best model yielded a recall of 87%, a specificity of 94%, a precision of 89%, a negative predictive value of 93%, an accuracy of 92%, an F-measure of 88%, and an AUC of 87%. Our study indicated that time series classification models among data mining techniques have great potential in creating a prognostic model for chronic diseases such as asthma. Furthermore, the time-series/time sequences of daily asthma symptoms also play a significant role in classifying asthma control levels.

Developing a short-term prediction model for asthma exacerbations from Swedish primary care patients’ data using machine learning - Based on the ARCTIC study

ObjectiveThe ability to predict impending asthma exacerbations may allow better utilization of healthcare resources, prevention of hospitalization and improve patient outcomes. We aimed to develop models using machine learning to predict risk of exacerbations. MethodsData from 29,396 asthma patients was collected from electronic medical records and national registers covering clinical and epidemiological factors (e.g. comorbidities, health care contacts), between 2000 and 2013. Machine-learning classifiers were used to create models to predict exacerbations within the next 15 days. Model selection was done using the mean cross validation score of area under precision-recall curve (AUPRC). ResultsThe most important predictors of exacerbation were comorbidity burden and previous exacerbations. Model validation on test data yielded an AUPRC = 0.007 (95% CI: ± 0.0002), indicating that historic clinical information alone may not be sufficient to predict a near future risk of asthma exacerbation. ConclusionsSupplementation with additional data on environmental triggers, (e.g. weather, pollen count, air quality) and from wearables, might be necessary to improve performance of the short-term predictive model to develop a more clinically useful tool.

Heterogeneity of Paucigranulocytic Asthma: A Prospective Cohort Study with Hierarchical Cluster Analysis

Asthma, a heterogeneous disease, can be divided into 4 inflammatory phenotypes using induced sputum cell counts-eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma, and paucigranulocytic asthma (PGA). Although research has focused on EA and NA, there is little known about PGA. To study the heterogeneity of PGA and identify possible PGA clusters to guide clinical treatment. Patients with PGA were grouped by hierarchical cluster analysis and enrolled into a prospective cohort study to validate the clusters, relative to future risk of asthma exacerbations in a real-world setting. Clusters were validated by tree analysis in a separate population. Finally, we explored PGA stability. Cluster analysis of 145 patients with PGA identified 3 clusters: cluster 1 (n= 110, 75.9%) was "mild PGA," cluster 2 (n= 20, 13.8%) was "PGA with psychological dysfunction and rhinoconjunctivitis and other allergic diseases," and cluster 3 (n= 15, 10.3%) was "smoking-associated PGA." Cluster 3 had significantly increased risk of severe exacerbation (relative risk [RR]= 6.43, P= .01), emergency visit (RR=8.61, P= .03), and hospitalization (RR= 12.94, P<.01). Results of the cluster analysis were successfully validated in an independent PGA population classified using decision tree analysis. Although PGA can transform into or develop from other phenotypes, 70% were stable over time. Among 3 identified PGA clusters, cluster 3 had a higher risk of severe exacerbation. PGA heterogeneity indicates the requirement of novel targeted interventions.

Risk Factors Predicting Severe Asthma Exacerbations in Adult Asthmatics: A Real-World Clinical Evidence.

PurposeMinimizing the future risk of asthma exacerbation (AE) is one of the main goals of asthma management. We investigated prognostic factors for risk of severe AE (SAE) in a real-world clinical setting.MethodsThis is an observational study evaluating subjects who were diagnosed with asthma and treated with anti-asthmatic medications from January 1995 to June 2018. Risk factors for SAE were analyzed in 2 treatment periods (during the initial 2 years and the following 3–10 years of treatment) using the big data of electronic medical records.ResultsIn this study, 5,058 adult asthmatics were enrolled; 1,335 (28.64%) experienced ≥ 1 SAE during the initial 2 years of treatment. Female sex, higher peripheral eosinophil/basophil counts, and lower levels of forced expiratory volume in 1 second (FEV1; %) were factors predicting the risk of SAEs (P < 0.001 for all). Higher serum total immunoglobulin E levels increased the risk of SAEs among the patients having ≤ 2 SAEs (P = 0.025). Patients with more frequent SAEs during the initial 2 years of treatment had significantly higher risks of SAEs during the following years of treatment (P < 0.001, for all) (patients with ≥ 4 SAEs, odds ratio [OR], 29.147; those with 3 SAEs, OR, 14.819; those with 2 SAEs, OR, 9.867; those with 1 SAE, OR, 5.116), had higher maintenance doses of systemic steroids, and showed more gradual decline in FEV1 (%) and FEV1/forced vital capacity levels maintained during the following years of treatment (P < 0.001 for all).ConclusionsAsthmatics having risk factors for SAEs (female sex, higher peripheral eosinophil/basophil counts, and lower FEV1) should be strictly monitored to prevent future risk and improve clinical outcomes.

Visceral obesity is associated with clinical and inflammatory features of asthma: A prospective cohort study.

Background: Although studies have consistently linked obesity and asthma, the potential influence of visceral obesity on asthma has not been well investigated. Objective: To study the associations of visceral fat area (VFA) and clinical and inflammatory features of asthma and to further explore the effects of VFA on the future risk of asthma exacerbation. Methods: A 12-month prospective cohort study based on the Australasian Severe Asthma Network was designed to observe patients with stable asthma grouped by the median value of VFA. The clinical and inflammatory features of asthma were compared between the low VFA (VFAlow) and high VFA (VFAhigh) groups. Relationships between VFA and clinical and inflammatory features of asthma were analyzed by using correlation analysis. Univariate and multivariable negative binomial regression analyses were performed to investigate the association of VFA with exacerbations within a 12-month follow-up period. Results: The patients in the VFAhigh group were older and had a longer asthma duration. Interleukin (IL) 6 and IL-8 in sputum were higher, whereas fractional exhaled nitric oxide (FeNO) and blood eosinophils were lower in the VFAhigh group. Gender-differentiated correlations of VFA with clinical and inflammatory variables were observed in age, FeNO, immunoglobulin E, blood total white cells and neutrophils, and sputum IL-1β and IL-8. Furthermore, compared with the VFAlow group, the VFAhigh group was at significantly increased risk of moderate-to-severe exacerbations (adjusted incidence rate ratio [IRR] 1.55 [95% confidence interval {CI}, 1.06-2.28; p = 0.025), severe exacerbations (adjusted IRR 2.25 [95% CI, 1.26-4.04]; p = 0.007), and emergency visits (adjusted IRR 5.33 [95% CI, 1.78-17.16]; p = 0.003). Conclusion: The level of VFA was associated with specific clinical and inflammatory characteristics of asthma. Furthermore, VFA, as an independent risk factor, was associated with an increased risk of exacerbations. It indicated that VFA would provide more potential clinical implications for asthma management.

Asthma control and exacerbations: two different sides of the same coin.

Optimal asthma management includes both the control of asthma symptoms and reducing the risk of future asthma exacerbations. Traditionally, treatment has been adjusted largely on the basis of symptoms and lung function and for many patients, this approach delivers both excellent symptom control and reduced risk. However, the relationship between these two key components of the disease may vary between different asthmatic phenotypes and disease severities and there is increasing recognition of the need for more individualized treatment approaches. A number of factors which predict exacerbation risk have been identified including demographic and behavioural features and specific inflammatory biomarkers. Type-2 cytokine-driven eosinophilic airways inflammation predisposes to frequent exacerbations and predicts response to corticosteroids, and the usefulness of sputum eosinophilia as both a marker of exacerbation risk and biomarker for adjustment of corticosteroid treatment has been established for some time. However, attempts to develop surrogate markers, which would be more straightforward to deliver in the clinic, have been challenging. Some patients with asthma have persistent symptoms in the absence of type-2 cytokine driven-eosinophilic airways inflammation due to noncorticosteroid responsive mechanisms (T2-low disease). Composite biomarker strategies using easily measured surrogate indicators of type-2 inflammation (such as fractional exhaled nitric oxide, blood eosinophil count and serum periostin levels) may predict exacerbation risk better but it is unclear if they can be used to adjust corticosteroid treatment. Biomarkers will be used to target novel biologic treatments but additionally may be used to optimize corticosteroid treatment dose and act as prognostics for exacerbation risk and potentially other important longer term asthma outcomes.

Does zafirlukast reduce future risk of asthma exacerbations in adults? Systematic review and meta-analysis

&#x0D; &#x0D; &#x0D; &#x0D; Background and objective: The purpose of asthma management is to achieve a total asthma control that involves current control and future risk. It has proven efficacy in reducing asthma exacerbations, but the effect size of zafirlukast for asthma exacerbations of various severity is not systematically explored.&#x0D; Methods: Randomized controlled trials were searched in PubMed Central, Web of Science, and Embase, where zafirlukast prevented asthma exacerbations in adults. The primary outcome was asthma exacerbations, the secondary outcomes were asthma exacerbations requiring systemic corticosteroids and emergency visits, respectively. Odds ratio (OR) with 95% confidence intervals (CI) were pooled.&#x0D; Results: Twelve trials were identified. As first-line therapy, compared to those having placebo, the patients with chronic asthma receiving zafirlukast experienced statistically lower asthma exacerbations (OR = 0.68, 95% CI = [0.45, 1.00]), but it was not found that zafirlukast was superior to placebo in asthma exacerbations requiring systemic corticosteroids (OR = 0.76, 95% CI = [0.45, 1.29]). Furthermore, zafirlukast was inferior to ICs in asthma exacerbations (OR = 2.11, 95% CI = [1.35, 3.30]) and requiring systemic corticosteroids (OR = 3.71, 95% CI = [1.82, 7.59]). As add-on therapy, zafirlukast was not superior to placebo in asthma exacerbations (OR =0.99, 95% CI = [0.54, 1.81] and requiring emergency visits (OR = 0.72, 95% CI = [0.18, 2.99]). Intriguingly, there was not a significant difference in asthma exacerbations between zafirlukast and ICs (OR = 1.12, 95% CI = [0.53, 2.34]).&#x0D; Conclusions: Our study suggests that zafirlukast, as the first-line therapy, significantly reduces mild to moderate but not severe asthma exacerbations. In the add-on regimen, zafirlukast could not reduce asthma exacerbations, which would perhaps result from small sample size and needs to be further studied.&#x0D; &#x0D; &#x0D; &#x0D;

Clinical Burden and Predictors of Asthma Exacerbations in Patients on Guideline-based Steps 4-6 Asthma Therapy in the TENOR Cohort

Patients with severe or difficult-to-treat asthma on guideline-recommended Steps 4/5/6 therapy have not previously been described. To characterize patients with severe or difficult-to-treat asthma on Steps 4/5/6 therapy and assess predictors of future asthma exacerbations. Patients ages ≥12 years with baseline and month 12 medication data were assigned to Steps 4/5/6 care levels from the 2007 National Heart, Lung, and Blood Institute guidelines. Demographic, atopic, and clinical characteristics at baseline and month 12 were assessed by using descriptive statistics. Asthma-related quality of life was assessed by using the Mini Asthma Quality of Life Questionnaire, and work and activity impairment was assessed by the Work Productivity and Activity Impairment Questionnaire-Asthma. Odds ratios (OR) and 95% CI for asthma exacerbation risk at month 12 were generated by using multivariable logistic regression. A total of 1186 patients were included. More than two-thirds of the patients (67.4%) were on ≥3 long-term controllers, and 55.1% were considered difficult to treat due to frequent exacerbations. Patients reported low asthma-related quality of life scores and considerable impairment in overall work and daily activity (21.4% and 32.1%, respectively). After adjustment for covariates, exacerbation history (hospitalization, OR 6.27 [95% CI, 3.61-10.88]; emergency department visit, OR 3.84 [95% CI, 2.50-5.91]; corticosteroid burst, OR 2.89 [95% CI, 2.18-3.82]) and very poorly controlled asthma (OR 1.95 [95% CI, 1.41-2.71] vs not well controlled) were independently associated with risk of a future exacerbation (all P < .001). Despite multiple long-term controller medications, patients with severe or difficult-to-treat asthma on Steps 4/5/6 therapy present with significant clinical burden and risk of future asthma exacerbations.

Does zafirlukast reduce future risk of asthma exacerbations in adults? Systematic review and meta-analysis.

Background and objectiveThe purpose of asthma management is to achieve a total asthma control that involves current control and future risk. It has proven efficacy in reducing asthma exacerbations, but the effect size of zafirlukast for asthma exacerbations of various severity is not systematically explored.MethodsRandomized controlled trials were searched in PubMed Central, Web of Science, and Embase, where zafirlukast prevented asthma exacerbations in adults. The primary outcome was asthma exacerbations, the secondary outcomes were asthma exacerbations requiring systemic corticosteroids and emergency visits, respectively. Odds ratio (OR) with 95% confidence intervals (CI) were pooled.ResultsTwelve trials were identified. As first-line therapy, compared to those having placebo, the patients with chronic asthma receiving zafirlukast experienced statistically lower asthma exacerbations (OR = 0.68, 95% CI = [0.45, 1.00]), but it was not found that zafirlukast was superior to placebo in asthma exacerbations requiring systemic corticosteroids (OR = 0.76, 95% CI = [0.45, 1.29]). Furthermore, zafirlukast was inferior to ICs in asthma exacerbations (OR = 2.11, 95% CI = [1.35, 3.30]) and requiring systemic corticosteroids (OR = 3.71, 95% CI = [1.82, 7.59]). As add-on therapy, zafirlukast was not superior to placebo in asthma exacerbations (OR =0.99, 95% CI = [0.54, 1.81] and requiring emergency visits (OR = 0.72, 95% CI = [0.18, 2.99]). Intriguingly, there was not a significant difference in asthma exacerbations between zafirlukast and ICs (OR = 1.12, 95% CI = [0.53, 2.34]).ConclusionsOur study suggests that zafirlukast, as the first-line therapy, significantly reduces mild to moderate but not severe asthma exacerbations. In the add-on regimen, zafirlukast could not reduce asthma exacerbations, which would perhaps result from small sample size and needs to be further studied.

A Computerized Asthma-Specific Quality of Life: A Novel Tool for Reflecting Asthma Control and Predicting Exacerbation

Background: Proper assessment of health-related quality of life is essential to achieve and maintain a controlled status in asthmatic patients. We developed our own computerized asthma-specific quality-of-life (cA-QOL) questionnaire based on in-depth interviews with adult asthmatic patients. In this study, we evaluated this cA-QOL in terms of the Asthma Control Test (ACT) score and Global Initiative for Asthma (GINA) guidelines as well as asthma exacerbation, and compared it with the asthma-related quality-of-life questionnaire (AQLQ). Methods: We conducted a multicenter, prospective, observational study in 133 adult asthmatic patients recruited from 5 university hospitals in South Korea, who were randomized into 2 groups according to the operating order of the cA-QOL and AQLQ. At every visit (3-month interval), physicians evaluated asthma control status with monitoring spirometry. The self-administered cA-QOL, AQLQ(S) and ACT were completed. Results: The cA-QOL scores correlated significantly with ACT and AQLQ(S) scores (r = 0.814, p < 0.001; r = 0.900, p < 0.001). The cA-QOL score was significantly lower where the ACT score was <19, in the patients with an uncontrolled asthma status according to the GINA guidelines and in those with asthma exacerbation (p < 0.001, respectively). A multivariate analysis showed that this cA-QOL was a significant parameter associated with an uncontrolled asthma status and asthma exacerbation (p < 0.001, p = 0.045, p = 0.019, respectively). Conclusion: The cA-QOL is a valid tool for reflecting current asthma control status and for assessment to predict the future risk of asthma exacerbation in adult asthmatics.

Is It Possible to Achieve Better Asthma Control by Using the Same Inhaler Device?

Achieving asthma control is central to optimizing patient quality of life and clinical outcomes. This definition of asthma control has two components: achieving current clinical asthma control and reducing future risk.1 The level of clinical asthma control is defined by the Global Initiative for Asthma (GINA) using a composite score comprising five measures. Reducing asthma exacerbations is a key factor for preventing future risk.2 The regular use of inhaled corticosteroids (ICS) is essential for controlling asthma symptoms and reducing asthma exacerbations. A previous study found that a history of exacerbations, poor asthma control, poor inhaler technique, a history of lower respiratory tract infections, poor adherence to medication, and the presence of co-morbid conditions all predicted the future risk of asthma exacerbation.3 Most control medications, including ICS, are delivered via inhalation. The correct use of inhaler devices is critical for optimizing drug delivery and obtaining clinical benefits.4 However, inhaler use still represents an important challenge for most asthmatic patients. The correct inhalation maneuver differs markedly for different inhaler types. The problems and prevalence of incorrect inhaler use have been the subject of several recent reviews.5-7 Improper technique remains common for both metered dose (MDIs) and dry power (DPIs) inhalers, and was associated with poor clinical control and increased unscheduled health-care demands in asthma clinics.8 Inhaler mishandling continues to be common among experienced outpatients referred to asthma clinics and is associated with increased unscheduled health care resource use.8 Nevertheless, inhaler technique status has not been included in most analyses examining the predictors of asthma exacerbation. Poor adherence to asthma medication is a dilemma, as it decreases the chance of achieving and maintaining proper asthma control. Education of both patients and health care professionals regarding proper inhaler technique will improve asthma control.9,10 The study by Price et al.11 in this issue is the first to compare outcomes for asthmatic patients prescribed the same inhaler device versus mixed device types for asthma control and relief therapy. This retrospective observational study identified patients with asthma (age 4-80 years) in a large primary care database who were prescribed an ICS. They compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for both the ICS controller and salbutamol reliever versus those using two devices (a BAI for the controller and a pressurized metered-dose inhaler [pMDI] for the reliever). Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15) and had significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95%) than those prescribed two devices (n=5,452). These finding suggest that prescribing the same device for both ICS and reliever therapy improves asthma control. A previous study evaluated the skill at handling inhalers and factors associated with these skills in 145 patients with asthma under the care of asthma specialists in Korea.12 When their skill at using the inhalers was assessed visually, the performance was inadequate for 12.8% of the participants using Turbuhaler, 6.2% using Diskus, and 23.4% using pMDIs. Most showed excellent skill at using their inhalers. However, older age and the absence of previous instructions for handling the inhalers were associated with inadequate techniques, indicating that this population requires more education to improve their inhalation technique. Several studies used repeated inhaler instructions as a method to improve inhaler technique.9,13 Educational adherence support should be a collaborative effort between the patient and health care professional.14 One limitation of this study is that it includes the potential for unrecognized confounding factors, including selection bias, as it was a retrospective study.11 This study examined a database of primary physicians in the U.K. As such, there were missing data for some patients, including smoking history, which could influence outcomes. There is no assurance that patients actually took the medications as prescribed. However, this study enrolled a larger cohort of patients using ICS, included for a 1-year outcome period, and provided good evidence of improved asthma outcome with improved adherence to medications using the same BAI device for both controller ICS and reliever salbutamol therapy.

Predicting asthma exacerbations: Peak expiratory flow revisited

The ability to predict and prevent future exacerbations has been a consistent focus of asthma research. Although some progress has been made on identifying factors associated with an increased risk of exacerbation at the population and individual levels, no measure or instrument is available for widespread use in the asthma community. In this issue of the Journal, Thamrin et al present a statistical method used to calculate the future exacerbation risk for a patient (as defined by deterioration in percent predicted peak expiratory flow [PEF]) based on the history of fluctuations in lung function (percent predicted PEF). The authors challenge us to reframe our analytic approach to asthma. Frey et al have suggested that a patient with asthma should be thought of as a complex, nonlinear dynamic systems network; such a network exhibits fluctuations over time in physiologic and clinical variables. However, such a system also exhibits memory effects, and although changes can occur over time, the recent past will include most of the pertinent information needed to predict the short-term future risk. Viewingasthma through this framework, it follows that the single best individual parameter to predict the risk of an exacerbation over the next year is the history of an exacerbation in the prior year. The natural history of asthma in any given patient is a summation of personal characteristics (eg, demographics, inflammatory profile, and lungmechanics), genetics, both the physical (exposure to environment [environmental tobacco smoke, pollution, and allergens]) and psychosocial (access to care) environment, and therapy (including adherence). The complex interaction of these factors results in the overall clinical phenotype expressed by a patient, and this helps explain why the recent past is a strong predictor of future events. Modeling asthma as a complex, nonlinear dynamic system also fits with our increasing recognition of the heterogeneity of asthma. Patients with asthma present differently in regard to symptoms, physiologic measures, inflammatory indices, and perception of obstruction; measuring a single parameter at a single point might not

Urinary Bromotyrosine Measures Asthma Control and Predicts Asthma Exacerbations in Children

To determine the usefulness of urinary bromotyrosine, a noninvasive marker of eosinophil-catalyzed protein oxidation, in tracking with indexes of asthma control and in predicting future asthma exacerbations in children. Children with asthma were recruited consecutively at the time of clinic visit. Urine was obtained, along with spirometry, exhaled nitric oxide, and Asthma Control Questionnaire data. Follow-up phone calls were made 6 weeks after enrollment. Fifty-seven participants were enrolled. Urinary bromotyrosine levels tracked significantly with indexes of asthma control as assessed by Asthma Control Questionnaire scores at baseline (R = 0.38, P = .004) and follow-up (R = 0.39, P = .008). Participants with high baseline levels of bromotyrosine were 18.1-fold (95% CI 2.1-153.1, P = .0004) more likely to have inadequately controlled asthma and 4.0-fold more likely (95% CI 1.1-14.7, P = .03) to have an asthma exacerbation (unexpected emergency department visit; doctor's appointment or phone call; oral or parenteral corticosteroid burst; acute asthma-related respiratory symptoms) over the ensuing 6 weeks. Exhaled nitric oxide levels did not track with Asthma Control Questionnaire data; and immunoglobulin E, eosinophil count, spirometry, and exhaled nitric oxide levels failed to predict asthma exacerbations. Urinary bromotyrosine tracks with asthma control and predicts the risk of future asthma exacerbations in children.

Predicting future risk of asthma exacerbations using individual conditional probabilities

Determination of future risk of exacerbations is a key issue in the management of asthma. We previously developed a method to calculate conditional probabilities (π) of future decreases in lung function by using the daily fluctuations in peak expiratory flow (PEF). We aimed to extend calculation of π values to individual patients, validated by using electronically recorded data from 2 past clinical trials. Twice-daily PEF data were analyzed from 78 patients with severe (study A) and 61 patients with poorly controlled (study B) asthma. For each patient, the π value was calculated from 5000 PEF data points simulated based on the correlation and distribution properties of observed PEF. Given an initial PEF, the π value was defined as the probability of a decrease in PEF to less than 80% of predicted value on 2 consecutive days within a month. These probabilities were then compared with actual occurrences of such events and clinically defined exacerbations within the following month. π Values were related to actual occurrences of decreases in PEF (adjusted R(2) > 0.800 for both studies). Every increase of 10% in π value was associated with an odds ratio of having a future exacerbation of 1.24 (95% CI, 1.07-1.43) for study Aand 1.13 (95% CI, 1.02-1.26) for study B, with better sensitivity and specificity than clinic-measured FEV(1). These results from 2 independent datasets with differing asthmatic populations and differing exacerbation criteria provide support that clinically relevant quantification of individual future risk of exacerbations is possible.

Current Control and Future Risk in Asthma Management

Despite international and national guidelines, poor asthma control remains an issue. Asthma exacerbations are costly to both the individual, and the healthcare provider. Improvements in our understanding of the therapeutic benefit of asthma therapies suggest that, in general, while long-acting bronchodilator therapy improves asthma symptoms, the anti-inflammatory activity of inhaled corticosteroids reduces acute asthma exacerbations. Studies have explored factors which could be predictive of exacerbations. A history of previous exacerbations, poor asthma control, poor inhaler technique, a history of lower respiratory tract infections, poor adherence to medication, the presence of allergic rhinitis, gastro-oesophageal reflux disease, psychological dysfunction, smoking and obesity have all been implicated as having a predictive role in the future risk of asthma exacerbation. Here we review the current literature and discuss this in the context of primary care management of asthma.

Asthma Control and Risk of Future Asthma Exacerbations: Evaluation of the Impairment Domain of the NHLBI Guidelines in the TENOR Cohort

Asthma Control and Risk of Future Asthma Exacerbations: Evaluation of the Impairment Domain of the NHLBI Guidelines in the TENOR Cohort