Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

BACKGROUND: As asthma symptoms worsen, patients typically rely on short-acting ß2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation. METHODS: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide (with each dose consisting of two actuations of 90 µg and 80 µg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 µg of albuterol and 80 µg of budesonide (with each dose consisting of two actuations of 90 µg and 40 µg, respectively [the lower-dose combination group]), or 180 µg of albuterol (with each dose consisting of two actuations of 90 µg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population. RESULTS: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups. CONCLUSIONS: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).

Advancing assessment of asthma control with a composite tool: The Asthma Impairment and Risk Questionnaire.

BACKGROUND: National and international asthma guidelines and reports do not include control tools that combine impairment assessment with exacerbation history in one instrument. OBJECTIVE: To analyze the performance of the composite Asthma Impairment and Risk Questionnaire (AIRQ) in assessing both domains of control and predicting exacerbation risk compared with the Global Initiative for Asthma (GINA) 4-question symptom control tool (GINA SCT), Asthma Control Test (ACT), and physician expert opinion (EO) informed by GINA SCT responses and appraisal of GINA-identified risk factors for poor asthma outcomes. METHODS: Multivariable logistic regressions evaluated AIRQ and GINA SCT as predictors of ACT. McNemar's test compared the proportion of patients categorized at baseline as completely or well-controlled by each assessment but with current impairment or previous-year and subsequent-year exacerbations. RESULTS: The analysis included 1064 patients aged 12 years or older; mean (SD) age 43.8 years (19.3); 70% female; 79% White; and 6% Hispanic or Latino. AIRQ and GINA SCT were highly predictive of ACT well-controlled vs not well-controlled and very poorly controlled (receiver operator characteristic area under curve AIRQ = 0.90, GINA SCT = 0.86, P = .03 AIRQ vs GINA SCT) and ACT very poorly controlled vs well-controlled and not well-controlled asthma (receiver operator characteristic area under curve AIRQ = 0.91, GINA SCT = 0.87, P = .01 AIRQ vs GINA SCT). AIRQ rated fewer patients as having completely or well-controlled asthma who had current impairment (P < .01) or with previous-year and subsequent-year exacerbations (P < .001) than did GINA SCT, ACT, and EO. CONCLUSION: AIRQ performs better in assessing both domains of current control and predicting exacerbation risk than do control tools and EO informed by GINA SCT and risk factors for poor asthma outcomes.

Number of patient-reported asthma triggers predicts uncontrolled disease among specialist-treated patients with severe asthma.

BACKGROUND: Patients with severe asthma (SA) experience a high disease burden, often precipitated by exposure to disease triggers. OBJECTIVE: To evaluate the prevalence and effects of patient-reported triggers on asthma disease burden in a cohort of subspecialist-treated patients with SA in the United States. METHODS: CHRONICLE is an observational study of adults with SA receiving biologics or maintenance systemic corticosteroids or whose disease is uncontrolled on high-dosage inhaled corticosteroids and additional controllers. Data were analyzed for patients enrolled between February 2018 and February 2021. This analysis evaluated patient-reported triggers from a 17-category survey and associations with multiple measures of disease burden. RESULTS: Among 2793 enrolled patients, 1434 (51%) completed the trigger questionnaire. The median trigger number per patient was 8 (interquartile range, 5-10). The most frequent triggers were weather or air changes, viral infections, seasonal allergies, perennial allergies, and exercise. Patients reporting more triggers experienced more poorly controlled disease, worse quality of life, and reduced work productivity. The annualized rates of exacerbations and asthma hospitalizations increased by 7% and 17%, respectively, for each additional trigger (both P < .001). For all measures, trigger number was a stronger predictor of disease burden than blood eosinophil count. CONCLUSION: Among US specialist-treated patients with SA, asthma trigger number was positively and significantly associated with greater uncontrolled disease burden across multiple measures, which highlights the importance of understanding patient-reported triggers in SA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Albuterol/budesonide for the treatment of exercise-induced bronchoconstriction in patients with asthma: The TYREE study.

BACKGROUND: PT027 is a fixed-dose combination of albuterol (salbutamol) and budesonide in a single pressurized metered-dose inhaler. OBJECTIVE: To evaluate the efficacy and safety of albuterol/budesonide compared with placebo in patients with asthma and exercise-induced bronchoconstriction (EIB). METHODS: In this randomized, double-blind, 2-period, single-dose crossover study, adolescents and adults with asthma and EIB (defined by ≥20% decrease from pre-exercise challenge forced expiratory volume in 1 second [FEV1]) were randomized to albuterol/budesonide (180/160 µg) followed by placebo (n = 29) or the reverse sequence (n = 31). Subjects were stratified by background therapy (as-needed short-acting ß2-agonist alone or low-to-medium dose inhaled corticosteroid plus as-needed short-acting ß2-agonist). FEV1 was measured 5 minutes pre-dose, 30 minutes postdose (5 minutes pre-exercise challenge [baseline]), and 5, 10, 15, 30, and 60 minutes postexercise. The primary end point was maximum percentage fall from baseline in FEV1 up to 60 minutes postexercise challenge. RESULTS: Least squares mean maximum percentage fall in FEV1 up to 60 minutes postexercise challenge was 5.45% with albuterol/budesonide vs 18.97% with placebo (difference, -13.51% [95% confidence interval, -16.94% to -10.09%]; P < .001). More subjects were fully protected (maximum percentage fall in FEV1 post-exercise challenge < 10%) with albuterol/budesonide than with placebo (78.3% vs 28.3%; P < .001). The treatment effect was consistent irrespective of background inhaled corticosteroid therapy, and albuterol/budesonide was well tolerated. CONCLUSION: In adolescents and adults with asthma and EIB, a single dose of albuterol/budesonide 180/160 µg taken approximately 30 minutes before exercise was significantly more effective than placebo in preventing EIB. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04234464.

Biologic use and outcomes among adults with severe asthma treated by US subspecialists.

BACKGROUND: Multiple biologics are now available for severe asthma (SA) treatment and can improve outcomes for patients. However, few available data describe the real-world use and effectiveness of multiple approved biologics, including biologic switching, among subspecialists in the United States. OBJECTIVE: To evaluate biologic use and associated exacerbation outcomes in a large cohort of subspecialist-treated US adults with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of subspecialist-treated US adults with SA receiving biologics, maintenance systemic corticosteroids, or those persistently uncontrolled by high-dose inhaled corticosteroids with additional controllers. For enrolled patients, sites report asthma exacerbations and medication use starting 12 months before enrollment. For patients enrolled between February 2018 and February 2021, biologic use and exacerbation outcomes before and after biologic initiation are described. RESULTS: Among 2793 enrolled patients, 66% (n = 1832) were receiving biologics. The most used biologic (> 1 biologic use per patient allowed) was omalizumab (47%), followed by benralizumab (27%), mepolizumab (26%), dupilumab (18%), and reslizumab (3%). Overall, 16% of patients had biologic switches, 13% had stops, and 89% had ongoing biologic use. Patients starting and switching biologics experienced a 58% (1.80 vs 0.76 per patient-year) and 49% (1.47 vs 0.75 per patient-year) reduction in exacerbations, respectively (both P < .001), with a numerically greater reduction observed among those starting non-anti-immunoglobulin E biologics compared with anti-immunoglobulin E. CONCLUSION: Real-world starting and switching of biologic therapies for SA were associated with meaningful reductions in exacerbations. With increasing biologic options available, individualized approaches to therapy may improve patient outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03373045.

Evaluating construct validity of the Asthma Impairment and Risk Questionnaire using a 3-month exacerbation recall.

BACKGROUND: Recurrent assessment of asthma control is essential to evaluating disease stability and intervention impacts. An assessment that can be administered between annual clinic visits is needed. The Asthma Impairment and Risk Questionnaire (AIRQ) is a cross-sectionally validated, 10-item, yes or no, composite control tool evaluating previous 2-week symptoms and previous 12-month exacerbations. OBJECTIVE: To evaluate the construct validity of the AIRQ using a 3-month recall period for exacerbation-based risk questions and retaining the 2-week recall for symptom-based impairment items. METHODS: At baseline, patients completed the AIRQ with 12-month recall exacerbation items, Asthma Control Test (ACT), St. George's Respiratory Questionnaire (SGRQ), and global self-assessments of asthma risk, control, and symptom severity. Patient-reported exacerbations were captured monthly. The AIRQ with 3-month recall exacerbation items, ACT, and global self-assessments was administered at months 3, 6, and 9, and SGRQ at month 6. RESULTS: A total of 1112 patients aged 12 years or older were enrolled (mean [SD] age, 43.9 [19.5] years). The AIRQ and each administration of the AIRQ with 3-month recall exacerbation items classified asthma control similarly to an ACT plus exacerbation validation standard. For both AIRQ versions, SGRQ scores were higher with worsening asthma control (P < .001). At months 3, 6, and 9, worse AIRQ control levels were associated with higher proportions of patients with 1 or more and 2 or more exacerbations in the previous 3 months and patient global self-assessments indicating greater asthma morbidity (all P < .001). CONCLUSION: The AIRQ using exacerbation risk items with a 3-month recall period exhibits construct validity for classifying current asthma control and can be administered between annual AIRQ assessments.

Severe asthma exacerbation rates are increased among female, Black, Hispanic, and younger adult patients: results from the US CHRONICLE study.

OBJECTIVE: To describe clinical outcomes in patients with severe asthma (SA) by common sociodemographic determinants of health: sex, race, ethnicity, and age. METHODS: CHRONICLE is an observational study of subspecialist-treated, United States adults with SA receiving biologic therapy, maintenance systemic corticosteroids, or uncontrolled by high-dosage inhaled corticosteroids with additional controllers. For patients enrolled between February 2018 and February 2020, clinical characteristics and asthma outcomes were assessed by sex, race, ethnicity, age at enrollment, and age at diagnosis. Treating subspecialists reported exacerbations, exacerbation-related emergency department visits, and asthma hospitalizations from 12 months before enrollment through the latest data collection. Patients completed the St. George's Respiratory Questionnaire and the Asthma Control Test at enrollment. RESULTS: Among 1884 enrolled patients, the majority were female (69%), reported White race (75%), non-Hispanic ethnicity (69%), and were diagnosed with asthma as adults (60%). Female, Black, Hispanic, and younger patients experienced higher annualized rates of exacerbations that were statistically significant compared with male, White, non-Hispanic, and older patients, respectively. Black, Hispanic, and younger patients also experienced higher rates of asthma hospitalizations. Female and Black patients exhibited poorer symptom control and poorer health-related quality of life. CONCLUSIONS: In this contemporary, real-world cohort of subspecialist-treated adults with SA, female sex, Black race, Hispanic ethnicity, and younger age were important determinants of health, potentially attributable to physiologic and social factors. Knowledge of these disparities in SA disease burden among subspecialist-treated patients may help optimize care for all patients.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

Differing perceptions of asthma control and treatment effectiveness by patients with severe asthma and treating subspecialists in the United States.

OBJECTIVE: For patients with severe asthma (SA), overestimation of asthma control may lead to poorer outcomes. The objective of this study was to assess concurrent patient and specialist assessments of asthma control and treatment effectiveness among a large US cohort of SA patients. METHODS: CHRONICLE is an ongoing observational study of patients with SA treated by US subspecialists. Asthma control was assessed using the patient-completed Asthma Control Test™ (ACT™) and specialist clinical assessment of control. Treatment effectiveness was measured using the Global Evaluation of Treatment Effectiveness (GETE) completed by patients and specialists. RESULTS: 1109 patients who completed online surveys at enrollment were included. 14%, 28%, 25%, and 33% of patients had ACT™ scores of 5-9, 10-15, 16-19, and 20-25, respectively. Compared with 67% of patients with uncontrolled asthma by ACT™, 44% were uncontrolled by specialist assessment. 54% of patients who were uncontrolled according to the ACT™ were rated as controlled by specialists, demonstrating overestimation of asthma control. Based on ACT™ score, asthma control was more frequent among patients treated with biologics compared to other treatments. Using the GETE, 90% of patients reported treatment effectiveness compared with 71% of specialists. Patient and specialist treatment effectiveness categorizations agreed 73% of the time. CONCLUSION: Specialists commonly overestimated asthma control relative to ACT™ scores. Patients reported treatment effectiveness more frequently than specialists. These findings emphasize the importance of validated instruments to assess asthma control and reduce potential treatment gaps associated with patient-specialist discordance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Tiotropium in children and adolescents with asthma.

BACKGROUND: Asthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium-a long-acting muscarinic antagonist-as add-on therapy to an inhaled corticosteroid with or without a long-acting ß2-agonist provides clinical benefit with a safety profile similar to placebo. OBJECTIVE: To review published evidence on the efficacy and safety of tiotropium as add-on a long-acting muscarinic antagonist therapy in children and adolescents with asthma that is uncontrolled despite use of an inhaled corticosteroid with or without additional controller medication(s). METHODS: We searched PubMed from inception until June 12, 2018, for randomized controlled trials of children and adolescents aged 1 to 17 years treated with tiotropium and reporting a primary outcome of any pulmonary function test and a secondary outcome of adverse events. RESULTS: Overall, 7 randomized controlled trials of 1902 preschool children (aged 1-5 years; n = 102), school-age children (aged 6-11 years; n = 905), and adolescents (aged 12-17 years; n = 895) with moderate to severe asthma were included in the analysis. Once-daily tiotropium (5, 2.5, or 1.25 µg) improved lung function parameters, including peak and trough forced expiratory volume in 1 second, vs placebo. Commonly reported adverse events across treatment groups included asthma worsening or exacerbations, decreased peak expiratory flow rate, nasopharyngitis, viral respiratory tract infection, and respiratory tract infection. CONCLUSION: Once-daily tiotropium as add-on therapy is efficacious and safe in adolescents and children with moderate to severe asthma. These results support the expanded indication by regulatory authorities for add-on tiotropium in patients 6 years or older.

From the pages of AllergyWatch®: November 2020.

For this month's edition of "From the Pages of AllergyWatch," I have chosen reviews of articles of interest to the clinical allergist. The first study found that wheezing infants with atopic sensitization at the time of the first wheezing episode was strongly associated with bronchial reactivity in childhood. The next review, of an article published in the Annals of Allergy, Asthma & Immunology, investigated the complexity of atopic sensitization to foods in children with atopic dermatitis (AD). The final study confirms the determination of the US Environmental Protection Agency to the likely causal link between exposures to particulate matter and ozone and respiratory illness.

Benralizumab efficacy for patients with fixed airflow obstruction and severe, uncontrolled eosinophilic asthma.

BACKGROUND: Fixed airflow obstruction (FAO) is associated with severe eosinophilic asthma. Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody for patients with severe, uncontrolled eosinophilic asthma. OBJECTIVE: We evaluated FAO influence on benralizumab treatment response. METHODS: We performed a post hoc analysis of pooled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) data for patients with severe, uncontrolled asthma with baseline blood eosinophil counts of 300 or more cells/µL who received benralizumab 30 mg every 8 weeks or placebo. Demographics, baseline clinical characteristics, and treatment responses were evaluated by FAO status. FAO+ and FAO- were defined as ratios of postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity of less than 70% and 70% or more, respectively, at baseline. RESULTS: FAO+ prevalence was 63% (935/1493). With benralizumab, similar annual asthma exacerbation rate (AER) reductions vs placebo were achieved for FAO+ and FAO- patients (rate ratio [95% confidence interval (CI)] = 0.56 [0.44-0.71] and 0.58 [0.41-0.83], respectively), whereas annual AER reductions associated with emergency department visits or hospitalizations were greater for FAO+ vs FAO- patients (rate ratio [95% CI] = 0.55 [0.33-0.91] and 0.70 [0.33-1.48], respectively). Prebronchodilator FEV1 (95% CI) increase from baseline to end of treatment was greater for FAO+ vs FAO- patients receiving benralizumab compared with placebo (0.159 L [0.082-0.236] vs 0.103 L [-0.008 to 0.215]). Other lung function measures, patient-reported outcomes, and symptom improvements were also numerically greater for FAO+ vs FAO- patients. CONCLUSION: Benralizumab improved asthma control across several measures for patients with severe, uncontrolled eosinophilic asthma and FAO. TRIAL REGISTRATION: SIROCCO trial: NCT01928771 (URL: https://clinicaltrials.gov/ct2/show/NCT01928771) CALIMA trial: NCT01914757 (URL: https://clinicaltrials.gov/ct2/show/NCT01914757).

Biologic and maintenance systemic corticosteroid therapy among US subspecialist-treated patients with severe asthma.

BACKGROUND: Severe asthma (SA) often requires subspecialist management and treatment with biologic therapies or maintenance systemic corticosteroids (mSCS). OBJECTIVE: To describe contemporary, real-world biologic and mSCS use among US subspecialist-treated patients with SA. METHODS: CHRONICLE is an ongoing, noninterventional study of US adults with SA treated by allergists/immunologists or pulmonologists. Eligible patients are receiving biologics or mSCS or are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Biologic and mSCS use patterns and patient characteristics were summarized for patients enrolled between February 2018 and February 2019. RESULTS: Among protocol-eligible patients, 58% and 12% were receiving biologics and mSCS, respectively, with 7% receiving both. Among 796 enrolled, most were women (67%), non-Hispanic white (71%), of suburban residence (50%), and had elevated body mass index (median: 31). Respiratory and nonrespiratory comorbidities were highly prevalent. With biologics (n = 557), 51% were anti-immunoglobulin E and 48% were anti-interleukin (IL)-5/IL-5Rα; from May 2018, 76% of initiations were anti-IL-5/IL-5Rα. In patients receiving mSCS, median prednisone-equivalent daily dose was 10 mg. Multivariate logistic regression found that patients of hospital clinics, sites with fewer nonphysician staff, and with a recorded concurrent chronic obstructive pulmonary disease diagnosis were less likely to receive biologics and more likely to receive mSCS. CONCLUSION: In this real-world sample of US subspecialist-treated patients with SA not controlled by high-dosage inhaled corticosteroids with additional controllers, mSCS use was infrequent and biologic use was common, with similar prevalence of anti-immunoglobulin E and anti-IL-5/IL-5Rα biologics. Treatment differences associated with patient and site characteristics should be investigated to ensure equitable access to biologics and minimize mSCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Efficacy of dupilumab on clinical outcomes in patients with asthma and perennial allergic rhinitis.

BACKGROUND: Comorbid perennial allergic rhinitis (PAR) or year-round aeroallergen sensitivity substantially contributes to disease burden in patients with asthma. Dupilumab blocks the shared receptor for interleukin (IL) 4 and IL-13, key drivers of type 2 inflammation that play important roles in asthma and PAR. In the LIBERTY ASTHMA QUEST trial (NCT02414854), dupilumab reduced severe asthma exacerbations and improved forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in patients with elevated type 2 inflammatory biomarkers at baseline (blood eosinophils and fractional exhaled nitric oxide). OBJECTIVE: To assess dupilumab efficacy in LIBERTY ASTHMA QUEST patients with comorbid PAR. METHODS: Severe asthma exacerbation rates, FEV1, asthma control (5-item Asthma Control Questionnaire), rhinoconjunctivitis-specific health-related quality of life (Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores), and type 2 inflammatory biomarkers during the 52-week treatment period were assessed. RESULTS: A total of 814 of the 1902 patients (42.8%) had comorbid PAR (defined as an allergic rhinitis history and ≥1 perennial aeroallergen specific immunoglobulin E (IgE) level ≥0.35 kU/L at baseline). Dupilumab, 200 and 300 mg every 2 weeks, vs placebo reduced severe exacerbations rates by 32.2% and 34.6% (P < .05 for both) and improved FEV1 at week 12 by 0.14 L and 0.18 L (P < .01 for both); greater efficacy was observed in patients with elevated baseline blood eosinophil counts (≥300 cells/µL) and fractional exhaled nitric oxide. Dupilumab treatment also numerically improved the 5-item Asthma Control Questionnaire and Standardized Rhinoconjunctivitis Quality of Life Questionnaire +12 scores and suppressed type 2 inflammatory biomarkers. CONCLUSION: Dupilumab improved key asthma-related outcomes, asthma control, and rhinoconjunctivitis-specific health-related quality of life while suppressing type 2 inflammatory biomarkers and perennial allergen-specific IgE in patients with moderate-to-severe asthma and comorbid PAR, highlighting its dual inhibitory effects on IL-4 and IL-13 and its role in managing asthma and PAR.

Symptoms and perception of airway obstruction in asthmatic patients: Clinical implications for use of reliever medications.

BACKGROUND: Asthma causes the unpleasant sensation of breathlessness (dyspnea) caused by airway obstruction. Patients with poor perception of airway obstruction are at risk of delay in seeking medical attention and undertreatment, which can lead to avoidable deaths. Conversely, those with heightened perception are at risk of overtreatment and iatrogenic adverse effects with reliever medications, anxiety, and unnecessary use of health care resources. OBJECTIVE: We sought to review evidence about symptom misperception in asthmatic patients and how to identify and manage affected patients, particularly with regard to reliever medications. METHODS: We conducted a systematic literature search for studies of perception of airway function in asthmatic patients. We searched the OVID (Medline and Medline [R] in process [PubMed]), Embase, and Adisearch/Odyssey databases, restricting our search to human studies published in English from 1990-2018, with no restrictions on age, sex, or racial origin. RESULTS: We found that both underperception and overperception assessed during induced bronchoconstriction or bronchodilation or during changes in airway resistance were common across all age groups and that aging, disease severity, smoking, sex, ethnicity, psychologic factors, and medication are all associated with differences in perception. Importantly, airway inflammation was associated with impaired perception and a history of severe or near-fatal asthma. We also identified knowledge gaps, such as whether an individual patient's perception varies over time and the influence perception has on patients' use of reliever medication. CONCLUSION: We found that abnormal perception of airway obstruction has important clinical implications for the management of patients with asthma.

The Asthma Controller Step-down Yardstick.

Asthma guidelines recommend a control-based approach to disease management in which the assessment of impairment and risk is linked to step-based therapy. Using this model, controller treatment is adjusted-upward or downward-according to a patient's level of asthma control over time. Strategies for stepping up controller therapy are well described, and the adult and pediatric Asthma Yardsticks provide operational recommendations based on patient profiles. Strategies for stepping down controller treatment are less clear, although stepping down to the minimum effective therapy is important and should be considered when a patient's asthma has been well controlled for an adequate period as defined by risk and impairment. This Yardstick presents recommendations for when and how to step down asthma controller therapy according to guideline-defined control levels. The objective is to provide clinicians who treat patients with asthma with a practical and clinically relevant framework for implementing a step-down in controller therapy.

More than a decade follow-up in patients with severe or difficult-to-treat asthma: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) II.

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study demonstrated high morbidity in patients with severe or difficult-to-treat asthma despite standard-of-care treatment. OBJECTIVE: We sought to determine the long-term natural history of disease and outcomes in patients in TENOR I after more than a decade. METHODS: TENOR I was a multicenter observational study (2001-2004) of 4756 patients with severe or difficult-to-treat asthma. TENOR II was a follow-up study of TENOR I patients using a single cross-sectional visit in 2013/2014. Overall, the sites participating in TENOR II originally enrolled 1230 patients in TENOR I. Clinical and patient-reported outcomes were assessed, including very poorly controlled asthma based on National Heart, Lung, and Blood Institute guidelines. RESULTS: A total of 341 (27.7%) patients were enrolled in TENOR II and were representative of the TENOR I cohort. The most frequent comorbidities were rhinitis (84.0%), sinusitis (47.8%), and gastroesophageal reflux disease (46.3%). Mean percent predicted prebronchodilator and postbronchodilator FEV1 were 72.7% (SD, 21.4%) and 78.2% (SD, 20.7%), respectively. A total of 231 (72.9%) of 317 patients had positive test responses to 1 or more allergen-specific IgEs. The mean blood eosinophil count was 200/µL (SD, 144/µL). Eighty-eight (25.8%) patients experienced an asthma exacerbation in the prior 3 months requiring hospital attention, oral corticosteroids, or both. More than half (197/339 [58.1%]) had very poorly controlled asthma. Medication use suggested undertreatment. CONCLUSION: TENOR II provides longitudinal data to characterize disease progression, heterogeneity, and severity in patients with severe or difficult-to-treat asthma. Findings show continued morbidity, including a high degree of comorbid conditions, allergic sensitization, exacerbations, and very poorly controlled asthma, including reduced lung function.

Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma.

BACKGROUND: Patients with severe asthma can have eosinophilic inflammation and/or allergen sensitization. Benralizumab is an anti-eosinophilic monoclonal antibody indicated for add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. OBJECTIVE: To investigate the efficacy of benralizumab by atopic status and serum immunoglobulin E (IgE) concentrations. METHODS: We analyzed pooled results from the SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase III studies. Patients 12 to 75 years old with severe, uncontrolled asthma on high-dosage inhaled corticosteroids plus long-acting ß2-agonists received 30 mg of subcutaneous benralizumab every 4 weeks or every 8 weeks (first 3 doses every 4 weeks) or placebo every 4 weeks. The analysis stratified patients who did and did not meet similar omalizumab-qualifying criteria of atopy and serum IgE levels 30 to 700 kU/L. Patients also categorized as having high serum IgE (≥150 kU/L) or low serum IgE (<150 kU/L) and as having atopy or no atopy. Efficacy outcomes were for all patients and by blood eosinophil counts and included annual exacerbation rate ratio and pre-bronchodilator forced expiratory volume in 1 second change at treatment end vs placebo. RESULTS: Benralizumab every 8 weeks decreased exacerbations by 46% (95% confidence interval 26-61, P = .0002) and increased forced expiratory volume in 1 second by 0.125 L (95% confidence interval 0.018-0.232, P = .0218) vs placebo for patients with at least 300 eosinophils/µL who met the atopy and IgE criteria. For patients with eosinophilia and high or low IgE, treatment with benralizumab every 8 weeks resulted in 42% and 43% decreases in exacerbation rate (P ≤ .0004) and 0.123- and 0.138-L increases in forced expiratory volume in 1 second (P ≤ .0041) vs placebo, respectively. CONCLUSION: Benralizumab treatment decreased exacerbations and improved lung function for patients with severe, uncontrolled eosinophilic asthma regardless of serum IgE concentrations and atopy status.

The pediatric asthma yardstick: Practical recommendations for a sustained step-up in asthma therapy for children with inadequately controlled asthma.

Current asthma guidelines recommend a control-based approach to management involving assessment of impairment and risk followed by implementation of treatment strategies individualized according to the patient's needs and preferences. However, for children with asthma, achieving control can be elusive. Although tools are available to help children (and families) track and manage day-to-day symptoms, when and how to implement a longer-term step-up in care is less clear. Furthermore, treatment is challenged by the 3 age groups of childhood-adolescence (12-18 years old), school age (6-11 years old), and young children (≤5 years old)-and what works for 1 age group might not be the best approach for another. The Pediatric Asthma Yardstick provides an in-depth assessment of when and how to step-up therapy for the child with not well or poorly controlled asthma. Development of this tool follows others in the Yardstick series, presenting patient profiles and step-up strategies based on current guidance documents, but modified according to newer data and the authors' combined clinical experience. The objective is to provide clinicians who treat children with asthma practical and clinically relevant recommendations for each step-up and each intervention, with the intent of helping practitioners better treat their pediatric patients with asthma, particularly those who do not always respond to recommended therapies.