Dedicated Severe Asthma Services Improve Health-care Use and Quality of Life

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1 [ Original Research Asthma ] Dedicated Severe Asthma Services Improve Health-care Use and Quality of Life David Gibeon, MBChB ; Liam G. Heaney, MD ; Chris E. Brightling, PhD, FCCP ; Rob Niven, MD ; Adel H. Mansur, PhD ; Rekha Chaudhuri, MD ; Christine E. Bucknall, MD ; and Andrew N. Menzies-Gow, PhD ; on behalf of the British Thoracic Society Difficult Asthma Network BACKGROUND: Systematic assessment of severe asthma can be used to confirm the diagnosis, identify comorbidities, and address adherence to therapy. However, the prospective usefulness of this approach is yet to be established. The objective of this study was to determine whether the systematic assessment of severe asthma is associated with improved quality of life (QoL) and health-care use and, using prospective data collection, to compare relevant outcomes in patients referred with severe asthma to specialist centers across the United Kingdom. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics, and health-care use between initial assessment and a median follow-up of 286 days. RESULTS: The study population consisted of 346 patients with severe asthma. At follow-up, there were significant reductions in health-care use in terms of primary care or ED visits (66.4% vs 87.8%, P,.0001) and hospital admissions (38% vs 48%, P ). Although no difference was noted in terms of those requiring maintenance oral corticosteroids, there was a reduction in steroid dose (10 mg [8-20 mg] vs 15 mg [10-20 mg], P 5.003), and fewer subjects required short-burst steroids (77.4% vs 90.8%, P 5.01). Significant improvements were seen in QoL and control using the Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire. CONCLUSIONS: To our knowledge, this is the first time that a prospective study has shown that a systematic assessment at a dedicated severe asthma center is associated with improved QoL and asthma control and a reduction in health-care use and oral steroid burden. CHEST 2015; 148(4): Manuscript received December 6, 2014; revision accepted February 25, 2015; originally published Online First March 19, ABBREVIATIONS: ACQ 5 Asthma Control Questionnaire; AQLQ 5 Asthma Quality of Life Questionnaire; GERD 5 gastroesophageal reflux disease; OC 5 oral corticosteroid; QoL 5 quality of life AFFILIATIONS: From Royal Brompton Hospital (Drs Gibeon and Menzies- Gow), London, England; Airways Disease (Dr Gibeon), National Heart and Lung Institute, Imperial College, London, England; the Centre for Infection and Immunity (Dr Heaney), Queen s University of Belfast, Belfast, Ireland; the University of Leicester (Dr Brightling), Leicester, England; the University of Manchester (Dr Niven), Manchester, England; the University Hospital of South Manchester (Dr Niven), South Manchester, England; Birmingham Heartlands Hospital (Dr Mansur), University of Birmingham, Birmingham, England; Gartnavel General Hospital (Dr Chaudhuri), University of Glasgow, Glasgow, Scotland; and Glasgow Royal Infirmary (Dr Bucknall), Glasgow, Scotland. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Andrew N. Menzies-Gow, PhD, Royal Brompton Hospital, Fulham Rd, London, SW3 6HP, England; A.Menzies- Gow@rbht.nhs.uk 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest Original Research [ 148 # 4 CHEST OCTOBER 2015 ]

2 Approximately 5% of patients with asthma have severe treatment-refractory disease. This group of patients has a high direct health-care cost including medication burden and high indirect costs caused by lost productivity as a result of time off work or school. Within this group, some patients have severe treatmentrefractory disease, whereas others may have an alternative diagnosis, and some may appear to have severe disease because of poor adherence to prescribed therapy. Severe asthma is defined as asthma requiring treatment with guideline medications for GINA (Global Initiative for Asthma) step 4 to 5 (high-dose inhaled corticosteroids and long-acting b -agonists or leukotriene modifier/theophylline) for the previous year or systemic corticosteroids for 50% of the previous year to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy. 1 The British Thoracic Society/Scottish Intercollegiate Guidelines Network guidelines, the European Respiratory Society Task Force, and the American Thoracic Society Workshop on Severe Asthma have all highlighted a need for an integrated approach to assessing severe asthma. 1,2 FOR EDITORIAL COMMENT SEE PAGE 843 At present, there is no standardized way that patients with severe asthma are assessed, and different asthma centers within the United Kingdom follow their own evaluation protocols. Previous studies evaluating the benefits of a systematic assessment have found that a coordinated series of investigations and assessments can highlight the mechanism of persisting symptoms, identify comorbid conditions, evaluate adherence to therapy, and confirm the diagnosis of severe asthma. 3,4 These factors can result in a targeted or personalized treatment approach, resulting in improved asthma symptoms and quality of life (QoL) and a tailored drug therapy, in addition to highlighting which patients may be suitable for alternative therapies such as novel biologic agents. To date, there has not been a prospective study confirming that a systematic approach results in these changes, and previous retrospective studies have not examined QoL. Materials and Methods In 2006, the British Thoracic Society Research Committee, together with physicians with a special interest in severe asthma, developed the National Registry for dedicated UK Difficult Asthma Services. 5 This project aimed to standardize specialist clinical services, to further define and characterize clinical phenotypes in subjects with well-characterized severe asthma, and to facilitate research into the assessment and management of difficult asthma. At present, 11 UK dedicated Specialist Difficult Asthma Services submit data to the National Registry. Patients referred with difficult asthma to centers within the National Registry undergo a set of coordinated investigations accompanied by a detailed history and examination. The National Registry is hosted online by Dendrite Clinical Systems Ltd and admits password-protected anonymized data after fully informed written consent has been obtained. Ethical approval for the National Registry was obtained from the Office for Research Ethics Committees Northern Ireland (ORECNI10/ NIR02/37). All patients underwent multiple investigations including a thorough medical history and examination, pulmonary function tests, allergy assessment (skin-prick testing, radioallergosorbent test, or both), and blood tests (incorporating blood eosinophil count and IgE). Investigations were performed according to the protocols at individual centers, and lung function % predicted values were calculated centrally. Skinprick testing results were included for aeroallergens tested at all the centers. Four hundred seventy-nine patients completed a systematic assessment between April 2009 and December 2010, of which 397 (81%) were deemed to have severe asthma. 6 Th ree hundred forty-six (70%) had follow-up data available and were eligible for entry into the study with a median follow-up period of 286 days (interquartile range, days). Lung function, health-care use, medication burden, and QoL at baseline were compared with outcomes at follow-up using prospective data collection. Statistical Analysis Statistical analysis was performed using GraphPad PRISM 5. Baseline visits were compared with follow-up visits using Wilcoxon matched pairs testing. Categorical variables were compared using x 2 analysis or the Fisher exact test as appropriate. Results Baseline demographics are shown in Table 1. Tables 2, 3, and 4 compare baseline and follow-up visits in terms of lung function, health-care use, corticosteroid use, and QoL. Th e study used a minimum follow-up period of 100 days, with a range of 100 to 833 days and a median value of 286 days. Table 5 divides the cohort into tertiles (1 5 shortest and 3 5 longest follow-up period) according to the time between baseline and follow-up. Values are presented as No. (%) or median (interquartile range). Baseline Demographics There was a predominance of women (65.7%) and whites (89.8%) in the study population. A total of 8.7% were current smokers and 24.5% were ex-smokers with a median 14-pack-year (5- to 30.8-pack-year) smoking history. The median BMI was in the obese range (30.8 [ ]), and the age at diagnosis was 16 years (4-33 years), with age at time of assessment of asthma at 46 years (34-55 years). journal.publications.chestnet.org 871

3 TABLE 1 ] Demographic Data Characteristics Participants (n 5 346) No. Female 231 (66.8) 346 White 305 (89.2) 342 Asian 27 (7.9) 328 Age at diagnosis, y 16 (4-33) 321 Age at assessment, y 46 (34-55) 346 BMI 30.8 ( ) 339 Smoking history 328 Current 37 (11.3) Ex 85 (25.9) Pack-y history 13 (5-31) Employment 330 Full-time work 123 (37.3) Not working, asthma cause Not working, other cause 95 (28.8) 83 (25.2) Part-time asthma 13 (3.9) Part-time other 16 (4.8) Medications OCs 143 (41.9) 341 ICs, BDP equivalent, m g 2,000 (1,600-2,000) 326 LABA 328 (97.6) 336 Theophylline 129 (37.8) 341 LTRA 204 (59.1) 345 Data are presented as No. (%) or median (interquartile range). BDP 5 beclometasone dipropionate; IC 5 inhaled corticosteroid; LABA 5 long-acting b -agonist; LTRA 5 leukotriene receptor antagonist; OC 5 oral corticosteroid. Medical History and Atopy A significant additional nonasthma diagnosis was noted in more than one-half of the study population (55.7%), and more than one-half (55%) reported a history of gastroesophageal reflux disease (GERD). A positive family history of asthma was reported in 59% of subjects, and 71.3% were atopic. Health-care Use Fewer subjects reported at least one primary care or ED visit at follow-up compared with at the baseline visit in the previous year (66.4% vs 87.8%, P,.0001), and the number of visits reported in those who attended primary care or visited an ED was lower (one [zero to three] compared with four [two to six], P,.0001). The number of subjects who reported an admission to hospital in the previous year was lower at follow-up compared with at the baseline visit (38% vs 48%, P ), although no significant difference was seen in the number of admissions in those subjects. Lung Function and Blood Tests A small but significant reduction in serum total IgE levels was noted at follow-up compared with at the baseline visit (178 ku/l [ ku/l] vs 230 ku/l [ ku/l], P 5.045). No significant difference was noted in peripheral blood eosinophils or exhaled nitric oxide. Significant increases in prebronchodilator FEV 1 % predicted (75% [58%-89%] vs 71% [51%-88%], P ) and FEV 1 /FVC ratio (70% [61%-77%] vs 66% [55%-75%], P,.0001) were seen at follow-up compared with at baseline. Corticosteroid Use, Steroid-Sparing Agents, and Anti-IgE Therapy Fewer subjects required rescue courses of oral corticosteroids (OCs) at follow-up compared with at baseline (77.4% vs 90.8%, P 5.01). Among those subjects reporting at least one course of OCs, there was a lower median total number of courses at follow-up compared with at baseline (three [one to five] compared with six [three to eight], P,.0001). No significant difference was seen in the proportion of patients requiring maintenance OC therapy (42.6% at follow-up vs 41.2% at baseline), but there was a reduction in the dose of steroids (prednisolone) taken at follow-up compared with at baseline (10 mg [8-20 mg] vs 15 mg [10-20 mg], P 5.003). More subjects were taking a steroid-sparing agent at follow-up compared with at baseline (9.2% vs 5.3%), although this did not reach statistical significance. An increase in the proportion of subjects receiving anti-ige therapy was noted at follow-up (13.6% vs 4.5%, P ). QoL and Asthma Control The Asthma Quality of Life Questionnaire (AQLQ) total score (3.7 [ ] vs 3.0 [ ], P,.0001) and its four subcomponents all revealed clinically significant improved scores at follow-up. Fifty-six subjects (47.5%) exhibited an improvement in the Asthma Control Questionnaire (ACQ) score of 0.5, and the median fell from 3.4 ( ) to 2.8 ( ) ( P 5.001), indicating a clinically significant improvement in asthma control. Discussion The usefulness of a systematic assessment for severe asthma was first evaluated in A study of 42 patients with difficult-to-control asthma (defined as requiring. 10 mg of prednisolone every other day for 3 consecutive mo/y) found that following a series of investigations, 31 were deemed no longer difficult to control Original Research [ 148 # 4 CHEST OCTOBER 2015 ]

4 TABLE 2 ] Comparison of Health-care Use and Lung Function at Baseline and Follow-up Health-care Use/Lung Function Baseline Follow-up Days Between Visits No. P Value Overall 286 ( ) 346 Health-care use ( 1 visit in past year) Primary care or ED, % 201 (87.8) 152 (66.4) 286 ( ) 229,.0001 Hospital admissions, % 131 (48.0) 90 (33.0) 285 ( ) Of those with 1 visit in past year Primary care or ED 4 (2-6) 1 (0-3) 286 ( ),.0001 Hospital admissions 2 (1-3) 2 (1-3) 285 ( ).28 Total IgE, ku/l 230 (58-690) 178 (54-620) 296 ( ) Blood eos count /L 0.3 ( ) 0.27 ( ) 281 ( ) F ENO, ppb 34.5 ( ) 28.5 ( ) 276 ( ) Lung function Pre-BD FEV 1, L 1.92 ( ) 2.03 ( ) 285 ( ) Pre-BD FEV 1 % predicted 71 (51-88) 75 (58-89) 283 ( ) Pre-BD FEV 1 /FVC ratio 66 (55-75) 70 (61-77) 285 ( ) 207,.0001 Post-BD FEV 1, L 1.93 ( ) 2.2 ( ) 266 ( ) Post-BD FEV 1 % 78 (54-89) 79 (57-96) 259 ( ) Data are presented as No. (%) or median (interquartile range). BD 5 bronchodilator; eos 5 eosinophil ; F ENO 5 fraction of exhaled nitric oxide; ppb 5 parts per billion. In addition, it identified two or more contributing factors to the asthma in 80% of subjects. Subsequent studies looking at a systematic assessment have noted similar findings in terms of the benefits in confirming a diagnosis of severe asthma, highlighting comorbidities, and assessing adherence to therapy. Robinson et al 3 found that of 100 patients investigated for severe asthma, 12% had been given a misdiagnosis, whereas Heaney et al 4 found that 53% of their cohort of 73 patients was found not to have treatment-resistant asthma. However, these studies were not designed to look at QoL and were retrospective. The severely asthmatic cohort in this study was predominantly female with a BMI in the obese range. Most were atopic with a strong family history of asthma and more than one-half reported a history of GERD. This compares to other large cohorts of severe asthma such as The Epidemiology and Natural History of Severe Asthma: Outcomes and Treatment Regimes (TENOR), in which the adult mean BMI was 30.4 and 71.2% were female, and Severe Asthma Research Program (SARP), in which 41% of patients with severe asthma had GERD.8,9 The significant reductions in health-care use seen in this cohort are likely to have followed a variety of different interventions following the baseline assessment. They may reflect changes in asthma medications, the identification of asthma triggers, and the tackling of comorbid conditions. Anti-IgE therapy use in severe asthma has been associated with improved QoL and reductions in health-care use, 10,11 a relevant factor in our cohort, in which there was a significant increase in the number of subjects receiving this therapy. An important consideration that may account for these improvements, at least in part, is regression to the mean. A randomized controlled trial would allow for this phenomenon, although given the suggested benefits that a systematic assessment of asthma provides, this is unlikely to be an ethically viable option. The overall corticosteroid burden had decreased at follow-up, with fewer subjects requiring short-burst therapy, and the total number of courses in those requiring steroids was halved at follow-up compared with at baseline. Even though 72 subjects (24.9%) changed their maintenance OCS requirements, the overall net effect was that four more subjects were on maintenance OCS at follow-up than at baseline. Among those requiring daily maintenance OCS, the dose was significantly lower at follow-up, with an average reduction of 5 mg. Further analysis looking at the treatment of comorbidities, weight loss, clinical psychology support, and asthma education at clinic visits would help identify which interventions may be responsible for this trend. journal.publications.chestnet.org 873

5 TABLE 3 ] Comparison of Corticosteroid Use, Steroid-Sparing Medications, and Anti-IgE Therapy at Baseline and Follow-up Therapy Baseline Follow-up Days Between Visits No. P Value Oral corticosteroids 1 course in the past y 217 (90.8) 185 (77.4) 285 ( ) No. courses in past y 6 (3-8) 3 (1-5),.0001 Maintenance oral corticosteroids 119 (41.2) 123 (42.6) 288 ( ) Yes to no 34 of 119 (28.6) No to yes 38 of 170 (22.4) Prednisolone, mg 15 (10-20) 10 (8-20) 306 ( ) Steroid-sparing medications 15 (5.3) 26 (9.2) 291 ( ) Azathioprine 4 4 Methotrexate 8 15 Cyclosporin 2 3 Mycophenolate 0 1 Drug trials Mepolizumab 0 3 Omalizumab 13 (4.5) 39 (13.6) 291 ( ) No to yes 30 Yes to no 4 No change 9 Data are presented as No. (%) or median (interquartile range). More patients were receiving steroid-sparing agents (predominantly methotrexate) at follow-up compared with at the baseline visit. However, the benefit of such changes, in terms of both symptoms and a reduction in steroid burden, remain unclear. 1,2 The AQLQ is an asthma-specific health-related QoL score, comprising 32 items in four domains over a 2-week recall period. A difference of 0.5 is viewed as clinically meaningful. In the cohort, the overall AQLQ score improved by 0.7 with increases of 0.5 in all subdivisions, indicating improved asthma-related QoL. The ACQ incorporates seven items and a 1-week recall time. It assesses the adequacy of asthma control and the change in asthma control over time. A change in score of 0.5 is considered to be clinically important. A change of 0.6 was noted in the cohort, with just under one-half of the subjects exhibiting an improvement of 0.5, indicating improved asthma control. The increases in the QoL scores may reflect a number of different factors. Improved asthma control secondary to therapeutic interventions or changes, the identification and treatment of comorbid conditions, and clinical TABLE 4 ] Comparison of QoL Scores at Baseline and Follow-up Score Baseline Follow-up Days Between Visits No. P Value AQLQ Overall score 3.0 ( ) 3.7 ( ) 294 ( ) 106,.0001 Symptomatic 3 ( ) 3.6 ( ) 293 ( ) 109,.0001 Activity 3.3 ( ) 4 (2.6-5) 295 ( ) 112,.0001 Emotional 3.1 ( ) 3.6 ( ) 294 ( ) 114,.0001 Environmental 3.3 ( ) 4.3 ( ) 295 ( ) 114,.0001 ACQ 3.4 ( ) 2.8 ( ) 292 ( ) Data are presented as median (interquartile range). ACQ 5 Asthma Control Questionnaire; AQLQ 5 Asthma Quality of Life Questionnaire; QoL 5 quality of life. 874 Original Research [ 148 # 4 CHEST OCTOBER 2015 ]

6 TABLE 5 ] Division of the Cohort by Length of Time Between Baseline and Follow-up Visit Questionnaire AQLQ overall score Tertile 1 (241 d [ d]) Tertile 2 (292 d [ d]) Tertile 3 (453 d [ d]) Baseline Follow-up Baseline Follow-up Baseline Follow-up 3.4 ( ) [37] ACQ 3.3 ( ) [41] 3.9 ( ) 2.9 ( ) [36] 2.9 (1.85-4) 3.4 ( ) [33] 3.55 ( ) 3.2 ( ) [37] 2.7 ( ) 3.55 ( ) [44] 4.3 ( ) 2.75 (2.1-4) Data are presented as median (interquartile range) [No.]. Tertile 1 is, 271 d; Tertile 2 is d; Tertile 3 is 337 d. See Table 4 for expansion of abbreviations. psychology input are likely to have played a role in combination. Sweeney et al 12 looked at a cohort of patients with severe asthma also taken from the National Registry for dedicated UK Difficult Asthma Services. Three hundred fifty-nine patients from four centers were analyzed retrospectively at baseline, with a median follow-up of 3.1 years. Similar findings were noted in terms of a reduction in emergency health-care visits, hospital admissions, and courses of rescue oral steroids. In addition, the number of patients receiving maintenance OCs at baseline (42%) was comparable to the number in this study (41.2%). However, at follow-up, there were more patients receiving maintenance steroids in the Sweeney et al 12 cohort (57% vs 42.6%). The proportion of patients whose steroid regimen had been stopped was similar in both cohorts (12%), but more patients had begun a regimen of steroids (22% vs 13%). This difference may reflect the shorter follow-up period or the higher proportion of patients receiving omalizumab in this cohort. Furthermore, this cohort is prospective, whereas Sweeney et al 12 reported on patients who were likely to have been attending difficult asthma services for some time, which may have resulted in an element of selection bias in terms of asthma severity and oral steroid dependence. A systematic assessment of severe asthma provides a valuable database and tool for research, as demonstrated by the National Registry. Anti-IgE therapy and the development of new monoclonal antibodies and other immunologic agents requires phenotyping to establish which patients may benefit. A dedicated severe asthma service helps identify these patients and monitor their response to therapy and fulfils an important economic role, given the high costs of these targeted therapies. Th ere are several limitations to this study, which should be considered when interpreting these results. Although the seven recruiting centers for this study have similar systematic assessment protocols for their patients, their staff meet regularly to discuss their content, and they adopt a multidisciplinary assessment approach, there is currently no standardized approach and there are some differences in their exact setup. Although 346 subjects were recruited to take part in the study, not all patients had comparable data for each variable. The study used available paired data only, and therefore, the total numbers available for analysis were limited for different factors. In addition, data on health-care use relied on patient recall and, therefore, are subject to recall bias. Although this study has noted significant reductions in health-care use, reductions in overall steroid burden, and improved QoL, it does not address the reasons for these improvements. Furthermore, the follow-up visit was not standardized; however, this is typical of data obtained from a clinical registry. This means that the health-care use comparison at baseline and follow-up may include an overlap period and may potentially represent an overestimation of improvement. Conversely, the same logic would suggest that QoL scores may be an underestimation at follow-up. However, analysis of the entire original cohort of 397 patients with severe asthma revealed that the baseline visit had similar scores compared with the subset used for the final matched data analysis, suggesting that this was a representative group. Furthermore, dividing the cohort into tertiles according to the time between baseline and follow-up ( Table 5 ) revealed that QoL score improvements were not significantly different, supporting the overall findings. There also may be a placebo-type effect, whereby the increased interventions in terms of multiple investigations, outpatient clinics, and meetings with different health-care professionals could result in improvements in QoL. However, this does not explain the changes in medications seen in this cohort and the difference in steroid burden. In conclusion, this prospective analysis of the use of systematic assessment for severe asthma has demonstrated, we believe for the first time, benefits in terms of asthma-related QoL and control and a reduction in unscheduled health-care use and medication burden. journal.publications.chestnet.org 875

7 Acknowledgments Author contributions: A. N. M.-G. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. D. G., L. G. H., C. E. Brightling, R. N., A. H. M., R. C., C. E. Bucknall, and A. N. M.-G. contributed to the study planning and conduct; D. G. contributed to the presentation of plans and data to the group; D. G. and A. N. M.-G. contributed to the data abstraction and statistical analysis and the writing of the manuscript; and D. G., L. G. H., C. E. Brightling, R. N., A. H. M., R. C., C. E. Bucknall, and A. N. M.-G. contributed to the manuscript revision and its final approval. Conflict of interest: L. G. H. has received research institutional grant funding from MedImmune, Novartis UK, Genentech, F. Hoffman-La Roche Ltd, AstraZeneca, and GlaxoSmithKline and has taken part on advisory boards and given lectures at meetings supported by GlaxoSmithKline, Merck Sharpe & Dohme Limited, Nycomed, Novartis AG, F. Hoffman-La Roche Ltd, Boehringer- Ingelheim GmbH, Teva Pharmaceuticals Industries Ltd, Chiesi, and AstraZeneca. He has received support funding to attend international respiratory meetings (AstraZeneca, Chiesi, Novartis AG, Boehringer-Ingelheim GmbH, and GlaxoSmithKline) and has taken part in asthma clinical trials (GlaxoSmithKline, Genentech, Synairgen, and F. Hoffman- La Roche Ltd) for which his institution was remunerated. C. E. B. has received consultancy and grant funding from AstraZeneca/ MedImmune, Roche/Genentech, Novartis AG, GlaxoSmithKline, Chiesi, Almirall, and Boehringer-Ingelheim GmbH. In the past 5 years, R. N. has received lecture fees from the following pharmaceutical companies: AstraZeneca, Novartis AG, GlaxoSmithKline, Boston Scientific, and Boehringer-Ingelheim GmbH. He has participated on advisory boards and has received income for this work over 5 years from the following companies: Vectura, Boston Scientific, GlaxoSmithKline, and Novartis AG. A. H. M. has received educational grants, travel sponsorship, and fees for lecturing and sitting in advisory board meetings for GlaxoSmithKline, AstraZeneca, Novartis AG, Boehringer-Ingelheim GmbH, NAPP, F. Hoffman-La Roche Ltd, and others. R. C. has received an unrestricted educational grant from Novartis AG to improve local asthma services and sponsorship to attend conferences from GlaxoSmithKline, Novartis AG, Teva Pharmaceuticals Industries Ltd, and Boehringer-Ingelheim GmbH; has participated in advisory board meeting (Novartis AG); and has taken part in asthma clinical trials (F. Hoffman-La Roche Ltd, GlaxoSmithKline, AstraZeneca, Janssen Pharmaceutica, Novartis AG, and Genentech) for which her institution was remunerated. C. E. B. has received speaker s fees and consultancy fees from Novartis AG, GlaxoSmithKline, and AstraZeneca which go to her research fund (ie, not personal) and financial support to attend international conferences from GlaxoSmithKline and Novartis AG. In the past 12 months, A. N. M.-G. has attended advisory boards for F. Hoffman- La Roche Ltd, Johnson & Johnson, Amgen, and Boehringer-Ingelheim GmbH. He has received lecture fees from Novartis AG, NAPP, GlaxoSmithKline, Boehringer-Ingelheim GmbH, and Chiesi. He has attended international conferences with Boehringer- Ingelheim GmbH and Novartis AG. He is currently participating in clinical studies funded by F. Hoffman-La Roche Ltd, Boehringer-Ingelheim GmbH, and GlaxoSmithKline. None declared (D. G.). References 1. Chung KF, Wenzel SE, Brozek JL, et al. 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