Respiratory Therapy Journal Assignment Paper

Respiratory Therapy Journal Assignment Paper

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3.Utilization ( How can you use this info in your practice of Respiratory Therapy)Respiratory Medicine 156 (2019) 1–7 Contents lists available at ScienceDirect Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed Severe asthma: Comparison of different classifications of severity and control T Alexssandra Maia Alvesa,∗, Luane Marques de Mellob, Aline Silva Lima Matosa, Álvaro Augusto Cruza a b ProAR Foundation, Federal University of Bahia, Brazil Ribeirão Preto Medical School, University of São Paulo, Brazil ARTICLE INFO ABSTRACT Keywords: Asthma Therapy Classifications Disease management Background: Criteria of asthma severity and control lack standardization. Objective: to compare classifications of asthma severity and control, applied to patients from a severe asthma clinic. Respiratory Therapy Journal Assignment Paper

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Methods: Cross-sectional study of 473 patients followed up for ≥6 months, reclassified using three criteria: 1) the World Health Organization (WHO) 2010, 2) the American Thoracic Society (ATS) 2000, and 3) the European Respiratory Society (ERS)/ATS 2014. In order to evaluate disease control, the 2012 and 2014 Global Initiative for Asthma (GINA) classifications were compared. Results: According to the definition of WHO 2010, 429 had Difficult-to-treat severe asthma and only 12 presented Treatment-resistant severe asthma. 114 patients had Refractory asthma by ATS 2000 and 88 had Severe asthma by ERS/ATS 2014. Considering the definitions of WHO 2010, only 9 out of 12 with Treatment-resistant and 64 out of 429 with Difficult-to-treat severe asthma met the criteria of ATS 2000 and ERS/ATS 2014. As for GINA classification of control, 208 (44%) of the 473 subjects were classified as having asthma controlled by the 2014 criteria, whereas only 45 (10%) patients had controlled asthma by the GINA 2012 criteria. The Kappa statistic indicates the highest agreement of the severity classification occurred between the criteria of ATS 2000 and ERS/ATS 2014 (0.64). Conclusion: Good agreement was found between Refractory asthma ATS 2000 and Severe asthma ERS/ATS 2014 classifications. However, poor agreement was observed between the severity rating proposed by the WHO and other classifications. The GINA control classifications of 2012 and 2014 also agreed poorly. 1. Introduction minority, this group exhibits high morbidity and is responsible for most of the health expenditures, which are higher than those of other chronic diseases, such as diabetes and nephropathies [3]. The categorization of severity involves understanding the definitions of severity and control. Severity is defined by the intensity of medication required by the patient to maintain adequate control of their symptoms, and control is evaluated by clinical manifestations (symptoms and limitations), which should be minimized with treatment [4]. The definitions of severity and control are essential for case Asthma constitutes a clinical syndrome associated to complex etiopathogenic mechanisms that lead to a variable limitation of expiratory airflow and several clinical symptoms that vary over time in their occurrence, frequency, and intensity [1]. The main treatment option for asthma is inhaled corticosteroids, although approximately 5% of patients do not respond adequately, even at moderate and high doses and in combination with other medications [2], being considered as patients with severe asthma. Despite its Abbreviations: ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; ATS, American Thoracic Society; ERS, European Respiratory Society; FEV1, Forced expiratory volume in 1 s; GERD, Gastroesophageal reflux disease; GA2LEN/ARIA, Global Allergy and Asthma European Network/Allergic Rhinitis and Its Impact on Asthma; GINA, Global Initiative for Asthma; ICS, Inhaled corticosteroids; LABA, Long-acting beta 2-agonist; NIH-NHLBI, National Institute of Health-National Heart, Lung, and Blood Institute; OCS, Oral corticosteroids; PEF, Peak expiratory flow; ProAR, Asthma Control Program of Bahia; SBPT, Brazilian Society of Pneumology and Pthisiology; WHO, World Health Organization ∗ Corresponding author.

Programa de Pós-Graduação em Ciências da Saúde da Universidade Federal da Bahia, Rua Carlos Gomes, 270, Centro de Saúde Carlos Gomes, 7° andar – CEP, 40060-330, Salvador, BA, Brazil. E-mail address: [email protected] (A.M. Alves). https://doi.org/10.1016/j.rmed.2019.07.015 Received 30 October 2018; Received in revised form 27 June 2019; Accepted 13 July 2019 Available online 17 July 2019 0954-6111/ © 2019 Elsevier Ltd. All rights reserved. Respiratory Medicine 156 (2019) 1–7 A.M. Alves, et al. definition in clinical investigation and comparability of results, as well as for the treatment of each individual patient. Several classifications have been proposed over the years, but there is still no uniformity in their application. In 1997, an NIH-NHLBI Panel of Experts [5] defined severe asthma according to frequency of symptoms, symptom intensity, limitations, frequency of exacerbations, and abnormalities in lung function, regardless of prior treatment. The Global Initiative for Asthma (GINA) created by the NIH-NHLBI adopted the same criteria in 2002 [6]. In 2000, the ATS [7] proposed the term “Refractory asthma” for patients with a disruptive disease, reflected by the need for high doses of ICS to maintain adequate control of symptoms, or those with persistent symptoms, exacerbations or airway obstruction, despite high doses of the medication. Such definition utilized major and minor criteria, based on treatment, pulmonary function, and exacerbations. In 2010, a group of experts gathered at the WHO [8] proposed the following severity classification: (i) Untreated severe asthma, when the condition of severity was due to lack of access to treatment; (ii) Difficult-to-treat severe asthma, when factors related to adherence, the inhalation technique, and control of comorbidities were present and interfered in the condition of severity; (iii) Treatment-resistant severe asthma, when the severity condition persists to the exclusion of the factors mentioned above. Finally, in 2014, an ERS and ATS task force proposed a new definition of severe asthma [9], based on the need for higher doses of continuous ICS or OCS to maintain disease control, or when not even high doses of ICS associated with other medications can control the disease (Table 1). Respiratory Therapy Journal Assignment Paper

Since 2006, GINA has introduced the classification of control in its strategy [10]. Up to the 2012 GINA strategy report, asthma control encompassed current symptom control, lung function, and future risks [11]. As of the 2014 GINA Report, the term ‘clinical control’ was replaced by ‘symptom control’ and ‘future risks’ were redefined as ‘risk factors for unfavorable outcomes’, such as exacerbations [12]. Abnormal pulmonary function, which previously pertained to the current control criteria, began to be considered a risk criterion for exacerbation since 2014 (Table 2). International terminology and definitions of severity and control have been modified over time. Thus, their standardization is crucial to facilitate the comparability of different studies and applicability of their results. In this context, the present study aimed to verify the agreement of the categorizations according to the main current international severity classifications proposed by experts gathered at the WHO, ATS, and ERS/ATS, as well as the agreement between the current control criteria (from 2014) and old GINA criteria, in a sample of patients treated at a reference outpatient clinic for severe asthma, created in 2003, when the definitions of severity were different from current criteria. Table 1 Severe asthma criteria according to different organizations. Classification Criteria Refractory Asthma ATSa 2000 [7] Major Characteristics In order to achieve control to a level of mild–moderate persistent asthma: – Treatment with continuous or near continuous (> 50% of year) oral corticosteroids – Requirement for treatment with high-dose inhaled corticosteroids# Minor Characteristics – Requirement for daily treatment with controller medication in addition to inhaled corticosteroids, e.g., long-acting agonist, theophylline or leukotriene antagonist – Asthma symptoms requiring short-acting β-agonist use on a daily or near daily basis Persistent airway obstruction (FEV1 < 80% predicted; diurnal PEF variability > 20%) – One or more urgent care visits for asthma per year – Three or more oral steroid “bursts” per year – Prompt deterioration with < 25% reduction in oral or inhaled corticosteroid dose - Near-fatal asthma event in the past Untreated severe asthma: patients without access to medication. Difficult-to-treat severe asthma: poor control due to factors extrinsic to asthma, such as incorrect inhalation technique and environmental exposure, and comorbidities, including allergic rhinitis*, obesity*, and gastroesophageal reflux disease*. Treatment-resistant severe asthma: classification following exclusion of extrinsic factors that interfere in control (cited above*). May be controlled or not (cortico-resistant). Asthma which requires treatment with guideline suggested medications for GINAd steps 4–5 asthma (high dose ICSe## and LABAf or leukotriene modifier/theophylline) for the previous year or systemic CSg ≥ 50% of the previous year to prevent it from becoming “uncontrolled” or which remains “uncontrolled” despite such therapy Uncontrolled asthma defined as at least one of the following: - Poor symptom control: ACQh consistently > 1.5, ACTi < 20 (or “not well-controlled” by NAEPP/GINAj guidelines) - Frequent severe exacerbations: two or more bursts of systemic CS (> 3 days each) in the previous year – Serious exacerbations: at least one hospitalization, ICUk stay or mechanical ventilation in the previous year – Airflow limitation: after appropriate bronchodilator withhold FEV1 < 80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal) Controlled asthma that worsens on tapering of these high doses of ICS or systemic lCS (or additional biologics) WHOb 2010 [8] Severe Asthma ERS/ATSc 2014 [9] # Dose inhaled corticosteroids (ICS) > 880 mcg de Fluticasone;##Dose > 1000 mcg of Fluticasone (HFA, MDI or DPI) in older than 12 years of age. a American Thoracic Society. b World Health Organization. c European Respiratory Society. d Global Initiative for Asthma. e Inhaled corticosteroids. f Long-acting agonist. g Systemic corticosteroids. h Asthma Control Questionnaire. i Asthma Control Test. j National Asthma Education and Prevention Program. k Intensive Care Unit. l Corticosteroids. 2 Respiratory Medicine 156 (2019) 1–7 A.M. Alves, et al. Table 2 GINA control classifications. Report GINA 2012 [11] GINA 2014 [12] Criteria Utilized Daytime symptoms Reliever need Activity limitation Night waking Lung function (PEF or FEV1a Daytime symptoms Reliever need Activity limitation Night waking Classification Well-controlled Partially controlled Uncontrolled ≤2 week ≤2 week None None Normal ≤2x/week ≤2x/week None None > 2x/week > 2x/week Any Any < 80% > 2x/week > 2x/week Any Any > 2x/week > 2x/week Any Any < 80% > 2x/week > 2x/week Any Any GINA-Global Initiative for Asthma. a The functional parameters used FEV1 < 80%. 2. Methods 2.5. Study procedures 2.1. Study design After the selection, eligible individuals were invited by phone to participate in the study, and a visit to the unit was scheduled. The patients who attended the unit were received by a member of the team and informed about the research details, and those who agreed to participate were invited to sign a Term of Informed Consent. Respiratory Therapy Journal Assignment Paper

A welltrained multidisciplinary team, composed of physicians, nurses, pharmacists, physiotherapists, nutritionists, and psychologists, performed the clinical evaluations and research procedures. The study was conducted in the period between January 2013 and July 2015. The anthropometric measurements were performed with the patient fasted. Individuals with BMI ≥30 kg/m2 (WHO standard [17]) were considered obese. The Skin Prick Test was conducted according to GA2LEN/ARIA guidelines [18] and evaluated hypersensitivity to the following aeroallergens: Dermatophagoides pteronyssinus, Dermatophagoides farinae, Apergillus flavus, Apergillus niger, Aspergillus fumigatus, Alternaria alternata, Cladosporium herbarum, dog epithelium, cat epithelium, Blatella germanica, Periplaneta americana, Paspalum notatum (Bahia grass), Cynodon dactylon (Bermuda grass) (GREER®) and Blomia tropicalis (FDA allergenics). Results were considered positive when papules were ≥3 mm in comparison with the papule of the negative control. Spirometry was carried out by a technician trained and certified by the Brazilian Society of Pneumology and Pthisiology (SBPT), using a Koko® spirometer (PDS Instrumentation Inc., Louisville, CO, USA), following the 1995 American Thoracic Society protocol [19]. The software of the spirometer was updated with Brazilian normality values [20]. The present cross-sectional study was performed by analysis of secondary data from a larger project entitled “Risk factors, biomarkers and endophenotypes of severe asthma.” Some results of this project have already been published, thus contributing to the understanding of the severe asthma phenotypes in our sample [13,14]. 2.2. Study population The study population consisted of adult patients, followed up regularly from 2003 at the outpatient clinic of the Asthma Control Program of Bahia (ProAR), a reference clinic for patients with severe asthma in Salvador, Bahia, Brazil. In order for enrollement to the outpatient clinic, patients were required to meet at least one of the following criteria of severity, in effect at the time, based on the directives of the NIH-NHBLI Guidelines for the Diagnosis and Management of Asthma (1997) [15] and GINA (2002)[16]: daily symptoms; limitation of daily activities (symptoms with minimal efforts); nocturnal symptoms > 2 times a week; use of bronchodilators > 2 times a day; PEF or FEV1 < 60% of the predicted value. This group of patients constitutes the ProAR Severe Asthma Cohort. The sample of the present assessment comprehended all patients of the ProAR Asthma Cohort patients under regular care who fulfilled the inclusion criteria and accepted to participate in the study. 2.3. Asthma diagnosis 2.6. Adherence and inhalation technique At the beginning of the original study, each patient was reassessed by two specialists for validation through a medical record review, when the presence of typical symptoms of asthma and spirometric abnormalities were verified, and at least one spirometry presenting an obstructive ventilatory disorder with significant reversibility (increase ≥ 12% and > 200 mL in FEV1 post-bronchodilator). When divergence in validation occurred, a third expert was consulted. The inhalation technique was checked systematically with each patient using the following devices: pressurized inhaler with and without a spacer, aerolizer, turbuhaler, and diskus. The absence of any of the following steps was considered a serious error: placing the device between the lips, inhaling, holding breath (all devices); actuate (pressurized inhaler); open the compartment and place the capsule inside, press the buttons of the inhaler (aerolizer), rotate the device (turbuhaler). Since most patients used more than one device, the number of evaluations was higher than the sample size. Adherence was assessed subjectively, through self-report, when the patient reported the consumption of at least 70% of the doses in the evaluation week. 2.4. Inclusion and exclusion criteria The inclusion criteria of the present study comprised the following: age ≥18 years, residency in Salvador or Lauro de Freitas – BA, Brazil, validated asthma diagnosis, and follow-up in the program for at least six months. Patients were excluded from the study when they presented conditions that could interfere with result interpretation, such as COPD, extensive tuberculosis sequelae, structural lung abnormalities, and pregnancy. 2.7. Asthma control The Asthma Control Questionnaire (ACQ-6) was used to evaluate the control of the disease [21]. Based on a study by Leite et al. (2008) of validation of the ACQ questionnaire in Brazil, asthma was considered 3 Respiratory Medicine 156 (2019) 1–7 A.M. Alves, et al. controlled in the present study when ACQ-6 ≤ 0.75 and uncontrolled when ACQ-6 ≥ 1.5[22]; intermediate scores indicated partially controlled asthma. The ACQ-6 does not take into account lung function. The 2012 and 2014 GINA control classifications were also considered for comparison. Patients who exhibited control of asthma symptoms on medium or low doses of ICS (< 1000 mcg/day of fluticasone or equivalent) were not included in any classification of severe asthma. The WHO 2010 and ATS 2000 classifications were performed by a physician at the time of clinical evaluation during data collection. ERS/ ATS 2014 classification was carried out through a retrospective analysis of the database since it did not exist when the study began. 2.8. Sociodemographic and clinical variables The patients were also assessed regarding sex, age (in years), selfreported skin color, age of symptom onset (before age 18), symptoms of chronic rhinitis, symptoms of gastroesophageal reflux disease, treatment, and history of current or past smoking. Low schooling was considered when the patient was illiterate or had only elementary education. 2.9.5. Statistical analysis The Statistical Package for the Social Sciences software for Windows version 20.0 (SPSS Inc., Chicago, IL, USA) was used in the present study, and the variables were described using the median and interquartile interval. The agreement analysis was performed by calculating the Kappa Index, and interpretation of the results was based on the classification proposed by Landis and Koch [23] (< 0.00 = poor; 0.00–0.20 = discrete; 0.21–0.40 = acceptable; 0.41–0.60 = moderate; 0.61–0.80 = substantial; 0.81–1.00 = almost perfect). The data are presented in a logical diagram (Venn Diagram), with the purpose of graphically representing the divergences and overlaps of the distinct categories of the analyzed sample, obtained from the different classifications utilized. 2.9. Definitions 2.9.1. Difficult-to-treat severe asthma WHO 2010 Based on the definition used in the document submitted to WHO [8], the individual was classified as a Difficult-to-treat severe asthma WHO 2010 patient when presenting partially or poorly controlled symptoms (according to GINA 2012 control classification) [11] and/ or ≥ 2 exacerbations per year, associated with any of the following factors: use of ICS subdoses (< 1000mcg/day of fluticasone or equivalent); inappropriate use of inhaler; low adherence to treatment; significant environmental exposure, and inadequate control of comorbidities that hindered asthma control. Environmental exposure was considered when the patient reported frequent contact with mold, dust, smoke, or domestic animals to which he/she had allergies. 2.9.6. Ethics This study was approved by the National Commission of Ethics in Human Beings (CONEP), protocol No. 450/10. 3. Results The application of the different definitions to the data obtained from the 473 analyzed patients showed that the category represented by the majority of the patients was Difficult-to-treat severe asthma (WHO 2010) [429 (90%)], followed by Refractory asthma (ATS-2000) [114 (24%)], Severe asthma (ERS/ATS 2014) [88 (18%)], and Treatmentresistant severe asthma (WHO 2010) [12 (2,5%)]. Thirty-two patients were not fit to any classification since their asthma was controlled with medium or low doses of ICS at the time of the study. A predominance of the female sex was observed in all groups, although the Treatment-resistant severe asthma (WHO 2010) group presented a lower proportion of females (66%) than the other categories [Difficult-to-treat severe asthma WHO 2010 (80%), Refractory asthma ATS 2010 (85%), and Severe asthma ERS/ATS 2014 (87%)]. Table 3 depicts the general characteristics of the study groups. The median age in the Difficult-to-treat severe asthma WHO 2010 group was slightly lower [52 years (IQ 43–61)] when compared to the other groups: Treatment-resistant severe asthma WHO 2010 [54 years (IQ 46–68)], Refractory asthma ATS 2000, 53 years (IQ 45–61), and Severe asthma ERS/ATS 2014, 53 years (IQ 45–62). Most of the patients began observing symptoms before age 18 [Difficult-to-treat severe asthma WHO-2010 (62%), Refractory asthma (59%), and Severe asthma ERS/ATS-2014 (55%)], except for the Treatment-resistant severe asthma WHO-2010 group (41%). The majority of the patients also presented positive skin tests for aeroallergens [difficult-to-treat severe asthma WHO-2010, severe asthma ERS/ATS2014 (59%), and refractory asthma (54%)]. However, in the treatmentresistant severe asthma group WHO-2010, such proportion was 50%. Only five patients reported current smoking 5 (1%), with equal proportions in both the difficult-to-treat severe asthma WHO-2010 and refractory asthma ATS 2000 groups.

The self-reported adherence rate was significantly high in all groups: difficult-to-treat severe asthma WHO-2010 (79%), refractory asthma (88%), and severe asthma ERS/ ATS-2014 (77%). Moreover, of the 977 evaluations of inhalation technique performed using different devices, only 6 (0.6%) assessments presented serious errors due to compromised inhalation technique. 2.9.2. Treatment-resistant severe asthma WHO 2010 Considering the definition used in the document proposed to WHO [8], Treatment-resistant severe asthma WHO 2010 was considered when the patient was using a high dose of ICS (≥1000 mcg/day of fluticasone or equivalent), with partially/poorly controlled symptoms and/or ≥ 2 exacerbations/year and appropriate inhaler use, good adhesion, without a relevant environmental exposure, and adequate control of comorbidities. Controlled patients requiring high doses of ICS (≥1000 mcg/day of fluticasone or equivalent) were also considered as Treatment-resistant severe asthma patients, according to WHO 2010. 2.9.3. Refractory asthma ATS 2000 Based on the ATS 2000 [7] proposals, Refractory asthma was identified when the patient presented one or two major criteria and two minor criteria, of those cited below: Major criteria: treatment with high doses of ICS (≥1000 mcg/day of fluticasone or equivalent) or continuous use of OCS or use of OCS for periods > 50% of the year prior to the evaluation. Minor criteria: associated daily use of LABA, theophylline or antileukotriene (in addition to ICS); daily asthma symptoms requiring immediate relief medication; persistent bronchial obstruction (FEV1 < 80% or PEF variation > 20%); one or more visits to the emergency room per year; ≥ 3 courses of OCS/year; rapid deterioration with ≤25% reduction in ICS or OCS dosage; near-fatal asthma in the past. 2.9.4.

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Severe asthma ERS/ATS 2014 According to the document presented by the ERS/ATS task force [9], Severe asthma ERS/ATS-2014 was considered when the patient used a high doses of ICS (≥1000 mcg/day fluticasone or equivalent) associated with another controller (long-acting bronchodilator, antileukotriene or theophylline) and/or OCS for periods ≥ 50% of the year prior to evaluation. 4 Respiratory Medicine 156 (2019) 1–7 A.M. Alves, et al. Table 3 Sociodemographic and clinical characteristics of the patients (n = 473). Characteristics Difficult-to-treat severe asthma WHO 2010a Treatment-resistant severe asthma WHO 2010a Refractory asthma ATS 2000 Severe Asthma ERS/ ATS2014 Frequency n (%) Female sex n (%) Age, years M (IQ 25–75) Mixed ethnicity n (%) Black n (%) Other ethnicities n (%) Low schooling n (%) Asthma beginning before 18 years n (%) Adherence by self-report n (%) Positive skin prick test for aeroallergens n (%) Smokers n (%) Ex-smokers n (%) Chronic rhinitis n (%) Symptoms suggestive of GERD n (%) Obesity n (%) FEV1 post-BD (L) M (IQ) ACQ-6 M (IQ) 429 (90) 344 (80) 52 (43–61) 214 (49) 180 (41) 35 (8) 103 (24) 270 (62) 342 (79) 258 (59) 12 (2.5) 8 (66) 54 (46–68) 9 (75) 1 (8.3) 2 (16) 3 (25) 5 (41) 12 (100) 6 (50) 114 (24) 97 (85) 53 (45–61) 57 (50) 41 (36) 16 (14) 28 (24) 68 (59) 101(88) 62 (54) 88 (18) 77(87) 53 (45–62) 40 (45) 33 (37) 4 (4) 25(28) 49 (55) 68 (77) 52 (59) 5 (1) 121 (28) 406 (85) 304 (70) 179 (42) 67 (57–78) 1 (0.5–1.8) 0 (0) 4 (33) 0 (0) 0 (0) 0 (0) 69 (58–84) 1.2 (0.4–1.7) 5 (1) 30 (26) 110 (95) 96 (84) 59 (52) 66 (57–79) 1.6 (1–2.5) 0 22 (25) 85 (96) 73 (82) 43 (48) 67 (55–80) 1.5 (0.8–2.3) a 32 patients did not fulfill the WHO classification since their asthma was well controlled with low doses of inhaled corticosteroids; ATS-American Thoracic Society; ERS-European Respiratory Society; WHO-World Health Organization; GINA-Global Initiative for Asthma; ACQ-Asthma Control Questionnaire; FEV1-Forced Expiratory Volume in 1 s; LABA-long-acting beta2-agonist; SABA-Short-acting beta2-agonist. 2000, 0.13, indicating poor agreement. According to the Kappa coefficient, the agreement between refractory asthma ATS 2000 and ERS/ ATS 2004 was of 0.64, considered strong. Among the GINA 2014 and GINA 2012 control classifications, the Kappa value was 0.30, suggesting reasonable agreement (Table 4). The primary comorbidities reported in all categories were symptoms of chronic rhinitis (85%), GERD (70%), and obesity (42%). The proportion of patients with chronic rhinitis, GERD, and obesity were 85%, 70%, and 42%, respectively, in patients with difficult-to-treat severe asthma WHO-2010, 95%, 84%, and 52% in the group with refractory asthma ATS-2000, and 96%, 82%, and 48% in the group with severe asthma ERS/ATS-2014. The median ACQ-6 was lowest in the difficult-to-treat severe asthma WHO 2010 [1.0 (0.5–5.8)] category. In all groups, the most commonly used drugs were budesonide + formoterol, beclomethasone, and fluticasone + salmeterol. Among the patients with difficult-to-treat severe asthma WHO 2010, the frequency distribution of medication was 77%, 40%, and 18%; treatment-resistant severe asthma OMS 2010 83%, 41%, and 8%; Refractory asthma 78%, 39%, and 14%, and severe asthma ERS/ATS2014 76%, 42%, and 17%, respectively. When analyzing the agreement between classifications by applying the Logical Venn Diagram, a partial overlap of categories was observed. Nine (2%) patients were simultaneously categorized as treatment-resistant severe asthma – WHO 2010, refractory asthma-ATS 2000, and severe asthma-ERS/ATS 2014. Meanwhile, sixty-four (13%) patients were also concurrently classified as difficult-to-treat severe asthma WHO 2010, refractory asthma-ATS 2000, and severe asthma-ERS/ATS 2014 (Fig. 1). When the data were analyzed according to the control classification using GINA 2014 criteria, the proportion of controlled, partially controlled, and uncontrolled asthma patients was 208 (44%), 171 (36%), and 94 (20%) respectively. In turn, when applying GINA 2012 criteria, the proportion of controlled, partially controlled, and uncontrolled patients was 46 (10%), 267 (57%), and 157 (33%), respectively. When considering the ACQ-6 instrument, 191 (40%) patients were classified as controlled asthma and 173 (36%) as uncontrolled asthma (Graph 1). In order to outline the agreement between the classifications, the Kappa coefficient was determined. When calculating the coefficient of agreement between difficult-to-treat severe asthma WHO 2010 and severe asthma-ERS/ATS 2014, a value of −0.21 was obtained, and between difficult-to-treat severe asthma WHO 2010 and refractory asthma ATS 2000, -0.02, suggesting disagreement (negative values). Regarding treatment-resistant severe asthma WHO 2010 and severe asthma ERS/ATS 2014, the value found was 0.16, and between treatment-resistant severe asthma WHO 2010 and refractory asthma-ATS 4. Respiratory Therapy Journal Assignment Paper

Discussion In the present study, the majority of patients were classified as having difficult-to-treat severe asthma, according to WHO 2010 criteria. Such result is explained by the high frequency of comorbidities and individuals classified as partially controlled/uncontrolled asthma patients. It is noteworthy that the definition of control utilized to compose this variable was based on the GINA 2012, in effect at the beginning of the original study, which included pulmonary function abnormalities as one of the criteria for poor control. Andrade et al. [24] studied children and adolescents with severe uncontrolled asthma also based on the WHO classification, in a Brazilian reference center. Contrarily to the present findings, the authors reported a higher frequency of patients with treatment-resistant severe asthma (55.6%) when compared to difficult-to-treat severe asthma (44.4%). Meanwhile, in a study conducted in Denmark, Bullow et al. [25] found 56% of patients classified as difficult-to-treat asthma (due to sub-optimal adherence or poor inhaler technique) and 12% as severe asthma by the ERS/ATS-2014 in a total of 117 patients with difficult-tocontrol asthma, from a sample of 1034 asthma patients treated at a specialized outpatient clinic. In another study carried out in Sweden, Backman et al. [26], while evaluating a cohort of patients with asthma, observed a prevalence of severe asthma, according to three definitions: 3.6% (US SARP), 4.8% (ERS/ATS 2014), and 6.1% (GINA) among subjects with current asthma. The frequency of severe asthma by the ERS/ATS-2014 in this study was higher than the others cited, probably since the present sample came from an outpatient clinic for patients with severe asthma, according to previous definitions. In order to be admitted in the ProAR, such patients are required to meet the severity criteria in effect at the time of program initiation (NIH-NHBLI Guidelines for the Diagnosis and Management of Asthma (1997) [5] and GINA (2002) [6]. The data obtained herein showed a predominance of women, a fact that has also been observed in several other studies [27,28] and which is based on discussions regarding a possible influence of sex hormones 5 Respiratory Medicine 156 (2019) 1–7 A.M. Alves, et al. Diagram. 1. Distribution of patients according to severity ratings n = 473. Thirty patients did not meet any classification since their symptoms were controlled using low doses of ICS. of continuing education in health and multiprofessional care, factors which explain the atypical results. The observed adhesion rate was higher than that found in the literature, ranging from 22 to 63% [35] in patients with asthma in general and 50% [36] in those with severe asthma. Santos et al., in an earlier study with severe asthma patients followed up at the ProAR outpatient clinic using objective methods [37], found a similar adherence rate to that observed in the present study, of around 80%. The high frequency of comorbidities such as rhinitis, GERD, and obesity has been reported in other studies involving patients with severe asthma [27,28,38,39]. The agreement of the WHO classification and other classifications was low, as observed both in the Logic Venn Diagram (Fig. 1) and by the Kappa coefficient (Table 4). One of the reasons for such observation may have been an excessive rigor in not classifying any patient with obesity, GERD, rhinosinusitis, environmental exposures or psycho-social problems, as having Treatment-resistant severe asthma (WHO 2010). The best agreement was found between the ATS 2000 and ERS/ ATS 2014 classifications, as verified by the Venn diagram and the Kappa coefficient. Despite some similarities, the doses of ICS considered high differ between the two definitions enough to justify the differences in the number of patients included in the two categories.In spite of the acceptable agreement according to Kappa statistics, there was a significant difference in the proportion of patients with the change in GINA control classification. The classification used in the 2014 report (which remains to the present day) resulted in a higher proportion of controlled patients, while the 2012 classification indicated in a higher proportion of uncontrolled patients. We also observed that the proportion of patients whose asthma was classified as controlled by the ACQ-6 approached that of patients with controlled asthma according to Graph. 1. Patient distribution according to the control classification. GINAGlobal Initiative for Asthma; ACQ-6-Asthma Control Questionnaire. on asthma, although the pathophysiological explanation is not yet well defined [29,30]. The majority of patients presented a history of earlyonset asthma and atopy profile, a phenotype already well described in the literature [31]. The proportion of current self-reported smokers was low. In Brazil, the prevalence of smokers in the general population is reduced, approximately 10%, much lower than the global prevalence [32], which is around 20%. A Brazilian study [33], previously performed among asthma patients, revealed a lower prevalence, of around 3%, despite the possibility of some omission in the patients’ reports [34]. The present study also showed a satisfactory rate of adherence to asthma treatment and a low proportion of serious errors in the use of inhalation devices, which can compromise the inhalation technique. In ProAR, patients receive free asthma medication, provided by the country’s Sistema Único de Saúde (SUS), and are submitted to a process Table 4 Agreement of classifications by Kappa analysis. Difficult-to-treat severe asthma WHO 2010 Treatment-resistant severe asthma WHO-2010 Refractory asthma ATS-2000 GINA 2014** Severe asthma ERS/ ATS 2014 Refractory asthma ATS 2000 Treatment- resistant severe asthma WHO 2010 Difficult-to- treat severe asthma WHO 2010 GINA 2012** −0.21* −0.02* NA NA NA 0.16* 0.13* NA NA NA 0.64* NA 0.13* −0.02* NA NA NA NA NA 0.30* WHO- World Health Organization; ERS-European Respiratory Society; ATS-American Thoracic Society; GINA-Global Initiative for Asthma; *p < 0.01 **Control classification; NA-No applicable. 6 Respiratory Medicine 156 (2019) 1–7 A.M. Alves, et al. GINA 2012, and the proportion of patients with uncontrolled asthma by the ACQ-6 was close to that of patients with uncontrolled asthma according to GINA 2014 (Graph 1). Thus, the questionnaire can be considered as a suitable tool for assessing control since it agrees with GINA definitions. The most favorable aspects of the present report are related to the extended follow-up of the cohort of patients with more severe forms of asthma, allowing a detailed cross-sectional study (nested in the cohort) to obtain previous detailed information relevant to a large sample of patients with severe asthma. Its main limitations are associated with the lack of an objective method of measuring adherence to treatment in the real-life environment and the variability of treatment due to the need to adapt to free or cheaper drugs. Respiratory Therapy Journal Assignment Paper

The change in GINA control classification may greatly interfere with patient management and even clinical trial results since the level of control constitutes a major indicator for stepwise management of asthma and eligibility criteria for clinical trials. Many studies have revealed a high proportion of uncontrolled patients in Brazil [40] and other countries [41] when using the old classification. In conclusion, the agreement between the refractory asthma ATS2000 and severe asthma ERS/ATS-2014 classifications was good, although poor between the WHO severity rating and other definitions, as well as between the 2012 and 2014 GINA control classifications. These results deserve attention, given they highlight the discrepancy of subsamples selected based on diverse severity criteria and reinforce the need to adopt a uniform classification. Moreover, the lack of standardization may compromise the comparability and external validity of clinical trials. 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