www.brn.cat PERMANYER BRN Rev. 2023;9(2):67-78 www.permanyer.com BRN Reviews REVIEW ARTICLE A New Therapeutic Approach Based on a Reinterpretation of Asthma Control Luís Pérez-de-Llano1#, Luís Manuel Entrenas2#, M. Inés-Carrascosa3, Ignacio Dávila4, Carlos Almonacid5, Beatriz Abascal-Bolado6, Francisco Javier Montoro7, Ana Isabel Sogo8, and Christian Domingo8#* 1Servicio de Neumología, Hospital Universitario de Lucus Augusti, EOXI Lugo, Monforte; 2Unidad de Gestión Clínica de Neumología, Hospital Universitario de Reina Sofía, Córdoba; 3Servicio de Neumología, Hospital de Urduliz, Vizcaya; 4Servicio de Alergología, Hospital Universitario Salamanca, Salamanca; 5Servicio de Neumología, Hospital Universitario Puerta de Hierro Majadahonda; 6Servicio de Neumología, Hospital Universitario Marqués de Valdecilla, Cantabria; 7Servicio de Alergología, Hospital de Llíria, Valencia; 8Servicio de Neumología, Hospital Universitario Parc Taulí, Universitat Autònoma de Barcelona, Barcelona. Spain # These authors contributed equally to this manuscript. ABSTRACT The concept of asthma control is fundamental because it establishes a target for treatment, but despite the diversity of definitions, a high proportion of patients fail to achieve it. In this article, we highlight the shortcomings of the current concept of control by discussing aspects such as the differences between patient- and physician-perceived control and the limitations of the tools used to assess it. We also comment on the drawbacks of the stepwise approach to achieve control recommended by guidelines: the absence of conclusive evi- dence on the exclusive use of as-needed budesonide/formoterol in mild asthma, the lack of consideration of the different pharmacological properties of the currently available inhaled corticosteroids (ICS) and ignoring the existence of different asthma endotypes, some of which are resistant to these drugs. Other aspects, such as adherence to medication, the use of rescue medication, the influence of the inhalation device, the particle size, the pharmacological characteristics, and the lung deposition of ICS, are also mentioned. As an alternative to the guidelines´ recommendations, we propose a more customized approach based on the identification of therapeutic goals and treatable traits. Keywords: Adherence. Asthma control. Inhaled corticosteroid. Inhaler device. Therapeu- tic index. Received: 04-07-2023 *Correspondence to: Accepted: 12-07-2023 Christian Domingo DOI: 10.23866/BRNRev:2023-M0089 E-mail: cdomingo@tauli.cat www.brnreviews.com BRN Rev. 2023;9(2) INTRODUCTION achieved in 40%-60% of cases5-7, a rate that is more consistent with real-world evidence Asthma is one of the most prevalent chronic of excessive use of rescue medication and respiratory diseases worldwide. In 2019, there high symptom burden5. A recent survey14 in were approximately 334 million asthmatics, 10,302 asthma patients from around the world and this number is expected to increase by a showed that while 67% believed their asthma further 100 million by 20251,2. In 2015, asthma to be well-controlled, control was achieved caused around 400,000 deaths1,3 and account- only in 9% of the patients according to GINA’s ed for 1.1% of the global burden of disabili- criteria15, and the Expert Panel Report-3 (EPR-3) ty-adjusted life years (DALYs)1. Current guide- guidelines16. Moreover, ≥ 60% of the patients lines for the clinical management of asthma believe that short-acting β-antagonists (SABA) focus on disease control in two domains: can be used daily as a symptom reliever, a symptom control and assessment of adverse practice not recommended in current guide- outcomes4. lines14. All this shows that most patients un- derestimate their symptomatology and per- Despite the efforts made to improve diagno- ceive their asthma to be under control when sis, pharmacological treatments, non-pharma- in fact, it is not17,18, suggesting a widespread cological approaches, and patient education acceptance of the symptoms of their disease and empowerment, asthma is poorly controlled and the extent to which it limits their every- in 40%-60% of patients5-11. Poor asthma control day life8,10. increases the risk of exacerbations, reduces patient’s quality of life (QoL), has a negative It is difficult for patients to adhere to the pre- impact on work productivity and significant- scribed medication if they do not perceive the ly increases healthcare costs8,12,13. need for treatment. Adherence is only achieved in 50% of patients with chronic disorders, and In this article, we intend to show that short- this percentage could be even lower in those comings in the current concept of control (ac- with respiratory disease19. Importantly, lack cording to Global Initiative for Asthma Man- of adherence to maintenance (anti-inflamma- agement (GINA) - Table 1-)4 lead to ineffective tory) medication results in uncontrolled air- or potentially iatrogenic therapeutic recom- way inflammation and can lead to functional mendations and propose rational alternatives limitations, worsened QoL, and increased use that could avoid these risks. of medical resources20. Good medication adherence has been shown ASTHMA CONTROL FROM in a meta-analysis to have a positive impact THE PATIENTS’ PERSPECTIVE on reducing exacerbations21. Most patients with difficult-to-control asthma are non-ad- A recent study showed that 45%-65% of asth- herent with their asthma medication. Patients ma patients perceived their disease to be com- showing poor adherence to inhaled cortico- pletely controlled or well controlled5, while steroids (ICS) had a lower post-bronchodilator other studies show that asthma control is not forced expiratory volume in one second (FEV1) BARCELONA 68 RESPIRATORY NETWORK Collaborative research L. Pérez-de-Llano et al. A Reinterpretation of Asthma Control T able 1. Level of asthma control A. Asthma symptom control In the past 4 weeks the patient had Well controlled Partially controlled Poorly controlled – Daytime asthma symptoms more than 2/w None of these 1-2 items 3-4 items – Any night waking due to asthma – SABA use for symptoms more than 2/w – Activity limitation due to asthma B. Risk factors for poor asthma control Assess risk factors at diagnosis and periodically, particularly for patients experiencing exacerbations. Measure FEV 1 at start of treatment, after 3–6 months of ICS-containing treatment to record the patient’s personal best lung function, then periodically for ongoing risk assessment. a. Risk factors for exacerbations* Uncontrolled asthma symptoms (Having uncontrolled asthma symptoms is an important risk factor for exacerbations) Medications High SABA use/Inadequate ICS Other medical conditions Obesity, chronic rhinosinusitis, GERD, confirmed food allergy, pregnancy Exposures Smoking, e-cigarettes, allergen exposure if sensitized, air pollution Psychological Major psychological or socioeconomic problems Lung function Major psychological or socioeconomic problems Type 2 inflammatory markers Higher blood eosinophils, elevated FENO (in adults with allergic asthma taking ICS) Exacerbation history Ever intubated or in intensive care unit for asthma, ≥1 severe exacerbation in last 12 months b. Risk factors for developing persistent airflow limitation History Preterm birth, low birth weight and greater infant weight gain, chronic mucus hypersecretion Medications Lack of ICS treatment in patient with history of severe exacerbation Exposures Tobacco smoke, noxious chemicals; occupational or domestic exposures Investigation findings Low initial FEV1, sputum or blood eosinophilia c. Risk factors for medication side-effects Systemic Frequent OCS, long-term, high-dose and/or potent ICS, P450 inhibitors Local High-dose or potent ICS, poor inhaler technique FENO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in one second; GERD: gastroesophageal reflux disease; ICS: inhaled corticosteroid; OCS: oral corticosteroid; SABA: short acting beta agonist; wk: week. *Factors that increase the risk of exacerbations even if the patient has few asthma symptoms. Adapted from Global Initiative for Asthma (GINA)4,16,72. (p=0.049). A poor inhalation technique also af- showed that correct inhalation technique in- fects asthma control22, and studies have shown creased FEV1 from 2.0 to 2.15 l (p < 0.001) and that 66% of patients with asthma misuse the improved the scores obtained in the asthma inhaler23. The Critikal study24 found that 32%- control test (ACT) from 18.0 to 20.75 (p < 0.001). 38% of dry powder inhaler (DPI) users made an insufficient inspiratory effort which was Patients with a poor inhalation technique must associated with poor asthma control and in- switch to another device they can use prop- creased risk of exacerbations. Khurana et al23. erly. DPI are the most widely used devices for BARCELONA RESPIRATORY NETWORK 69 Collaborative research BRN Rev. 2023;9(2) asthma treatment and can be grouped accord- the cost-effectiveness results are conflicting, ing to their intrinsic resistance25. Choosing a and more information is needed for these tools DPI with medium resistance has been associ- to be definitively incorporated into the edu- ated with the highest mean airflow rates, while cational plan of asthma patients36. low rates were achieved with devices with low or high resistance26. ASTHMA CONTROL FROM THE Evidence shows that the selection of an effec- CLINICIANS’ PERSPECTIVE tive inhaler device significantly influences the level of asthma control. Other factors affect- Strategies to achieve control ing device performance are particle size and in the lower steps of asthma lung deposition. Particles should be 1 – 5 μm severity in diameter. Due to the peculiar lung anatomy, larger particles are likely to be deposited in The overuse of rescue inhaler therapy re- the oropharynx space, while very small parti- mains widespread, despite decades of guide- cles will either be deposited in the upper air- lines and initiatives recommending the oppo- way or exhaled27, so ICSs should be formulated site. A survey of the habits of 3415 asthma to optimize lung deposition28. Older inhalers patients showed that 74% used only SABA, presented lung deposition of 10% - 15%29 and despite having been prescribed maintenance new inhalers 40% - 60%30. therapy, and 51% presented poorly controlled asthma, as assessed by the asthma control Simplifying the treatment regimen could pro- questionnaire (ACQ). Moreover, patients clas- mote adherence and improve asthma con- sified as well-controlled presented an average trol31,23. Using an inhaler that is simple to of six exacerbations/year, and the most com- handle and not reliant on the inhalation tech- mon response to symptom worsening is the nique is also helpful33,34, and the type of de- use of SABA8. vice prescribed should be revised in patients with poorly controlled disease, the “one-size-­ Several studies have shown that repeated in- fits-all” notion is no longer applicable, and correct exposure to SABA without ICS is as- the inhaler should be chosen on the basis sociated with adverse effects (AE). For exam- of the patient’s specific characteristics and ple, in a randomized comparison of terbutaline, preferences35. budesonide, combined treatment, and match- ing placebo, Hancox et al.37 observed a tem- The use of mHealth (mobile health, an um- porary increase in morning peak flows and a brella general term for using mobile phones larger-than-expected increase in evening peak and other wireless technology in medical flows in the first two days of treatment with care) offers promising prospects for improv- terbutaline, due to the development of tol- ing the management of asthma patients. Some erance to the bronchodilator effect (of tachy- studies have shown that mHealth can improve phylaxis). Moreover, morning peak flows the quality of life of asthma patients com- decreased following treatment withdrawal, pared to conventional monitoring. However, suggesting bronchoconstriction. These effects BARCELONA 70 RESPIRATORY NETWORK Collaborative research L. Pérez-de-Llano et al. A Reinterpretation of Asthma Control are likely mediated by the downregulation reliever5, which is contrary to the original rec- of the β-receptor during treatment37. Similar- ommendation. ly, in a retrospective chart study, Nwaru et al. 38 found that overuse of SABA (defined as Studies evaluating the efficacy of MART ≥ 2 canisters/year compared to ≤ 2 canisters/ therapy in mild asthma39,40,42,43 have shown year) without ICS was associated with an in- either no reduction39,40 or modest reduction43 creased risk of exacerbation: 3 - 5 canisters in annual exacerbations. In contrast, mainte- hazard ratio (HR): 1.26 (95% CI = 1.24 - 1.28); nance ICS monotherapy measured by ACQ 6 - 10 canisters HR: 1.44 (1.41 - 1.46); and ≥ 11 has demonstrated similar or better asthma con- canisters HR: 1.77 (1.72 - 1.83). Moreover, the trol40,42,43. This comparison should be viewed risk of mortality was also associated with with caution, because asthma severity varied the overuse of SABA compared to ≤ 2 canis- in the foregoing studies. A critical appraisal ters/year; 3 - 5 canisters HR: 1.26 (95% CI = found that only 17.1% of patients receiving 1.14 - 1.39); 6 - 10 canisters 1.67 (1.49 - 1.87); and ICS/FOR are controlled44. In seven trials last- ≥ 11 canisters 2.35 (2.02 - 2.72). Approximately ing between six and twelve months, patients 85% of asthma patients overusing SABA at using this therapeutic approach were awo- baseline had continuous overuse during the ken by asthma symptoms once every sev- study, whereas the proportion of patients not en-ten days (weighted average of 11.5%), taking any ICSs more than doubled by the suffered asthma symptoms more than half end of the study38. As mentioned, SABA use of the days (weighted average of 54.0%), and in these studies does not follow the indication one in five patients had one severe exacer- found in asthma guidelines. bation per year44. The long-term consequenc- es of MART therapy have not been studied, The maintenance and reliever therapy (MART) although in one study, the use of MART for strategy was designed to improve control in over one year was associated with a signif- patients already on maintenance therapy from icant increase in sputum and biopsy eosin- GINA step 3 and beyond and has started to ophilia44. The authors concluded that no recommend using the combination ICS/for- evidence exists that better asthma treatment moterol (FOR) for steps 1 and 24, partly based outcomes can be obtained with the as-need- on Symbicort Given as Needed in Mild Asth- ed use of ICS/LABA therapy compared with ma (SYGMA) studies39,40. This approach relies conventional maintenance ICS/LABA ther- on rapid as-needed adjustments in ICS/long-­ apy. Airway eosinophils are a well-known acting β-antagonist (LABA) when the patient symptom of inflammation in asthmatic pa- would otherwise draw on SABA41. This strat- tients 45. A recent study46 showed that in egy, described and recommended in GINA patients following MART therapy, the geo- and a few more guidelines, merits analysis. metric mean percent sputum eosinophils re- For example, it is interesting to note that mained unchanged (1.6% - 1.9%), whereas 9% - 29% of patients and 24% - 45% of phy- there was an increase in subepithelial eosin- sicians are unaware of this strategy, and ophils in biopsy specimens (6.2 cells/mm2 - among those who prescribed MART, 80% - 95% 12.3 cells/mm2). These same parameters de- prescribed an additional (non-ICS) as-needed creased with high fixed-dose treatment (2.2% BARCELONA RESPIRATORY NETWORK 71 Collaborative research BRN Rev. 2023;9(2) - 1.2%; 7.7 cells/mm2 - 4.8 cells/mm2, respec- The dose escalation strategy recommended in tively), resulting in significant treatment dif- guidelines is based on equivalence/equipo- ferences of 0.7% (ratio, 1.8; 95% CI, 1.2 - 2.8; tency tables52. GINA recently published an p = 0.0038) and 7.5 cells/mm2 (ratio, 2.9; 95% update that is based on a limited number of CI, 1.6 - 5.3; p < 0.001), respectively, which studies and product information4. Tradition- remained within the range associated with ally, however, the potency of topical cortico- stable clinical control. Other parameters, such steroids has been estimated using McKenzie’s as reticular basement membrane thickness, indirect method53, a test based on the skin-­ exhaled nitric oxide, exacerbation frequency, bleaching properties of corticosteroids53 caused or FEV1 remain unaltered46. by vasoconstriction. It should be noted that McKenzie’s study did not consider that the In conclusion, further studies are needed to therapeutical effects of ICS in asthma patients reach appropriate conclusions regarding the are mainly due to their genomic effect on the convenience of therapy in steps 1 and 2 of airway54. This is important, because the step- GINA guidelines as concluded in other recent up approach in asthma management leads to works47. an increase in the ICS dose in patients with poor asthma control4,55 without considering the pharmacological properties of each avail- Problems with the stepwise able alternative. There is a widespread be- strategy lief, possibly promoted by asthma treatment guidelines, that all ICSs have the same phar- The step-up approach recommends increas- macological properties29. These, however, are ing the ICS dose to achieve asthma control in determined by the molecular structure, which patients failing to achieve control at the cur- in turn affects important aspects such as drug rent dose48. However, it has been shown that potency, lipophilicity, and by the pharmaco- 80% - 90% of the maximum benefit is normal- kinetic and pharmacodynamic characteris- ly obtained with low doses of ICS (100 - 200 μg tics, which determine efficacy and systemic of fluticasone propionate or equivalent), and exposure to ICS and cause the main adverse higher doses expose the patient to a signifi- effects. The relationship between these two cantly higher risk of systemic AE with no key factors is clearly expressed by the thera- clear clinical benefit49,50. Similarly, a recent peutic index (TI), insofar as a high TI means meta-analysis comparing low, moderate, and that the desired clinical effect will be achieved high starting doses of ICS in monotherapy or with a low risk of adverse effects. A simple combination with a LABA found that all dos- classification of ICS into low, medium, and es were comparable with respect to night- high doses does not reflect their pharmaco- time rescue medication, symptom burden and logical characteristics, as shown in table 2. FEV1 improvement. The authors concluded that high starting doses of ICS did not confer It is also essential to consider that high ICS significant benefits compared to lower doses doses are associated with a significant risk of and could potentially present more safety systemic AEs50 that include cataracts, bone den- concerns51. sity abnormalities, increased risk of diabetes, BARCELONA 72 RESPIRATORY NETWORK Collaborative research L. Pérez-de-Llano et al. A Reinterpretation of Asthma Control T able 2. Pharmacological properties and therapeutic index of some inhaled corticosteroids ICS/dose form Relative Lipophilicity Plasmatic Bioavailability F Therapeutic glucocorticoid (log P) protein binding (%) index receptor binding (%) affinity Fluticasone furoate DPI 2989 4.17 99.7 15DPI 1oral 18.6 Fluticasone propionate DPI 1775 3.89 99.3 16 DPI 1oral 1.84 Budesonide DPI 935 2.32 91.4 39 DPI 11oral 1.31 DPI: dry powder inhaler; the therapeutic index is calculated as ED50 = dose at which 50% of the maximum effect is achieved/AMP PC20 = provocative concentration of adenosine-5′-monophosphate causing a ≥ 20% decline in forced expiratory volume in one second. Adapted from Daley-Yates et al.29,73. and suppression of the adrenal function56. A Global Initiative for Obstructive Lung Dis- recent systematic review found that the few ease (GOLD)60 suggests that changing the studies that assess the systemic effects of ICSs drug, the device, or both, should be consid- present conflicting findings, multiple biases, ered before stepping up treatment in patients and residual confounding56 A meta-­analysis with poor control. showed that 6.8% of asthma patients on aver- age presented adrenal insufficiency. The risk As discussed above, the effectiveness of chron- of this AE varied according to the dose used: ic disease management is affected by difficul- 1.5% with low-dose ICS (95% CI: 0.2 - 9.4), 5.4% ties in achieving optimal compliance. In the with medium-dose ICS (95% CI: 2.7 - 10.4) and case of asthma, a disease defined by the great 18.5% with high-dose ICS (95% CI: 8.7 - 35.2)57. variability of its clinical expression, patients Another critical issue is that medication is not may choose to match medication to symp- usually stepped down58,59, for example, a study toms. To avoid this, emphasis needs to be found that step-down was only attempted in placed on a good education program7,61. 6% of patients, even though 60% had achieved asthma control59. The inflammatory endotype The stepwise strategy can result in ICS over- is not considered in asthma treatment and iatrogenic side effects. Al- treatment guidelines though, as stated above, ICSs are pharmaco- logically different, guidelines only marginally Therapeutic recommendations found in asthma consider switching between them, proba- guidelines do not consider the inflammatory bly due to the lack of studies evaluating this characteristics of asthma patients (endotypes) possibility4,55. Theoretically, switching the and their clinical manifestations (phenotypes)62. ICS could help to improve asthma control Studies have shown that patients with low by widening the TI, thus favouring lower sputum eosinophils may not respond to glu- doses with higher receptor affinity binding cocorticoids63. Moreover, it has been found and lower systemic exposure29. Although in that a majority (73%) of patients with mild per- another type of obstructive lung disease, the sistent asthma have low sputum eosinophil BARCELONA RESPIRATORY NETWORK 73 Collaborative research BRN Rev. 2023;9(2) T able 3. Therapeutic goals and treatable traits Therapeutic Goals Treatable Traits Biomarkers Associated with Therapeutic Traits Improved symptoms: Bronchial obstruction FEV1 – Dyspnoea – Night awakenings Non-adherence Questionnaires (TAI) – Health-related QoL Aggravating factors (allergens, environmental pollution, etc.) Environmental levels Smoking COHb Comorbidities Patient variability Mucus hypersecretion CT scan Lung hyperinflation Inspiratory capacity Reduced risk of: Eosinophilia Eosinophils in Peripheral blood or airway – Mortality – Disease progression Chronic infection Germ isolation – Exacerbations Adrenal insufficiency Cortisol – Adverse effects of medication Chronic bronchitis Chronic bronchitis Chronic hypoxemia PaO2/SaO2 AT: anti-trypsin; COHb: carboxyhemoglobin; FEV1: forced expiratory volume in one second; Pa: partial pressure; QoL: quality of life; TAI: test of adherence to inhalers. Adapted from Pérez de Llano et al.65. levels and no significant difference in their Shortcomings of tools to estimate response to an ICS (mometasone) or long-act- control ing muscarinic antagonist (tiotropium) com- pared with placebo64. While it would be ideal Guidelines recommend the use of numerical to prescribe treatment according to each pa- questionnaires (Table 4) to assess the level tient’s endotype, we must acknowledge that of control in asthma patients4,55. A moderate the biomarkers available for clinical practice correlation was found between ACT scores still have many limitations. and outcomes such as rescue medication use, exacerbations, sleep quality, and work In an attempt to overcome these drawbacks, and productivity, but a poor correlation be- some authors suggest an asthma manage- tween general health-related QoL, use of ment strategy based on identifying patient-­ healthcare resources, and costs 66. ACQ is specific therapeutic goals (the objectives set significantly associated with asthma-related to improve the clinical condition of the pa- QoL67 but is a poor predictor of lung func- tient) and treatable traits (characteristics that tion and exacerbations68. These tools do not can be targeted by treatment)65. The therapeu- consider the presence of exacerbations in the tic goals, treatable traits, and associated bio- preceding 12 months, which is known to be markers are shown in table 365. an important prognostic factor for future ex- acerbations69. The recently developed Asthma This approach requires further evidence be- Impairment and Risk Questionnaire (AIRQ) fore it can be recommended in guidelines. predicts exacerbation risk over 12 months BARCELONA 74 RESPIRATORY NETWORK Collaborative research L. Pérez-de-Llano et al. A Reinterpretation of Asthma Control T able 4. Asthma control assessment tools #items Age Symptom Reliever Activity Nocturnal Exacerbations Additional frequency use limitation symptoms measures Asthma Control Test (ACT)75 5 >12 Yes Yes Yes Yes No Self-perception of control Childhood ACT (cACT)76 7 4-11 Yes No Yes Yes No Self-perception of control Asthma Control 6 >12 Yes Yes Yes Yes No FEV1 Questionnaire (ACQ)77 Asthma Therapy 4 ≥18 No Yes Yes Yes No Self-perception Assessment of control Questionnaire (ATAQ)78 Lara Asthma Symptom 8 >3 Yes No No Yes Yes Parent perception Scale (LASS)79 of control Asthma Impairment and 10 >12 Yes Yes Yes Yes Yes Self-perception Risk Questionnaire (AIRQ) of control This table displays the questions asked to the patients, the age to which the test has been validated and some clinical specific information. Adapted from Alzahrani and Becker74. and the probability of time to first exacer- be prevented by treatment71. More initiatives bation70. like this one are needed to bridge the gap between current control and future risk. Validated tools are available to assess the de- gree of symptom control in each patient, and others are being developed that estimate the DISCUSSION/CONCLUSIONS risk of exacerbations. However, the concept of “future risk” needs to be defined more rigor- Despite the efforts made over the years to ously. It is not yet possible to clearly identify achieve asthma control, it is still an issue for which patients will develop long-term fixed many patients. Lack of adherence to medica- obstruction and which will develop an exac- tion or treatment guidelines, poor inhalation erbation. The latter has been the most widely technique, and incorrect use of SABA without researched risk to date, but it remains unclear ICS as rescue therapy negatively affect con- to what extent factors such as eosinophilia trol. GINA and a limited number of scientific and high fractional exhaled nitric oxide (FENO) societies presently recommend this strategy has are in themselves predictors of exacerbations; shown little to no improvement in asthma a more precise identification of future risk is control compared to regular ICS/LABA. The needed before it can be translated into specif- step-up approach recommended by asthma ic therapeutic strategies. In this sense, a proto- guidelines does not consider the different type scale (OxfoRd Asthma attaCk risk ScaLE pharmacologic profiles of available ICSs. It is [ORACLE]) based on biomarkers of type 2 also important to bear in mind that not all inflammation has shown feasibility and po- patients will respond to anti-inflammatory tential to predict asthma attacks that might treatment, especially those who do not present BARCELONA RESPIRATORY NETWORK 75 Collaborative research BRN Rev. 2023;9(2) bronchial eosinophilic inflammation. High- Leti, Novartis, Sanofi; for a consultancy from dose ICS increases the risk of iatrogenic injury Allergy Therapeutics, ALK-Abello, AstraZen- and has no clear therapeutic benefit for the pa- eca, GSK, Merck, MSD, Novartis, Sanofi; and tient. Besides, it is still essential to verify treat- grants for Thermofisher Diagnostics. ment adherence and inhalation technique in patients with poor asthma control, and if nec- CA has received payment for lectures, includ- essary, consider switching to a drug with dif- ing service on speaker’s bureaus from Astra- ferent characteristics to achieve control without Zeneca, Chiesi, GSK, Novartis, Boehringer the need for high doses of ICS. The concept of Ingelheim, Sanofi; for a consultancy from control needs to be further defined, and new ALK-Abello, AstraZeneca, GSK, MSD, Novar- tools that estimate future risk would enable cli- tis, Sanofi; and grants from GSK. nicians to make more accurate therapeutic de- cisions. In the meantime, a strategy based on BAB has received payment for lectures, in- identifying therapeutic goals and treatable traits cluding service on speaker’s bureaus from would facilitate a more personalized treatment. AstraZeneca, Chiesi, GSK, Novartis, Faes-Far- ma, Sanofi. CONFLICTS OF INTEREST JM has received payment for lectures, includ- ing service on speaker’s bureaus from Astra- LPLl has received grants, personal fees, and Zeneca, Chiesi, Menarini, Diater, GSK, No- non-financial support from AstraZeneca, Teva, vartis, Faes-Farma, Sanofi, ALK-Abelló and Sanofi; personal fees and non-financial sup- for a consultancy from Sanofi and Chiesi. port from GSK, Novartis, Chiesi, personal fees from MSD, Techdow Pharma, Leo-Phar- AIS has received payment for lectures, in- ma, Gebro, Gilead; grants and non-financial cluding service on speaker’s bureaus from support from Faes Farma. AstraZeneca, ALK-Abelló, Immunotek, Chie- si, Diater, GSK, Faes Farma, Menarini, MSD, LME has received payment for lectures, in- Novartis, Pfizer, Roxall, Sanofi and Teva. cluding service on speaker’s bureaus from AstraZeneca, Böehringer Ingelheim, Chiesi, CD has received payment for lectures and GSK, Faes Farma, Menarini, MSD, Novartis, travel expenses from ALK, Allergy Therapeu- Pfizer, Sanofi and Teva; for a consultancy tics, Almirall, AstraZeneca, Boehringer Ingel- from AstraZeneca, GSK, MSD and Sanofi. heim, Chiesi, Esteve, GSK, HAL Allergy, In- munotek, Menarini, Novartis, Pfizer, Sanofi, IC has received payment for lectures, from Stallergenes Greer, Takeda, Teva GSK, Boehringer Ingelheim, and Chiesi; for a consultancy from Sanofi. AUTHOR CONTRIBUTIONS ID has received payment for lectures, includ- ing service on speaker’s bureaus from Allergy LPLl, LME and CD collaboratively designed Therapeutics, AstraZeneca, Chiesi, Diater, GSK, the conceptual outline of the review and BARCELONA 76 RESPIRATORY NETWORK Collaborative research L. Pérez-de-Llano et al. A Reinterpretation of Asthma Control contributed to all sections. All authors con- 12. Demoly P, Annunziata K, Gubba E, Adamek L. Repeated cross-sectional survey of patient-reported asthma control in Europe in the past 5 years. tributed to the article and approved the sub- Eur Respir Rev. 2012;21:66-74. 13. Demoly P, Gueron B, Annunziata K, Adamek L, Walters RD. Update on mitted version. asthma control in five European countries: results of a 2008 survey. Eur Respir Rev. 2010;19:150-7. 14. Nathan RA, Thompson PJ, Price D et al. 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