Journal of Asthma ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ijas20 Consensus on mild asthma management: results of a modified Delphi study Christian Domingo, Gabriel Garcia, Bilun Gemicioglu, Giap Vu Van, Désirée Larenas-Linnemann, Hugo Neffen, Orapan Poachanukoon, Hironori Sagara, Norbert Berend, Emilio Pizzichini, Elvis Irusen, Bhumika Aggarwal, Volkan Eken & Gur Levy To cite this article: Christian Domingo, Gabriel Garcia, Bilun Gemicioglu, Giap Vu Van, Désirée Larenas-Linnemann, Hugo Neffen, Orapan Poachanukoon, Hironori Sagara, Norbert Berend, Emilio Pizzichini, Elvis Irusen, Bhumika Aggarwal, Volkan Eken & Gur Levy (2023) Consensus on mild asthma management: results of a modified Delphi study, Journal of Asthma, 60:1, 145-157, DOI: 10.1080/02770903.2022.2034850 To link to this article: https://doi.org/10.1080/02770903.2022.2034850 © 2022 GlaxoSmithKline. Published with View supplementary material license by Taylor & Francis Group, LLC. Published online: 21 Feb 2022. Submit your article to this journal View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ijas20 Journal of Asthma 2023, VOL. 60, NO. 1, 145–157 https://doi.org/10.1080/02770903.2022.2034850 Consensus on mild asthma management: results of a modified Delphi study Christian Domingo, MD, PhDa, Gabriel Garcia, MDb, Bilun Gemicioglu, MD, PhDc , Giap Vu Van, MD, PhDd, Désirée Larenas-Linnemann, MDe , Hugo Neffen, MD f, Orapan Poachanukoon, MD, PhDg, Hironori Sagara, MD, PhDh, Norbert Berend, Mbbs, MDi, Emilio Pizzichini, MD, PhDi, Elvis Irusen, MD, PhDj, Bhumika Aggarwal, MBBSk , Volkan Eken, MDl and Gur Levy, MDm a Pneumology Service, Corporació Parc Taulí, Sabadell, Spain; bServicio de Neumonología, Hospital Rossi La Plata, La Plata, Argentina; c Department of Pulmonary Diseases, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey; dRespiratory Center, Bach Mai Hospital, Hanoi, Vietnam; eMedica Sur, Clinical Foundation and Hospital, Mexico City, Mexico; fCentro de Alergia e Inmunología-Santa Fe, Santa Fe, Argentina; gCenter of Excellence for Allergy, Asthma and Pulmonary Diseases, Thammasat University Hospital, Pathum Thani, Thailand; hDivision of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; iRespiratory Franchise, GlaxoSmithKline, Middlesex, London, United Kingdom; jGlaxoSmithKline, Cape Town, South Africa; kRespiratory, Global Classic & Established Products, GlaxoSmithKline, Singapore, Singapore; lMedical Department, GlaxoSmithKline, Istanbul, Turkey; mRespiratory Medical Emerging Markets, GlaxoSmithKline, Panama City, Panama ABSTRACT ARTICLE HISTORY Objective: In order to understand the role of regular controller inhaled corticosteroids (ICS) Received 29 October 2021 versus as-needed ICS-formoterol in managing mild asthma, we performed a modified Delphi Revised 20 January 2022 procedure. Accepted 23 January 2022 Methods: Opinions from 16 respiratory experts to three surveys and during a virtual scientific workshop helped to develop final consensus statements (pre-defined as 70% agreement). KEYWORDS Results: Thirteen participants completed all rounds (response rate 81%). At the end of the Delphi procedure; inhaled procedure, there was final consensus on: regular daily ICS being the recommended treatment corticosteroids; ICS; approach in mild persistent asthma, with better symptom control and robust long-term ICS-formoterol; mild asthma clinical data compared with as-needed ICS-formoterol (85%); to avoid noncompliance, frequently seen in mild asthma patients, regular ICS dosing should be accompanied by ongoing education on treatment adherence (100%); treatment aims should be targeting asthma control (92%) and reduction of exacerbation risk (85%). No consensus was reached on whether GINA or national guidelines most influence prescribing decisions. Conclusions: It is important to encourage patients to be adherent and to target both asthma control and exacerbation risk reduction. There is robust clinical evidence to support proactive regular dosing with ICS controller therapy plus as-needed short-acting beta-agonists for the management of patients with mild asthma. Abbreviations. ACQ-5: Asthma Control Questionnaire-5; BHBIA: British Healthcare Business Intelligence Association; CME: continuing medical education; EphMRA: European Pharmaceutical Market Research Association; FeNO: fractional exhaled nitric oxide; GDPR: General Data Protection Regulation; GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; SABA: short-acting beta-agonist Introduction activity limitations or more recently on the intensity of treatment required to control symptoms and prevent Asthma is a heterogenous, chronic, respiratory disease characterized by airway inflammation, a history of future risks (4,5). The definition of mild asthma is respiratory symptoms and variable airway obstruction still debated and in need of further clarification (1,6). (1). Although the majority of patients with asthma It is well recognized that airway inflammation is pres- (50–75%) are reported to have mild asthma (2,3), there ent in mild asthma and patients with mild asthma have been multiple definitions of mild asthma in the often have suboptimal asthma control, putting them past based either on symptoms, airflow limitation and at risk of disease progression, severe exacerbations and CONTACT Christian Domingo cdomingo@tauli.cat Pneumology Service, Corporació Sanitària Parc Taulí, Parc Taulí s/n, 08208, Sabadell (Barcelona), Spain. Supplemental data for this article can be accessed at publisher’s website. © 2022 GlaxoSmithKline. Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unre- stricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 146 C. DOMINGO ET AL. an impaired quality of life (2–5,7–9). A recent large and treating mild asthma, focusing on the role of reg- US database study reported that 19.8% of patients with ular controller ICS in managing mild asthma as well mild asthma (defined as Global Initiative for Asthma as in the use of GINA and other national guidelines. (GINA) treatment step 2) had uncontrolled asthma (10). Inhaled corticosteroids (ICS) are the cornerstone Methods of treatment across all severities of asthma (1,11,12), and early intervention with regular ICS treatment Study design shows benefits in term of achieving asthma control, This study used a modified Delphi technique to develop and in reducing the risk of asthma-related exacerba- consensus-based statements on factors determining the tions, hospitalizations and death (1,13,14). However, management of patients with mild asthma. The Delphi adherence with asthma medications in the community procedure is a facilitated group technique that uses is poor (1), and patients with mild asthma are par- structured questionnaires, usually delivered via mail or ticularly at risk of poor adherence (15). Another chal- email, to reach a consensus on a specific topic among lenge in treating patients with mild asthma is that a panel of selected experts (27–29). The technique uses patients frequently do not report their symptoms (16), anonymity, controlled feedback and group responses to or have poor perception of their airways obstruction, reach consensus. In this study, in addition to the struc- which may result in under treatment with appropriate tured, anonymous, Delphi questionnaires, an on-line, ICS or ICS/long-acting beta-agonist regular controller virtual scientific workshop was conducted which medication and an increased risk of exacerbation (17). involved open discussion between the participants and The GINA report recommends two treatment hence we employed a ‘modified’ Delphi method. tracks for mild asthma, low dose as-needed The Delphi survey was run by an independent spe- ICS-formoterol (preferred option) or regular low cialist market research team at Ashfield MedComms, dose ICS plus as-needed short-acting beta-agonist part of Ashfield Health (Macclesfield, United Kingdom). (SABA) (1). The 1-year, randomized, double-blind, Following a literature search, the research team prepared double-dummy, studies in adults evaluating the the survey questionnaire, hosted the online surveys as-needed ICS-formoterol treatment strategy demon- using Decipher software, and analyzed data generated strated that treatment with as-needed ICS-formoterol in each survey. The research was designed in compli- resulted in similar annual severe exacerbation rates ance with UK General Data Protection Regulation but worse asthma symptom control (between treat- (GDPR) and with the British Healthcare Business ment difference in mean change from baseline: Intelligence Association’s (BHBIA) Legal & Ethical Asthma Control Questionnaire-5 (ACQ-5): 0.11– Guidelines, along with the European Pharmaceutical 0.15) and lower change from baseline in Market Research Association’s (EphMRA). No formal pre-bronchodilator forced expiratory volume in 1 s ethical approval was required as this non-interventional (FEV 1) (between treatment difference: 33–54 ml) physician survey fell outside the remit of the Research compared with regular maintenance daily ICS and Government Framework. All participants provided their as-needed SABA (18–20). Subsequently, in two informed consent for each survey and any information 1-year, randomized, open label, controlled trials, provided was kept confidential and anonymous. one showed better symptom control and one showed similar symptom control with regular maintenance Participants treatment compared with as-needed ICS/formoterol, whilst both showed less severe exacerbations in the Twenty respiratory experts were invited to participate ICS-formoterol group as compared to daily ICS and in all rounds of the process. Respiratory physicians as-needed SABA (20–22). However, around the with expertise and experience in managing patients world, there is not full agreement among several with asthma were invited to participate, representing recommendations for the management of mild 10 countries (Argentina, Indonesia, Japan, Mexico, asthma with some recommending regular daily low Malaysia, Philippines, Spain, Thailand, Turkey, and dose ICS and as-needed SABA (11,23), and others Vietnam). Participants were selected due to their recommending as-needed ICS-formoterol as an knowledge of asthma and having an interest in improv- alternative to regular ICS (24–26). ing patient outcomes, for having experience as an inves- In view of these recommendations, we undertook a tigator in asthma studies or being a member of modified Delphi procedure, incorporating three rounds international and/or national guideline committees, and, of surveys and a scientific workshop, with the aims of in some cases, due to their own country having national understanding asthma specialists’ goals in managing asthma guidelines in place. Journal of Asthma 147 The industry sponsors organized and facilitated the Delphi surveys and scientific workshop scientific workshop but did not complete any of the Participants were emailed the first Delphi survey Delphi surveys. which was completed prior to the scientific work- shop. The survey consisted of 11 questions (7 close-ended questions and 4 open-ended questions). Stages of the Delphi procedure The objectives of this survey were to: (a) under- stand prescribers’ preferences for the treatment and The Delphi procedure comprised three stages: (1) management of patients with mild asthma; (b) development of research questions; (2) Delphi surveys explore the advantages and disadvantages of pre- and scientific workshop; and (3) development of final scribing daily ICS treatment vs. as-needed post-survey consensus statements (Figure 1). ICS-formoterol treatment to patients with mild asthma; and (c) to understand how guidelines and Survey questionnaire development other factors impact the prescribing choices of A review of the literature on management of mild healthcare professionals. asthma in adults, including treatment and manage- Participants in the round 1 Delphi survey were ment guidelines was used to develop the first survey invited to participate in an on-line, virtual scientific questionnaire. Subsequent questionnaires were devel- workshop to discuss the scientific and clinical data oped based on participant group responses. for regular ICS dosing versus as-needed ICS/ Figure 1. Research procedure. 148 C. DOMINGO ET AL. formoterol as well as GINA and national guidelines Results with respect to management of mild asthma. Participants Following the scientific workshop, participants were emailed the second Delphi survey which consisted of Twenty respiratory experts were invited to participate 10 close-ended questions with space for open com- and 16 accepted, completed the first Delphi survey and ment following 1 question. The objective of the attended the scientific workshop (response rate of 80%) post-workshop survey was to assess level of consensus (Figure 1). Of the 16 who accepted the initial invita- on key topics following survey 1 results and workshop tion, 15 completed the post-workshop Delphi survey discussions, specifically, (a) the clinical evidence on 2 (response rate 94%) and 13 completed Delphi survey the different treatment regimens for controlling mild 3 (response rate 81%). The participant characteristics asthma and differences in outcomes; (b) the extent are summarized in Table S1. Among participants, there to which treatment adherence and patient perception was an equal distribution of males and females, their of symptoms impact treatment choices and asthma mean age was 56.8 years and they resided across 10 control; and (c) to understand views on using GINA countries. All participants had medical degrees and treatment recommendations or local country guide- had been working in the respiratory field for ≥ 15 years. lines for the holistic management of patients with mild asthma In the last step of the Delphi procedure, partici- Delphi survey 1 results pants were emailed final follow-up questions consist- ing of six 5-point Likert-type questions (Strongly Participants defined mild asthma in a range of differ- disagree, somewhat disagree, neither agree nor dis- ent ways, most frequently referring to the GINA defi- agree, somewhat agree, and strongly agree). Space for nition and based on infrequent symptoms, no impact open comment followed each question. The objectives on daily life, and exacerbations easily controlled by were to obtain a consensus amongst the participants Step 1 or 2 treatment. Participants indicated that 45% on their understanding and beliefs on, (a) the reasons of patients with mild asthma currently receive daily for recommending regular daily dosing for patients ICS (alone or plus another controller) plus as-needed with mild asthma and (b) targeting asthma control SABA and 25% receive as-needed ICS-formoterol or severe exacerbations reduction primarily for asthma (Table 1). Participants’ preferred treatment regimen in management mild asthma, was indicated as daily ICS (alone or plus another controller) plus as-needed SABA for 44% and as-needed ICS-formoterol for 44% (Table 1). Data analysis The most important factors driving treatment All data were analyzed descriptively. The results of choices for mild asthma were efficacy (Figure 2). the first survey and the scientific workshop were When considering the advantages and disadvantages subjected to a content analysis to identify and clas- of daily ICS versus as-needed ICS-formoterol, the sify common elements in the overall opinion of the main advantage of daily ICS was efficacy (69% of panel, and for development of survey 2. A similar participants) and the main disadvantage was adher- approach was used to develop survey 3, the final ence (56%); whereas the main advantages of as-needed set of questions. Full feedback on the results of ICS-formoterol were reported as efficacy (31%), con- each survey was given to the panelists for consid- venience (25%) and adherence (25%), and the main eration and discussion before the next survey was disadvantages were cost (44%) and, also, level of effi- sent out. The phrasing of questions and the rating cacy (31%). When asked if there are situations/par- of responses using a Likert scale were decided by ticular patients for whom as needed ICS-formoterol market research experts in line with best practice would be recommended over daily treatment, 56% and other Delphi surveys (27,28,30). For data qual- agreed, while 44% voted against. ity checks, all responses were checked by a data Eighty-eight percent of participants strongly or analyst at Ashfield Health to ensure consistency and somewhat agreed that there are clear guidelines on quality of response. the recommended approach to achieving good asthma For the results of surveys 2 and 3, a consensus control in their own country. GINA was most com- was pre-defined as achieving 70% agreement. This monly cited as the global document used to guide proportion has been considered appropriate in pre- prescribing decisions for asthma management and vious studies that used the Delphi procedure most participants also listed their own local/national (31–33). guidelines as influencing their prescribing decisions. Journal of Asthma 149 Table 1. Participants’ current and preferred treatments for patients with mild asthma (Delphi survey 1). Q: Thinking about all your patients diagnosed with mild asthma, please indicate what percentage are currently prescribed each of the following treatments. Treatment Patients (%) ICS + as-needed SABA 30 As-needed ICS-formoterol 25 Daily ICS + LABA + as-needed SABA 13 As-needed SABA 11 Daily LTRA + as-needed SABA 3 Daily ICS + LTRA + as-needed SABA 2 As-needed ICS and SABA 2 Other* 13 Q: What is your preferred treatment regimen for patients diagnosed with mild asthma (i.e. patients whose asthma can be well controlled with Step 1 or Step 2 treatment, as defined by GINA)? Treatment Patients physicians (%) ICS + as-needed SABA 38 As-needed ICS-formoterol 44 Daily ICS + LABA + as-needed SABA 6 As-needed SABA – Daily LTRA + as-needed SABA – Daily ICS + LTRA + as-needed SABA – As-needed ICS and SABA – Other* 13 *Listed as either daily ICS + as-needed ICS-formoterol or as-needed ICS + SABA. ICS: Inhaled corticosteroid; LABA: long-acting beta-agonist; LTRA: leukotriene receptor antagonist; SABA: short-acting beta-agonist. Figure 2. Most important factors driving treatment choices for mild asthma. Scientific workshop summary agreement amongst the panel that regular mainte- nance dosing with ICS is the best asthma manage- The main findings of the scientific workshop are ment strategy in mild asthma and that the key studies summarized in Table 2 with examples of individual evaluating as-needed ICS-formoterol showed that feedback presented in Table S2. There was general regular ICS was superior or equivalent to as-needed 150 C. DOMINGO ET AL. ICS-formoterol for asthma control parameters, but 87% agreed that daily ICS improves lung function not superior for reducing the risk of severe exacer- and reduces symptom frequency, 73% agreed that the bations. Adherence with regular ICS dosing was chronic inflammation in mild asthma can only be raised as an issue and it was agreed by most that it controlled by regular daily ICS, and 73% agreed that is yet unknown whether a variable dosing regimen regular ICS is more likely to prevent exacerbations would ensure real life adherence in the community. compared with as-needed treatment (Figure 4). Eighty Most participants agreed that GINA is a good doc- seven percent of physicians reported that the propor- ument about asthma, based on the assessment of tion of patients with mild asthma who should be published literature, although it does not use GRADE prescribed as-needed ICS-formoterol rather than daily methodology (1), and would benefit from being more ICS ranges between 0% and 40% (Figure S1), with balanced in this respect. It was also acknowledged the main reason given as ‘lack of adherence to that GINA is an outlier in terms of recommending daily ICS’. as-needed ICS-formoterol as the preferred treatment No consensus was reached on which ICS treatment option in mild asthma and national treatment guide- regimen is believed to be most successful for con- lines have taken a consensus- and evidence-based trolling mild asthma (60% favored regular ICS over approach, with some not recommending as-needed as-needed ICS-formoterol and 33% regarded both ICS-formoterol at all for mild asthma (11,12,23), some options equally effective), or on the statement, recommending as-needed ICS-formoterol as an alter- ‘as-needed treatment is unlikely to be successful as it native to regular ICS in mild persistent asthma (24– is dependent on patients’ own accurate perception of 26), and some recommending either regular ICS plus symptoms’ (53% agreed). as-needed SABA or as-needed ICS-formoterol as a Physicians somewhat or strongly agreed that low treatment option for mild asthma (34). adherence is seen across all treatment regimens in asthma management (87%), that patients are less likely to be adherent to treatment if they are feeling well Delphi survey 2 results (100%) or to a treatment they need to use every day Following the scientific workshop and completion of versus a treatment used less frequently (73%), and the second survey, a number of consensus statements that there is wide variation in patients’ abilities to were reached. There was a consensus among partici- accurately assess/perceive their own symptoms (73%). pants (80% agreed somewhat or strongly) that they A consensus was reached on the following state- would usually or always recommend daily ICS for ments about GINA: GINA should be treated as an patients with mild asthma (Figure 3). In addition, opinion statement rather than a guideline (87%), Table 2. Summary of scientific workshop discussions. Theme discussed Summary of discussion Regular dosing versus variable • General acceptance that regular maintenance dosing is the best asthma management strategy in mild asthma dosing in asthma due to better outcomes in asthma control and inflammation suppression. management: the clinical • Results of RCTs unequivocally stated that regular ICS was superior or equivalent to as-needed ICS-formoterol evidence for asthma control parameters • General agreement that the clinical studies supporting the variable dosing strategy were not conducted in GINA step 1 patients, questioning their scientific validity in relation to patients with mild asthma • The issue of real-world compliance with regular dosing, and use of a variable dosing strategy as an alternative approach, was highlighted by several participants. The question remains whether a variable dosing regimen would ensure adherence. • The importance of considering both asthma control and severe exacerbation risk was emphasized GINA update for mild asthma • Most agreed that GINA is a good document about asthma but is an opinion statement, not a guideline; and comparison with national guidelines are more relevant in individual countries GEMA 5.0 guidelines • General agreement that GINA, based on literature review and not GRADE methodology, would benefit from being more balanced in its evidence evaluation to reach consensus recommendations • GEMA 5.0 developed by a multidisciplinary, representative team; uses Delphi panel evaluations and is accredited by AGREE II • In GEMA, three alternatives recommended for Step 1 treatment: SABA only, as-needed ICS-formoterol or as-needed SABA + ICS PRN. Step 2 (persistent mild asthma) recommends regular daily low dose ICS plus as-needed SABA Discussion on approach by • Other treatment guidelines taken a consensus- and evidence-based approach; some do not recommend other guidelines as-needed ICS-formoterol at all for mild asthma (Japanese, BTS, NEAPP guidelines) and some recommend as-needed ICS-formoterol as an alternative to regular ICS in mild asthma (Thai and Canadian guidelines) • Guidelines provide consensus- and evidence-based guidance at a group level; individual patient requirements should also be considered BTS: British Thoracic Society; GEMA: Spanish Guideline on the Management of Asthma; GINA: Global Initiative for Asthma; ICS: Inhaled corticosteroid; RCT: Randomized controlled trial; SABA: short-acting beta-agonist. Journal of Asthma 151 Figure 3. Approach to mild asthma treatment. ICS: inhaled corticosteroid. Figure 4. Benefits of asthma control treatment regimens. ICS: inhaled corticosteroid. GINA is a useful document for physicians to refer to recommended treatment approach in mild persistent for the management of patients with asthma (80%) asthma, supported by better outcomes and robust and there is a need for GINA to include more appro- long-term clinical data compared with as-needed priate clinical evidence in its strategy (73%). ICS-formoterol (85%); that a regular daily dosing treatment regimen should be accompanied by ongoing education in the importance of adherence to treatment Delphi survey 3 results (100%); that exacerbation reduction is achieved with A consensus was reached on all six of the final treatment targeting asthma control (92%) and that Likert-style questions with physicians agreeing that asthma control is achieved with treatment targeting regular daily dosing with ICS should be the moderate to severe exacerbation risk (85%) (Figure 5). 152 C. DOMINGO ET AL. Discussion and the airway wall structural changes observed in mild asthma, supporting a treatment strategy for reg- The aim of this modified Delphi procedure was to ular daily ICS (35,37). Support for regular treatment develop consensus-based statements on factors deter- also comes from long-term clinical studies that show mining the management of patients with mild asthma. the benefit of early intervention with ICS on asthma After the four-round process, a consensus was reached symptoms, in reducing the risk of exacerbations, and that, in terms of long-term clinical data and clinical on functional changes associated with asthma, (lung outcomes, regular maintenance dosing with ICS should function and airway responsiveness) (13,14,38,39). be the preferred treatment option in mild persistent Inflammation and bronchial responsiveness can persist asthma to achieve symptom control and reduce exac- even in the absence of asthma symptoms (40,41), both erbations, supported by patient education to encourage of which are related to lung function decline (42,43). treatment adherence. It was also agreed that effective Jayaram et al. showed in patients with very mild or treatment results from targeting both asthma exacer- mild asthma that a clinical control strategy to guide bation reduction and asthma control. There was agree- ICS maintenance treatment (based on symptoms and ment at the scientific workshop that GINA would spirometry) was similar to a strategy guided by benefit from being more methodological in its eval- inflammation (sputum cell counts) in reducing the uation of the evidence to reach a consensus on rec- number of exacerbations (44). A risk of ommendations. Although traditionally GINA symptom-driven, as-needed therapy is that inflamma- recommendations about asthma have been widely tion and remodeling may persist in periods when accepted, the last proposal regarding step 1 and 2 symptoms are not apparent. The long-term impact of have not been incorporated by many medicine agen- t h i s s t r at e g y on ai r w ay i n f l am m at i on , cies such as the European Medicines Agency. No con- hyper-responsiveness, remodeling and asthma mortal- sensus was reached on whether GINA or ity compared with regular ICS usage is as yet country-specific guidelines are more rigorous or objec- unknown, and further research would be warranted tive, or which have the most influence in driving (45). Regular daily ICS therapy with as-needed SABA prescribing habits. resulted in better asthma symptom control and similar Airway inflammation and airway remodeling are risk of severe exacerbations compared with as-needed present even in mild asthma (2,35,36), and treatment ICS-formoterol, in two double-blind, randomized, con- with ICS leads to decreases in airway inflammation trolled trials (18,19). In an open-label, randomized, Figure 5. Final consensus statements. ICS: inhaled corticosteroid. Journal of Asthma 153 controlled trial, regular, daily ICS therapy with (15,50–52), and having mild asthma is particularly as-needed SABA was associated with better suppres- associated with poor adherence (15), putting patients sion of inflammation (fractional exhaled nitric oxide at risk of poorer outcomes, including death due to (FeNO), similar symptom control and lung function, underuse of ICS (1,4,9). The anti-inflammatory pro- but less reduction in the moderate/severe exacerbation tective effect of ICS treatment builds up over time; rate, compared with as-needed ICS-formoterol (22). this benefit has been shown when ICS are taken reg- In another study comparing regular maintenance dos- ularly and consistently over the long-term (53). ing with budesonide with intermittent, symptom-guided Because of the central role ICS play in achieving short courses of corticosteroids (inhaled budesonide effective asthma control, addressing poor adherence or oral prednisolone), Boushey et al. reported similar continues to be of paramount importance. This rates of exacerbations for the two groups but signifi- involves an understanding of a patient’s beliefs and cantly greater improvements in markers of inflamma- perceptions about their asthma and the reasons for tion (bronchial reactivity, the percentage of eosinophils their poor adherence – which could be related to in sputum, and FeNO) following regular daily main- technical, behavioral or educational reasons – so that tenance treatment (46). adherence interventions can be implemented and tai- The uncertainty surrounding the long-term impacts lored to individual patients (1,15,51,54). Moreover, in of as-needed ICS-formoterol treatment in mild asthma some situations primary care physicians are still reluc- is reflected in the differing treatment recommenda- tant to prescribe ICS for prolonged periods, making tions by national guidelines compared with GINA ‘continuing medical education’ (CME) an important (1,11,12,23–26,34,47), some of which do not recom- tool as well. For patients with adherence issues, reg- mend or mention as-needed ICS-formoterol at all for ular asthma reviews of inhaler technique and adher- the treatment of mild asthma. This indicates a need ence (2), and using a personalized action plan (agreed for clarity in defining mild asthma and in determin- between the patient and healthcare professional) can ing the most appropriate treatment for these patients, empower patients to make short-term changes to their and may require further development of national medication in response to changes in their symptoms guidelines and adaptations to local healthcare systems. and when to seek professional help (55). Real life The collection of real-life data in different countries adherence to an as-needed dosing strategy in the will contribute to these discussions. It seems clear community is not yet known. A major concern is that achieving asthma symptom control is not the that as-needed treatment relies on patients perceiving key objective of as-needed ICS-formoterol therapy, it their symptoms and patients who are under-perceivers being more focused on the reduction of severe exac- may delay starting appropriate treatment, increasing erbations, and there appears to be some acceptance the risk of an exacerbation (17). Interestingly, in a that this treatment strategy would be expected to one-year open-label study in a real-world setting, result in worse symptom control versus regular daily regular ICS therapy resulted in better symptom con- maintenance treatment (21,22). Individual patient trol measured by ACQ-5 and a numerically lower characteristics, risk factors, comorbidities and pheno- annualized exacerbation rate, despite a low adherence and endotypes are important factors when consider- of 56% in this group, compared with as-needed ing the effects of a particular treatment on a patient’s ICS-formoterol (annualized exacerbation rates of 0.175 symptoms and exacerbation risk (1), as well as prac- versus 0.195, respectively) (21). tical issues such as inhaler technique, adherence and The Delphi procedure has been well-described as affordability (1,48). Recently, the benefits of type 2 a useful technique for obtaining a group consensus inflammation assessment (FeNO and blood eosino- on a specific topic, particularly in circumstances where phils) in addition to symptoms and spirometry were there is contradictory or insufficient information (27– reported as useful to determine the effective use of 29). The method is based on the assumption that the ICS in asthma (49), but these tools are not routinely opinions of a group are more valid than that of an available in general practice. Certainly, a blanket individual and the use of an independent facilitator strategy to treat all mild asthma patients with and anonymous controlled feedback ensures a robust- as-needed ICS-formoterol is not supported by the ness in the process. Previous studies in asthma and current available evidence (20). COPD suggest that a panel with at least 12 members One of the main problems in maintaining a treat- is sufficient to reach a meaningful consensus (56–58). ment regimen with regular ICS is that treatment The Delphi procedure used in the current study has adherence is poor, with reported adherence rates with some strengths and limitations. A strength of this controller therapies ranging between 22% and 78% study is that response rates were relatively high among 154 C. DOMINGO ET AL. the selected panel with 81% of participants completing MedComms, Ashfield Health. All authors contributed to all four rounds, indicating a good level of interest and the interpretation of results, drafting, reviewing, and criti- engagement in the process. Another strength of this cally revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects study is that physicians were invited to participate of the work. from a broad range of countries and backgrounds (public and private health care), representing different viewpoints. Industry sponsors organized and facilitated Declaration of interest the scientific workshop but did contribute to the con- CD has received personal grants from Novartis, Sanofi, sensus statements derived from the Delphi surveys. GSK, TEVA, MSD, Esteve, AstraZeneca, Chiesi, Menarini, A limitation of this study is that only respiratory spe- Ferrer, Stallergenes, ALK-Abelló, Allergy therapeutics, Hall cialists were included and their views do not reflect Allergy, Inmunotek and Roxall; a grant from GSK paid to physicians in primary care where most patients with the Parc Tauli Foundation; consulting fees from Novartis, Sanofi, GSK, TEVA, MSD, AstraZeneca, Menarini, Pfizer, mild asthma are treated. Another limitation is that Ferrer, Stallergenes and ALK-Abelló; payment for expert there is no evidence of reliability with the Delphi testimony and/or honoraria for presentations, speakers methods i.e. that other expert panels would reach the bureaus, manuscript writing or educational events from same conclusions (29), and so these results should be Novartis, Sanofi, GSK, MSD, Esteve, TEVA, Almiral, interpreted accordingly. Whilst all participants were AstraZeneca, Chiesi, Menarini, Pfizer, Ferrer, ALK-Abelló; experts in asthma, their views were not homogenous, and support for travel/attending meetings from Novartis, Sanofi, GSK, Chiesi, MSD. BG’s institution has received suggesting the panel represented a range of views. honoraria for presentations, speakers’ bureaus, manuscript writing or educational events from Deva, Sandoz, Abdi Ibrahim, AstraZeneca, Chiesi; and has received support for Conclusions travel/attending meetings from GSK, Astra, Chiesi. GVV has received honoraria for presentations, speakers’ bureaus, The objective of this study was to understand the role manuscript writing or educational events from GSK, of proactive regular controller ICS in the management Boehringer Ingelheim, Novartis, AstraZeneca, MSD, Pfizer, of mild asthma. The participants in this Delphi study Sanofi, Chiesi, Bayer. DLL’s institution has received grants reached the following consensus recommendations: from GSK, Novartis, Sanofi, AstraZeneca, Circassia; has They agreed that regular maintenance dosing with received speaker’s fees and/or fees for participation in ICS should be the preferred initial treatment option AdBoards from AstraZeneca, GSK Mexico, Novartis, Sanofi, Chiesi, Carnot, DBV Technologies; and support for travel/ in mild persistent asthma, supported by patient edu- attending meetings from Sanofi, AstraZeneca, Novartis. GG, cation to encourage treatment adherence. It was also HN, OP and HS have no competing interests. The following agreed that effective treatment should target both are GSK employees and hold GSK shares: NB (part-time), asthma severe exacerbation reduction and asthma EP, EI (part-time), BA, VE, GL. control. As no consensus was reached on whether GINA or country-specific guidelines are more rigorous or objective, or which have the most influence in Data sharing statement driving prescribing habits, this highlights a need for Information on GlaxoSmithKline R&D’s data sharing com- the development of national guidelines in each coun- mitments and requesting access can be found at: https:// try or region which consider local healthcare systems, www.clinicalstudydatarequest.com. with a specific focus on mild asthma. ORCID Acknowledgements Désirée Larenas-Linnemann http://orcid.org/0000-0002-5713-5331 Bhumika Aggarwal http://orcid.org/0000-0002-8370-9319 The authors would like to thank all the scientific workshop participants for their helpful contributions to the discus- sions. This study (GSK study 217879) was funded by References GlaxoSmithKline (GSK). Editorial support was provided by Kate Hollingworth of Continuous Improvement Ltd and 1. Global Initiative for Asthma. 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