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New approach to intermittent and mild asthma therapy: evolution or revolution in the GINA guidelines?

New approach to intermittent and mild asthma therapy: evolution or revolution in the GINA... New recommendations from the Global Initiative for Asthma (GINA) were released in a pocket guide form on April 12, 2019. These recommendations provide very important changes to the management of asthma, especially regarding the treatment of intermittent and mild asthma. Due to safety concerns, GINA experts no longer recommend treat‑ ment with a short‑acting β2 agonist alone. Henceforth, all adults and adolescents (but not yet children) with mild asthma should receive either symptom‑ driven or daily low‑ dose ICS. The main goal of this new approach is to reduce the risk of serious asthma exacerbations and asthma‑related deaths in the population of patients with mild asthma. Herein, the authors present the epidemiological and clinical data regarding the risks of excessive SABA use and the benefits of regular treatment with inhaled corticosteroids. The authors deliver a critical review on the evolution of the changes in the GINA experts’ standpoint and provide evidence‑based background for the new approach to asthma treatment. Moreover, the authors identify gaps and unmet needs still present in the current asthma management recommendations and discuss them thoroughly. Keywords: GINA guidelines, Symptom‑ driven therapy, Short‑acting β2 agonist, Inhaled corticosteroids asthma should receive low-dose inhaled corticosteroids Background (ICS) either for symptom-driven use or as a regular daily On April 12, 2019, new recommendations from the medication to reduce the risk of serious exacerbations. Global Initiative for Asthma (GINA) were released [1]. The withdrawal of the recommendation for on-demand Initially, the report was available only in a shortened form short-acting β2 agonists (SABA) as monotherapy as the (a “pocket guide”), yet it heralded a long-awaited break- first step of asthma treatment and the introduction/addi through in asthma management, especially regarding the - approach to intermittent and mild asthma treatment. tion of symptom-driven ICS treatment on the first/sec - According to GINA experts, changes proposed in the ond step of asthma therapy is the major paradigm shift 2019 report are the most fundamental change to asthma from the previous GINA report. therapy in the last 30 years, which is approximately since The main goal of these changes is to reduce the risk of the first guidelines were developed. serious asthma exacerbations and asthma-related deaths In brief, currently experts recommend introducing in the population of patients with mild asthma. It has anti-inflammatory treatment at the very initiation of been widely known that SABA medications, while they asthma therapy, i.e., all adults and adolescents with mild provide quick relief from asthma symptoms, provide no anti-inflammatory effects and therefore do not treat the underlying cause of airway constriction. Consequently, *Correspondence: Izabela.kuprys‑lipinska@umed.lodz.pl when used alone, SABA treatments do not prevent severe Department of Internal Medicine, Asthma and Allergy, Norbert Barlicki exacerbations. Moreover, their regular or frequent use University Hospital in Lodz, Medical University of Lodz, 22 Kopcinskiego Str., 90‑153 Lodz, Poland © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 2 of 14 even increases the risk of near-fatal and fatal asthma efficacious, epinephrine caused serious adverse event due attacks. to its effect on α and ß -ARs in the cardiovascular system. Herein, the authors present the epidemiological and Isoprenaline [5] and metaproterenol [6] were next AR clinical data regarding the risks of excessive SABA use agonists interacting only with ß-AR but non-selective to and the benefits of adding of inhaled corticosteroids to their subtypes (Fig.  1) [2–16]. Their administration was the asthma therapy. The authors deliver a critical review complicated by cardiac adverse events as they did not on the evolution of the changes in the GINA experts’ discriminate between ß1- and ß2-ARs (Fig.  2) [17, 18]). standpoint since 1995 till 2019 regarding SABA usage The development of selective ß2-AR agonists salbutamol and show the development of new concept in manage- [7, 8], terbutaline [9, 10] and fenoterol [11] started the ment of intermittent and mild asthma. Authors provide modern era of short acting ß2 agonists (SABA) (Fig.  1). evidence-based background for use of budesonide-for- These drugs were used by inhalation route thanks to the moterol (BUD-FORM) as a rescue medication and pre- construction of the first personal inhalers in 1940s–1950s sent the pros and cons of such regimen. Moreover, the [19, 20]. High efficiency in relieving acute bronchospasm authors identify gaps and unmet needs still present in the resulted in the popularity of these drugs and their mar- current asthma management recommendations and dis- ket increased rapidly all over the world, but quite early, cuss them thoroughly. there were doubts about their safety due to numerous side effects, especially serious affecting the circulatory Epidemiological data and clinical studies and respiratory systems (Fig. 3 [21, 22]). on excessive use of SABA The notorious reputation of SABA therapies dates The use of adrenoceptor (AR) agonists dates back to back to the 1970s, when soon after their introduction to 3000 BC when Chinese medicine practitioners used ma the market, an increase in asthma-related mortality was huang (Ephedra equisetina) extracts containing ephed- observed. A series of papers published during that time rine in the treatment of respiratory symptoms [2]. At the alarmed the public to the epidemic of sudden deaths due beginning of twentieth century, the nonselective α-AR to asthma in England, Wales, Scotland, Ireland, Australia and ß-AR agonist epinephrine was introduced into clini- and New Zealand and linked it to an increase in the con- cal practice and administered by the subcutaneous route sumption of isoprenaline (a nonselective β mimetic) [23] for the treatment of acute asthma [3, 4]. Although highly and then fenoterol (classified as a selective β2 mimetic Fig. 1 Timeline for the introduction of adrenergic receptor agonists in asthma treatment [2–16]. AR adrenoceptor K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 3 of 14 Fig. 2 Localization and function of β‑adrenoceptors [17, 18]. AR adrenoceptors Fig. 3 Adverse effects and harmful drug interaction in patients using SABA. #salbutamol [21], ~ fenoterol [22] Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 4 of 14 but with some affinity for β1 receptors) [24, 25]. The experts to use this treatment regimen in patients with mechanism behind this correlation was not known, but sporadic and mild asthma remained unchanged. in 1989 in New Zealand, fenoterol was withdrawn from Again, great concerns over the use of β2 mimetics the market, which resulted in a reduction in the country’s surfaced in 2006 when the results of the SMART study asthma-related mortality [26]. (Salmeterol Multicenter Asthma Research Trial) were In the early 1990s, Spitzer et al. [27] reviewed the Sas- published [33]. In this study, salmeterol, a long-acting katchewan Canadian province database and found an β2-agonist (LABA), was included as an add-therapy to association between the regular use of SABA and mor- previous asthma treatments. The study was conducted bidity and mortality in asthmatics. The authors proved on a very large population of asthmatic patients (26,000). that SABA use was associated with an increased risk Statistical analysis showed a small but statistically sig- of death from asthma (odds ratio, 2.6 per canister per nificant increase in mortality and life-threatening events month, 95% CI 1.7–3.9). They concluded that, regard - associated with asthma in the group of patients using sal- less of whether or not beta-agonists are directly respon- meterol. This research sparked a new discussion on the sible for these serious side effects or are simply a marker association of these events with the use of LABA, and of more severe asthma, the excessive use of SABA by connections to the negative experiences with SABA were patients should alarm providers to the urgent need of drawn. It was concluded that the cause of these deaths patient status reassessment. may have been inadequate anti-inflammatory treatment Two years later, the same team [28] published results in these patients, because 9 out of 13 reported deaths of an epidemiological analysis showing an association occurred in patients who were not using ICS at the time between the use of fenoterol, salbutamol and oral corti- of salmeterol inclusion. This finding reinforced the rec - costeroids in the previous year and sudden asthma deaths ommendations of GINA experts to use LABA only with as well as between the number of hospitalizations due ICS and to prefer a fixed combination of ICS-LABA, but to asthma in the previous 2  years and fatal cases. They it did not change their position on SABA monotherapy also calculated that the risk of death increased dramati- at the first stage of asthma treatment. Thus, a ques - cally after exceeding the usage of 1.4 SABA canisters per tion arises: Why weren’t these SABA recommendations month. changed earlier? In 1998, this team issued another publication [29] ana- Intermittent and mild asthma was considered to be lyzing the reasons for hospital admissions due to asthma. primarily a disease of bronchoconstriction, although in The investigators observed that the inclusion of regular 1988, Wardlaw et  al. [34] had already shown that both therapy with ICS in the year in which asthma was diag- symptomatic and asymptomatic mild asthmatics had air- nosed reduced the risk of hospital admission by 40% way inflammation. Using bronchoalveolar lavage (BAL), compared with theophylline therapy. In 2000, Suissa et al. they found a significantly increased percentage of mast [30] reported that the use of low doses of ICS reduced the cells in all asthmatics and a significant elevation in eosin - risk of sudden death from asthma. They calculated that ophil count and in the concentration of major basic pro- the rate of death from asthma decreased by 21% with tein (MBP) in the group of symptomatic patients. They each additional canister of ICS used in the previous year. also showed an inverse correlation between PC20 and the However, the mortality rate of patients who discontinued percentage of mast cells (p < 0.01), eosinophils (p < 0.05), ICS therapy increased quickly within the first 3 months epithelial cells (p < 0.05), and the amount of MBP in BAL of treatment discontinuation. (p < 0.01). In 1990, Foresi et al. [35] confirmed the occur - In the same year, two more interesting studies were rence of marked airway inflammation in asymptomatic published. Hancox et al. [31] showed that the regular use asthmatic patients. They performed bronchoscopy, bron - of terbutaline led to the development of tolerance to the chial biopsies and BAL in young lifetime nonsmoking bronchodilating effect of the drug, and the discontinua - subjects with a history of asthma who had diurnal PEF tion of such treatment caused rebound bronchoconstric- variability lower than 20% and were free from acute res- tion. In the second study, Aldridge et al. [32] showed that piratory infections or spontaneous asthma attacks within regular, high-dose terbutaline monotherapy increased the previous month. These patients controlled their eosinophil infiltration in the bronchi compared to the asthma symptoms with only SABA as needed or on a placebo group; however, using the same doses of terb- daily basis and held off using their medication for a 24-h utaline concurrently with budesonide reduced the initial period before the bronchoscopy. The investigators found eosinophilia. Both of these studies provided insight into greater cell infiltration of the epithelium and submucosa the pathomechanism of adverse reactions associated with in the asthmatic subjects compared with healthy sub- SABA monotherapy and warned against the use of SABA jects. Additionally, eosinophils and intraepithelial mast monotherapy, but the recommendations from GINA cells were higher in the asthmatic group. A thickened K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 5 of 14 Fig. 4 Timeline for SABA position changes in asthma management according to the GINA guidelines 1995–2019 [36, 37]. ICS inhaled corticosteroids, LABA long acting beta2 agonist, RABA rapid acting beta2 agonist, SABA short acting beta2 agonist, SMART single inhaler maintenance and rescue therapy, MART maintenance and rescue therapy, BUD budesonide, BDP beclomethasone, FORM formoterol basement membrane was associated with more marked In the late 1990s, two big international epidemiologi- cell infiltration in the submucosa. The cells in BAL cal studies were carried out (ARIE [38] and Asthma in broadly reflected cell infiltration of the submucosa, and America [39]), which indicated the need for changes in the degree of bronchial responsiveness was correlated asthma management. They showed that, despite the pro - with ciliated cells in BAL and with intraepithelial cells in gress in pharmacological therapy and the updated rec- bronchial biopsies. ommendations for asthma management, most patients were symptomatic, with up to 50% feeling significantly The previous GINA recommendation impaired in their activities of daily living due to asthma, for intermittent and mild asthma management approximately 11–23% making emergency depart- Despite obvious evidence of airway inflammation in ment visits in the previous year, and 7–9% having severe patients with mild asthma, SABA held a strong position exacerbations that required hospitalization. Moreover, in the GINA recommendations from 1995 until 2019 patients relied too heavily on SABAs and did not use ICS (Fig.  4) [36, 37]. The only changes over the years con - as they should have (while 63% of patients used a SABA, cerned the recommended maximum number of SABA only 23% used an ICS). inhalations during the first step of treatment, which var - Since the publication of the first guidelines in 1995, ied from 1 inhalation per week in 1995 to 2 inhalations many important changes have been introduced to per week in 2006 and fewer than 2 inhalation per month improve asthma outcomes. In 2006, the severity classifi - in 2014. In 2002, formoterol, a long-acting β2-agonist cation was changed to assess control when making thera- with a rapid onset of action was recommended as a res- peutic decisions, and single inhaler maintenance and cue medication but only in patients receiving ICS. The reliever therapy (SMART) was recommended. The man - question then arises: Why was SABA not also consid- agement of intermittent and mild asthma was unchanged, ered as a rescue medication for use only in patients using however, and remained consistent from when SABAs ICS? In 2014, a fixed combination of ICS with formoterol were introduced for use approximately 50 years ago. (budesonide and beclomethasone) was recommended Moreover, later cross-sectional studies showed that, as a rescue medication from the third step of treatment despite the very important changes in GINA recom- in patients receiving such medications as a maintenance mendations, asthma control was still suboptimal in therapy but not during the first or second steps, where a approximately 50% (45–56, 5%) of patients. Severe exac- SABA was the only preferred rescue medication [36]. erbations were still common and had occurred in 44% of patients within the previous year; 24% of those patients Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 6 of 14 had needed an emergency department visit, and 12% most of these patients could not correctly identify drugs had been hospitalized [40]. Uncontrolled asthma was the for asthma prescribed by doctors. reason for a poor asthma-related quality of life (QoL), a There is one more interesting study from 1997 per - high risk of exacerbations and significant consumption of formed by Donahue et al. [45]. The investigators showed healthcare resources [41]. that SABA use was associated with an increased risk of It was a sign that there was a need for further changes hospitalization. The overall relative risk (RR) of hospi - in recommendations. talization among those who received inhaled steroids was low and was 0.5 (95% confidence interval [CI], 0.4–0.6) New concept in management of intermittent after adjusting for SABA dispensing. The steroid-asso - and mild asthma ciated protection was most marked among individu- The epidemiological data proved that mild, intermittent, als who received the largest amount of SABA, while the and persistent asthma are the most frequent forms of the group of patients using eight or more SABA inhalations disease and concern more than 50% of patients (ARIA), per day and ICS as maintenance therapy experienced which explains their great impact on the overall asthma a nearly 75% decrease in the risk of exacerbations com- burden. pared to patients using only SABA. A fixed combination of SABA/rapid acting beta2 agonists (RABA) and ICS as Risk of severe exacerbations in mild asthma a rescue medication therefore may protect against severe In 2007, Dusser et  al. [42] published a review show- exacerbations. ing that patients suffering from mild asthma quite often experience severe exacerbations at a frequency rang- History of the BUD‑FORM as needed concept ing from 0.12 to 0.77 per patient per year. Severe exac- In 2008, in their review on the position of BUD-FORM, erbations in mild asthma represent as many as 30–40% Kuna and Kupryś-Lipińska [46] proposed an extension of of asthma exacerbations requiring emergency consulta- SMART and the inclusion of BUD-FORM as the medica- tion. Even patients with mild symptoms meeting the cri- tion to be used on demand from the first step of therapy teria of asthma controlled by GINA are at risk of severe according to the GINA guidelines. BUD-FORM serving exacerbations (experiencing symptoms varying from 0 to as a rescue medication during the first and second steps 1–2 times per week). They constituted more than 70% of of treatment could be a smooth transition to SMART patient consults for acute asthma and patients with acute in the further steps. The idea of using BUD-FORM on near fatal asthma in emergency departments. demand as the preferred therapy for the first and second steps of treatment was based on the clinical experience of Risk of asthma exacerbation in patients overusing SABA the authors as well as the previous clinical studies and the or using them in monotherapy knowledge of patient preferences and behavior, which Later, Stanford et  al. [43] determined the magnitude were presented in the review. of the risk of asthma exacerbation depending on SABA Studies using formoterol or BUD-FORM as a res- demand. Based on two large databases, researchers cal- cue drug provided the most important support for this culated that the consumption of 3 or more SABA canis- concept. ters within the previous year increased the risk of asthma exacerbation. For adults, such a marker may be the use of Pharmacological basis of the BUD‑FORM as needed 2 or more SABA canisters in a shorter 3–6 month period. concept The use of an additional SABA canister resulted in a cor - In 1996, Schreurs et  al. [47] demonstrated the dose- responding increase in the risk of asthma exacerbation dependent effect of formoterol (6, 12 and 24  µg#) in the by 8% to 14% and 14% to 18% in children and adults, maintenance therapy of patients with moderate asthma. respectively. Compared to placebo, 6  μg formoterol b.i.d. was found In a survey conducted by Price et al. [44] in eight Asian to be the lowest effective dose for improving the morn - countries, only 14.5% of respondents taking exclusively ing (p = 0.008) and evening (p = 0.0041) peak expiratory rescue medications had controlled asthma, and two- flow (PEF). Increasing the dose from 6 to 24 μg b.i.d. pro - −1 thirds had experienced severe exacerbations in the previ- vided an additional effect of 18 L  min (p = 0.035) in ous year. Unfortunately, in this study, similar proportions the evening PEF. In 1998, Malolepszy et  al. [48] demon- of adverse events were also found in the group taking strated the effectiveness and safety of formoterol at high controller medications, which may be because respond- doses in the treatment of acute severe airway obstruction. ents confess that they fear the regular use of asthma Adult patients with asthma and COPD who had been drugs and then only take them occasionally; additionally, admitted to intensive care units with acute severe bron- choconstriction (FEV1 = 20–50% of the predicted value) K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 7 of 14 were randomized to receive 20 inhalations of either for- more beneficial than using RABA alone in patients with moterol (4.5 μg^) or terbutaline (0.5 mg) within the first intermittent asthma and signs of airway inflammation. 3 h of therapy, but all received 40 mg of methylpredniso- lone i.v. in the 90th min of therapy. High doses of formo- Patient preferences and commitment as an essential terol were equally as effective as terbutaline in improving element of therapy effectiveness supporting the concept lung function. Additionally, formoterol therapy resulted of BUD‑FORM as needed in significantly lower pulse rates than terbutaline therapy, For physicians working with patients, solving patents’ which confirmed the safety profile of formoterol admin - everyday problems and meeting expectations are essen- istered in high doses. Five years later, a similar study was tial elements of asthma management. Understanding the performed comparing formoterol with salbutamol in an factors that influence patient behavior may help to deter - emergency setting [49]. In this study, using 54 µg^ of for- mine the most effective regimen. Therefore, the results moterol compared to 3600  µg of salbutamol resulted in of the study on patients’ adherence to therapy are vitally greater acute lung function improvement over the 4-h important. assessment period. The Respiratory Patients Opinions Survey In 2001, Palmqvist et  al. [50] showed the rapid onset (RESPONSE) [54], performed in Europe, showed that of bronchodilation (within the first 3 min) after inhala - the majority of patients prefer to use fewer asthma drugs tion of BUD-FORM (160/4.5 µg^ one or two doses). This and to have just one inhaler. Further studies of patient effect was not observed after FLUT-SALM administra - behavior revealed that over half of patients tend to rely tion compared to placebo. on reliever medication [55] and thus underuse ICS [38]. Another group of investigators [51] confirmed the Studies show that fewer than 50% of patients adhere to immediate bronchodilation following BUD-FORM in the prescribed schema [56, 57]. Regardless of the fact that patients with methacholine-induced moderate-to-severe people forget to take drugs regularly, patients are also bronchoconstriction and demonstrated rapid improve- concerned about the side effects of long-term therapy ment of dyspnea (1 min after inhalation) as well as a and dependence [58] and therefore decrease the doses shorter recovery time to 85% baseline lung function themselves or even stop taking drugs when they feel bet- (approximately 3 min) than FLUT-SALM (approximately ter. A fixed combination of ICS with RABA as a reliever 9 min) or the placebo (30 min). therapy eliminates the risk of using RABA relievers alone and thus increases safety. Clinical evidence from first short term studies supporting Patients with chronic conditions tend to have a strong the BUD‑FORM as needed concept influence on the treatment process, regardless of the effi - In 2006, two very interesting studies on the use of BUD- cacy of the therapy. Therefore, asthma management must FORM as a rescue medication were published. In Bate- be a compromise between patient and physician prefer- man et  al. [52] study, budesonide-formoterol (with a ences. The goal for physicians is complete asthma control, total dose of 1280/36  µg^) and formoterol (with a total while from a patient’s perspective, limiting the influence dose of 36  µg^) provided similarly rapid relief of acute of asthma and its therapy on real life is most important. bronchoconstriction in patients with asthma who were The fixed ICS and formoterol combination has been previously refractory to SABA treatment. The second shown to improve both the safety and the effectiveness of study was SOMA, performed by Haahtela et  al. [53] asthma therapy as well as patients’ health-related quality The investigators compared the as-needed use of RABA of life. The usage of one inhaler with a simple and intui - (formoterol 4.5  µg^) with the as-needed use of a RABA tive regimen is the most preferred asthma therapy option and corticosteroid fixed combination (BUD-FORM by both patients and physicians. It also improves anti- 160/4.5  µg^) as the only medication in asthma patients inflammatory therapy in mild asthmatics, since patients’ with intermittent symptoms. The study population con - perception of ICS effectiveness is low and often results sisted of patients who had previously only used RABA as in the discontinuation of these drugs. Thus, when using a needed with FeNO > 20  ppb. Baseline FeNO was 60  ppb fixed dose combination product, with every rescue inha - and 59  ppb in the BUD-FORM and formoterol groups, lation, patients also receive anti-inflammatory treatment. respectively. During the 24 weeks of the study, FeNO was In 2008, the present authors emphasized that the fixed significantly reduced in patients receiving a combination combination of BUD-FORM as a reliever therapy elimi- of drugs from the fourth week of therapy until the end. nated the risk of SABA use as monotherapy, thus increas- The number of days of rescue medication use was signifi - ing patient safety. We also stressed that considering a cantly lower in the BUD-FORM group compared to the patient’s behavior and preferences is one of the ways to FORM group (21 days compared to 74 days). The authors improve a treatment’s effectiveness. concluded that the as-needed use of ICS-RABA may be Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 8 of 14 Fig. 5 Pro and con for using SABA and ICS‑FORM as relivers. SABA short acting beta2 agonist, ICS inhaled corticosteroids, FORM formoterol This innovative proposal was then criticized by review - options for the second step of treatment. The alternative ers, mainly due to the lack of registration of the drug for options include low-dose ICS whenever SABA is taken as this indication, although the benefits from using BUD- well as a leukotriene receptor antagonist. FORM as needed form the 1st step of therapy clearly out- What changes have caused these recommendations to weighed the doubts (Fig. 5.) appear? New GINA recommendation for mild asthmatics The proof of concept studies for the use At the time the 2019 GINA Report was published, nei- of ICS‑FORM as a reliever in first and second level ther BUD-FORM nor BDP-FORM had been registered therapy as on-demand relievers when not used in maintenance Over the last 10  years, several important clinical trials treatment; nonetheless, the GINA experts issued this rec- have been published. ommendation. For safety reasons, GINA no longer rec- In 2007, Papi et  al. [59] published the results of the ommends using SABAs as monotherapy. BEST study. This study showed that in patients with mild GINA experts recommend low-dose ICS-FORM as asthma, BDP-SALB (Salbutamol) 250/100 μg in a single needed (off label) as the preferred treatment option dur - inhaler, administered as needed, was as effective as the ing the first step of treatment for patients who suffer regular use of inhaled BDP (250 micrograms, twice daily) from asthma symptoms less than twice per month and and more effective than as needed SALB in improving who are not at risk of exacerbation. An alternative option morning PEF and in the prevention of exacerbations. is the use of low-dose ICS whenever SABA is taken. Martinez et al. [60] demonstrated in the TREXA study Maintenance use of low-dose ICS was recommended in that in children with mild persistent asthma, the most 2014 for patients with risk factors, but this therapy is no effective therapy to prevent exacerbations is regular, low- longer recommended due to the low rate of compliance dose ICS (BDP 40  μg 2 inhalations/day); however, ICS in these patients and the risk of exposing them to SABA- as a rescue medication along with SABA (BDP 80 μg for only treatment. each dose of SALB PRN) could be an effective strategy In addition to the other preferred options, low-dose for the prevention of exacerbations in children with well- ICS-FORM as needed and low-dose ICS and SABA as controlled mild asthma and is more effective than SABA needed were added by experts to the list of potential monotherapy. This new regimen allows children to avoid K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 9 of 14 daily inhaled corticosteroid treatments and their related by patients during the first step of therapy, but on the side-effects, such as growth impairment. other hand, these recommendations were much stricter Lazarinis et al. [61] demonstrated that combined BUD- and more inflexible during the second through fifth steps FORM (200/6 μg#) on demand improves asthma control of therapy. by reducing exercise-induced bronchoconstriction in the Experts also emphasize that the recommended changes same order of magnitude as regular budesonide (400 μg* are meant to counteract the trend of patients who rely once daily) treatment and terbutaline on demand, despite solely on rescue medications, which results in the dis- a substantially lower total steroid dose. Both these treat- continuation of ICS therapy because it is perceived as less ments were superior to terbutaline alone  on demand, effective in treating patients’ symptoms while also carry - which did not alter the bronchial response to exercise. ing risks of side effects. Patients using SABA as mono - A post hoc analysis of the START study results car- therapy have unconsciously increased their risk of severe ried out by Reddel et al. [62] showed that the use of low- exacerbations. Therefore, the need to track patterns of dose ICS (BUD 200 μg*/day in children or 400 μg*/day in patient behavior is a necessity to improve the adherence adults), even in patients with sporadic symptoms (zero to and safety of treatment (Fig. 5). one time per week), reduced the risk of exacerbating the disease by half compared to patients using only SABA. BUD‑FORM as needed for everyone or for patients Two studies published in 2018, SYGMA 1 and 2, seem with specific asthma phenotypes/endotypes to have been decisive for the change in GINA recommen- RABAs are considered the most effective drugs that dations. O’Byrne et  al. [63] (SYGMA 1) demonstrated reverse bronchospasm, and their choice does not require that in patients with mild asthma, a fixed combination the determination of asthma phenotypes or endotypes. of BUD-FORM (200/6  μg*) used as needed reduced There are studies mention above which show that for - the frequency of exacerbations by 64% compared to moterol is as effective and fast in bronchodilatation as SABA monotherapy. Moreover, the studies by O’Byrne salbutamol [49] and has good or even a better safety pro- (SYGMA 1) and Bateman (SYGMA 2) [64] both showed file [48]. The adding of BUD to FORM does not change that a BUD-FORM treatment regimen (200/6  μg* PRN) the bronchodilatory response [50] but guarantees taking protected mild asthmatics against exacerbations equally of ICS by patients who used relievers. The combination as effectively as low-dose ICS (BUD 200  μg* BID and of a low dose of BUD-FORM as a rescue medication is SABA as a rescue). preferred by GINA experts for treatment at the 1st and 2nd steps of treatment and for patients who use the same The reasons for changes in the GINA guidelines drug in maintenance therapy from step 3. Another com- The results of these studies coincided with the publica - bination—low dose of BDP-FORM can be also used as tion of alarming epidemiological data from England and reliever. SMART/MART therapy is especially recom- Wales, which showed the growing trend of deaths from mended for patients with asthma with the phenotype of asthma. In the last decade, the number of deaths due to frequent exacerbations, but it can be used in any patient asthma has increased there by 25%, reaching the highest who requires ICS-LABA [37]. number per year in this century [65]. However, neither BUD/BDP-FORM combinations are Since effective, safe medications are available and the the only recommended ICS-LABA by GINA experts, nor recommendations for how to effectively treat asthma are is BUD-FORM at the 1st and 2nd steps the only recom- commonly known, what is causing this increase? mended therapeutic option as described previously. If One of the problems seems to be the overuse of SABA other than ICS-FORM combined ICS-LABA is preferred, in monotherapy by patients with mild asthma. Therefore, SABA must be used as reliever. At 1st and 2nd step SABA for safety reasons, GINA no longer recommends treat- may be used but always with concurrent use ICS in one ment using only SABA monotherapy in any step. or separate inhalers [37]. The introduction of symptom-driven treatment that Leaving the classic regimens for asthma therapy is jus- combines RABA and ICS in the first step of therapy uni - tified by the availability of medical preparations and their fies the message (to providers and patients) of the prin - costs, by the patients’ habituation to the traditional treat- ciples of treating this disease, which had up to now been ment regimen and the choice of the suitable drug delivery contradictory. From the beginning, it has been com- system, by the lack of SMART/MART effectiveness in monly known that asthma is an inflammatory disease, certain patients, and finally by the possible but rare intol - but anti-inflammatory drugs were recommended only erance to formoterol. in the second step of therapy. Another problem was the From the above mentioned reasons, the biggest barrier ambiguous message given to patients: on one hand, the in popularizing BUD-FORM as a rescue medicine seems recommendations assumed freedom in the use of drugs to be the habit of patients and physicians holding to Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 10 of 14 traditional regimens of asthma therapy. And so, despite This approach to therapy was previously proposed by the availability of BUD-FORM in Poland and its reim- the authors in their review in 2008 [46]. bursement by the National Health Fund, one-third of Lack of clear indications for asthma treatment inten- patients using low dose BUD-FORM still use SABA as a sification may lead to uncertainty and limit the num - rescue [66]. ber of providers applying this treatment algorithm on a regular basis. Unmet needs in the GINA guidelines The second problem is the maintenance of SABA This chapter presents the personal views of the authors monotherapy in children during step one of treatment, regarding the needs for the development of asthma despite studies showing the beneficial effects of symp - guidelines tom-driven therapy with ICS in this age group and the Current changes to the GINA guidelines in the treatment popularity of this pattern with pediatricians. Declara- of patients with mild asthma are long-awaited changes tions on the shift from asthma being sheer bronchoc- with very strong evidence of efficacy, safety and patient onstriction to asthma as an inflammatory disease do acceptance [37]. not seem to apply to children. However, the new guidelines lack practical advice for Finally, the authors believe that the symptom-driven doctors and patients to seamlessly switch from the symp- approach in asthma therapy would be easier to imple- tom-driven therapy during the first and second steps of ment if the new approach was clearly separated from treatment to SMART therapy during the third through previously recommended treatments by modifying the fifth steps of treatment; furthermore, they do not clearly main GINA asthma management graph. This would state when to increase the maintenance dose of ICS dur- provide greater clarity regarding the new methods and ing SMART treatment. Perhaps by default, symptoms of would emphasize the flexibility of ICS doses, which uncontrolled asthma, as defined by GINA experts, should means a fluid rather than a rigid stepwise transition to be such a signal. the next level of therapy. As a reminder, the symptoms of uncontrolled asthma The authors’ proposed graphs can be found below: are daytime asthma symptoms appearing more fre- Fig.  6 (the new approach) and Fig.  7 (the conventional quently than twice a week, any nighttime waking due to approach). asthma, the need for reliever use due to asthma symp- And the last problem to think about for future is toms more than twice per week, and any limitation to whether biological therapies should be really at the end of activity due to asthma. the therapeutic ladder. In patients with severe asthma, the pathomorphological and pathophysiological changes may Fig. 6 Symptom‑ driven approach. ICS inhaled corticosteroids, FORM formoterol K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 11 of 14 Fig. 7 Conventional approach. ICS inhaled corticosteroids, LABA long acting beta2 agonist, SABA short acting beta2 agonis be irreversible. Earlier introduction of biological thera- and the results from clinical trials require years of analy- pies could prevent the development of severe asthma as sis. Therefore, we are witnessing an evolution rather than well as complications after OCS and high doses of ICS. a revolution in changing treatment patterns. Undoubt- It may also lead to a full remission of the disease as it was edly, an important lesson from the implementation of observed in anti-IgE therapy in children [67] and perhaps these asthma guidelines is that the careful observation of may be available in coming soon anti-TSLP or anti-IL-33 patients’ behavior can contribute to significant progress therapy. Due to the high costs of these therapies and the in the treatment of chronic diseases. The effectiveness of problematic route of administration, they may not gain treatment not only depends on the efficacy of the drug acceptance in mild asthma, but if every day good asthma itself and the systems for its administration, but it also control is interrupted by severe life-threatening attacks, depends on the patient’s acceptance and compliance. it may be worth considering anti-IgE in such asthmatics Treatment does not depend solely on the best medicine with an allergic background. being written on the prescription, but the one bought by the patient and used as recommended. The use of Summary SABA monotherapy in the treatment of chronic asthma Current changes in the asthma recommendations have is no doubt falling out of favor, but in order to completely been long-awaited and are focused on reducing the risk eliminate this treatment, the popularity of using com- of morbidity and mortality, which have been repeatedly bined preparations of ICS-RABA must be increased. emphasized by experts. One might wonder why these For those who are still unconvinced, new changes in changes were introduced so late, since it has been known the GINA guidelines, which are symptom-driven dur- for many years that the use of SABA monotherapy is ing the first and second steps of therapy together with associated with a serious risk of exacerbations and death. SMART treatment during the third through fifth steps, A fixed combination of ICS and RABA has been available create the most personalized asthma therapy we know, for many years, and it has been known that this combi- regardless of asthma phenotype and endotype, where nation increases the safety of patients, although there is the ICS dose is best-suited to asthma activity. It allows also an option to simultaneously use ICS and RABA from treatment with the lowest dose of ICS, which ensures a separate inhalers. One of the explanations for the delay low risk of side effects (which is extremely important for in changing the recommendations is that evidence from long-term treatment), while maintaining effectiveness to clinical trials is needed in order to make positive changes, ensure unhampered life activities and preventing severe Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 12 of 14 Availability of data and materials exacerbations. In addition, that is why, until the discovery All papers discussed in the review are accessible through medical databases of a drug that will cure asthma (which will be revolution- and are listed in the references. ary), the symptom-driven approach in asthma manage- Ethics approval and consent to participate ment, according to the authors, is the best therapeutic Not applicable. option and the most personalized option currently avail- able for the majority of patients. Consent for publication All authors provided written consent for the publication of this article. No personal patient data requiring consent for publication were used. Conclusions Competing interests IK‑L received personal fees for lectures from AstraZeneca, Chiesi, GSK, Nexter, 1. Many epidemiological, clinical and experimental data Novartis and Teva; PK received personal fees for lectures from Adamed, Allergopharma, Almirall, Astra‑ Zeneca, GSK, HAL, Meda, Pfizer, Polfarmex, have shown that SABA monotherapy and/or overuse Stallergen, Teva, and LekAM, and for lectures and advisory board activities are associated with a serious risk of exacerbations from Boehringer Ingelheim, Celon Pharma, Chiesi, FAES, MSD, Novartis, and and death. Polpharma. MK‑F received personal fees for lectures from AstraZeneca and Novartis. 2. Changes proposed in the 2019 GINA report (with- drawal of the recommendation for SABA in mono- Received: 31 October 2019 Accepted: 13 April 2020 therapy and the introduction of symptom-driven ICS-RABA therapy on 1st and 2nd step) are the most fundamental change to asthma therapy in the last 30 years. References 3. A fixed combination of ICS and RABA prevents 1. Global Initiative for Asthma. Pocket guide for asthma management and prevention. 2019. https ://ginas thma.org/pocke t‑guide ‑for‑asthm intentional and unintentional using SABA in mono- a‑manag ement ‑and‑preve ntion /. Accessed 1 May 2019. therapy by patients and therefore increases their 2. Sears MR, Lötvall J. Past, present and future–beta2‑adrenoceptor agonists safety. in asthma management. Respir Med. 2005;99:152–70. 3. Solis‑ Cohen S. The use of adrenal substances in the treatment of asthma. 4. Therapy tailored to the patient’s behavior improves J Am Med Assoc. 1900;34:1164–6. the effectiveness of asthma treatment. 4. Bullowa JG, Kaplan DM. On the hypodermic use of adrenalin chloride in 5. There are still several gaps in recommendation, the the treatment of asthmatic attacks. Med News. 1903;83:787–90. 5. Segal MS, Beakey JF. The use of isuprel for the management of bronchial lack of the practical tips when to switch from the asthma. 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Some pharmacological properties of terbuta‑ #: Metered dose; ^: Delivered dose; *: Off‑label, data for BUD ‑Form; BDP ‑FORM line (INN), 1‑(3,5‑ dihydroxyphenyl)‑2‑(t ‑butylamino)‑ ethanol, a new or BUD‑Form; BAL: Bronchoalveolar lavage; FeNO: Exhaled nitric oxide; GINA: sympathomimetic β ‑receptor ‑stimulating agent. Acta Med Scand. Global Initiative for Asthma; ICS: Inhaled corticosteroids; LABA: Long acting 1970;512(suppl):11–9. beta2 agonist; MBP: Major basic protein; PRN: As needed; RABA: Rapid acting 11. https ://www.boehr inger ‑ingel heim.com/histo ry/histo ry‑miles tone/1948‑ beta2 agonist; SABA: Short acting beta2 agonist; SMART : Single inhaler main‑ 1988 Accessed 20 Jan 2020. tenance and rescue therapy. 12. *https ://www.gsk.com/media /1287/50‑years ‑of‑randd ‑innov ation .pdf Accessed 20 Jan 2020. 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Springer Nature remains neutral with regard to jurisdictional claims in pub‑ org/10.1183/13993 003.congr ess‑2019.pa426 0. lished maps and institutional affiliations. 67. Baena‑ Cagnani CE, Teijeiro A, Canonica GW. Four‑ year follow‑up in children with moderate/severe uncontrolled asthma after withdrawal of a 1‑ year omalizumab treatment. Curr Opin Allergy Clin Immunol. 2015;15:267–71. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Translational Allergy Springer Journals

New approach to intermittent and mild asthma therapy: evolution or revolution in the GINA guidelines?

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Abstract

New recommendations from the Global Initiative for Asthma (GINA) were released in a pocket guide form on April 12, 2019. These recommendations provide very important changes to the management of asthma, especially regarding the treatment of intermittent and mild asthma. Due to safety concerns, GINA experts no longer recommend treat‑ ment with a short‑acting β2 agonist alone. Henceforth, all adults and adolescents (but not yet children) with mild asthma should receive either symptom‑ driven or daily low‑ dose ICS. The main goal of this new approach is to reduce the risk of serious asthma exacerbations and asthma‑related deaths in the population of patients with mild asthma. Herein, the authors present the epidemiological and clinical data regarding the risks of excessive SABA use and the benefits of regular treatment with inhaled corticosteroids. The authors deliver a critical review on the evolution of the changes in the GINA experts’ standpoint and provide evidence‑based background for the new approach to asthma treatment. Moreover, the authors identify gaps and unmet needs still present in the current asthma management recommendations and discuss them thoroughly. Keywords: GINA guidelines, Symptom‑ driven therapy, Short‑acting β2 agonist, Inhaled corticosteroids asthma should receive low-dose inhaled corticosteroids Background (ICS) either for symptom-driven use or as a regular daily On April 12, 2019, new recommendations from the medication to reduce the risk of serious exacerbations. Global Initiative for Asthma (GINA) were released [1]. The withdrawal of the recommendation for on-demand Initially, the report was available only in a shortened form short-acting β2 agonists (SABA) as monotherapy as the (a “pocket guide”), yet it heralded a long-awaited break- first step of asthma treatment and the introduction/addi through in asthma management, especially regarding the - approach to intermittent and mild asthma treatment. tion of symptom-driven ICS treatment on the first/sec - According to GINA experts, changes proposed in the ond step of asthma therapy is the major paradigm shift 2019 report are the most fundamental change to asthma from the previous GINA report. therapy in the last 30 years, which is approximately since The main goal of these changes is to reduce the risk of the first guidelines were developed. serious asthma exacerbations and asthma-related deaths In brief, currently experts recommend introducing in the population of patients with mild asthma. It has anti-inflammatory treatment at the very initiation of been widely known that SABA medications, while they asthma therapy, i.e., all adults and adolescents with mild provide quick relief from asthma symptoms, provide no anti-inflammatory effects and therefore do not treat the underlying cause of airway constriction. Consequently, *Correspondence: Izabela.kuprys‑lipinska@umed.lodz.pl when used alone, SABA treatments do not prevent severe Department of Internal Medicine, Asthma and Allergy, Norbert Barlicki exacerbations. Moreover, their regular or frequent use University Hospital in Lodz, Medical University of Lodz, 22 Kopcinskiego Str., 90‑153 Lodz, Poland © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 2 of 14 even increases the risk of near-fatal and fatal asthma efficacious, epinephrine caused serious adverse event due attacks. to its effect on α and ß -ARs in the cardiovascular system. Herein, the authors present the epidemiological and Isoprenaline [5] and metaproterenol [6] were next AR clinical data regarding the risks of excessive SABA use agonists interacting only with ß-AR but non-selective to and the benefits of adding of inhaled corticosteroids to their subtypes (Fig.  1) [2–16]. Their administration was the asthma therapy. The authors deliver a critical review complicated by cardiac adverse events as they did not on the evolution of the changes in the GINA experts’ discriminate between ß1- and ß2-ARs (Fig.  2) [17, 18]). standpoint since 1995 till 2019 regarding SABA usage The development of selective ß2-AR agonists salbutamol and show the development of new concept in manage- [7, 8], terbutaline [9, 10] and fenoterol [11] started the ment of intermittent and mild asthma. Authors provide modern era of short acting ß2 agonists (SABA) (Fig.  1). evidence-based background for use of budesonide-for- These drugs were used by inhalation route thanks to the moterol (BUD-FORM) as a rescue medication and pre- construction of the first personal inhalers in 1940s–1950s sent the pros and cons of such regimen. Moreover, the [19, 20]. High efficiency in relieving acute bronchospasm authors identify gaps and unmet needs still present in the resulted in the popularity of these drugs and their mar- current asthma management recommendations and dis- ket increased rapidly all over the world, but quite early, cuss them thoroughly. there were doubts about their safety due to numerous side effects, especially serious affecting the circulatory Epidemiological data and clinical studies and respiratory systems (Fig. 3 [21, 22]). on excessive use of SABA The notorious reputation of SABA therapies dates The use of adrenoceptor (AR) agonists dates back to back to the 1970s, when soon after their introduction to 3000 BC when Chinese medicine practitioners used ma the market, an increase in asthma-related mortality was huang (Ephedra equisetina) extracts containing ephed- observed. A series of papers published during that time rine in the treatment of respiratory symptoms [2]. At the alarmed the public to the epidemic of sudden deaths due beginning of twentieth century, the nonselective α-AR to asthma in England, Wales, Scotland, Ireland, Australia and ß-AR agonist epinephrine was introduced into clini- and New Zealand and linked it to an increase in the con- cal practice and administered by the subcutaneous route sumption of isoprenaline (a nonselective β mimetic) [23] for the treatment of acute asthma [3, 4]. Although highly and then fenoterol (classified as a selective β2 mimetic Fig. 1 Timeline for the introduction of adrenergic receptor agonists in asthma treatment [2–16]. AR adrenoceptor K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 3 of 14 Fig. 2 Localization and function of β‑adrenoceptors [17, 18]. AR adrenoceptors Fig. 3 Adverse effects and harmful drug interaction in patients using SABA. #salbutamol [21], ~ fenoterol [22] Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 4 of 14 but with some affinity for β1 receptors) [24, 25]. The experts to use this treatment regimen in patients with mechanism behind this correlation was not known, but sporadic and mild asthma remained unchanged. in 1989 in New Zealand, fenoterol was withdrawn from Again, great concerns over the use of β2 mimetics the market, which resulted in a reduction in the country’s surfaced in 2006 when the results of the SMART study asthma-related mortality [26]. (Salmeterol Multicenter Asthma Research Trial) were In the early 1990s, Spitzer et al. [27] reviewed the Sas- published [33]. In this study, salmeterol, a long-acting katchewan Canadian province database and found an β2-agonist (LABA), was included as an add-therapy to association between the regular use of SABA and mor- previous asthma treatments. The study was conducted bidity and mortality in asthmatics. The authors proved on a very large population of asthmatic patients (26,000). that SABA use was associated with an increased risk Statistical analysis showed a small but statistically sig- of death from asthma (odds ratio, 2.6 per canister per nificant increase in mortality and life-threatening events month, 95% CI 1.7–3.9). They concluded that, regard - associated with asthma in the group of patients using sal- less of whether or not beta-agonists are directly respon- meterol. This research sparked a new discussion on the sible for these serious side effects or are simply a marker association of these events with the use of LABA, and of more severe asthma, the excessive use of SABA by connections to the negative experiences with SABA were patients should alarm providers to the urgent need of drawn. It was concluded that the cause of these deaths patient status reassessment. may have been inadequate anti-inflammatory treatment Two years later, the same team [28] published results in these patients, because 9 out of 13 reported deaths of an epidemiological analysis showing an association occurred in patients who were not using ICS at the time between the use of fenoterol, salbutamol and oral corti- of salmeterol inclusion. This finding reinforced the rec - costeroids in the previous year and sudden asthma deaths ommendations of GINA experts to use LABA only with as well as between the number of hospitalizations due ICS and to prefer a fixed combination of ICS-LABA, but to asthma in the previous 2  years and fatal cases. They it did not change their position on SABA monotherapy also calculated that the risk of death increased dramati- at the first stage of asthma treatment. Thus, a ques - cally after exceeding the usage of 1.4 SABA canisters per tion arises: Why weren’t these SABA recommendations month. changed earlier? In 1998, this team issued another publication [29] ana- Intermittent and mild asthma was considered to be lyzing the reasons for hospital admissions due to asthma. primarily a disease of bronchoconstriction, although in The investigators observed that the inclusion of regular 1988, Wardlaw et  al. [34] had already shown that both therapy with ICS in the year in which asthma was diag- symptomatic and asymptomatic mild asthmatics had air- nosed reduced the risk of hospital admission by 40% way inflammation. Using bronchoalveolar lavage (BAL), compared with theophylline therapy. In 2000, Suissa et al. they found a significantly increased percentage of mast [30] reported that the use of low doses of ICS reduced the cells in all asthmatics and a significant elevation in eosin - risk of sudden death from asthma. They calculated that ophil count and in the concentration of major basic pro- the rate of death from asthma decreased by 21% with tein (MBP) in the group of symptomatic patients. They each additional canister of ICS used in the previous year. also showed an inverse correlation between PC20 and the However, the mortality rate of patients who discontinued percentage of mast cells (p < 0.01), eosinophils (p < 0.05), ICS therapy increased quickly within the first 3 months epithelial cells (p < 0.05), and the amount of MBP in BAL of treatment discontinuation. (p < 0.01). In 1990, Foresi et al. [35] confirmed the occur - In the same year, two more interesting studies were rence of marked airway inflammation in asymptomatic published. Hancox et al. [31] showed that the regular use asthmatic patients. They performed bronchoscopy, bron - of terbutaline led to the development of tolerance to the chial biopsies and BAL in young lifetime nonsmoking bronchodilating effect of the drug, and the discontinua - subjects with a history of asthma who had diurnal PEF tion of such treatment caused rebound bronchoconstric- variability lower than 20% and were free from acute res- tion. In the second study, Aldridge et al. [32] showed that piratory infections or spontaneous asthma attacks within regular, high-dose terbutaline monotherapy increased the previous month. These patients controlled their eosinophil infiltration in the bronchi compared to the asthma symptoms with only SABA as needed or on a placebo group; however, using the same doses of terb- daily basis and held off using their medication for a 24-h utaline concurrently with budesonide reduced the initial period before the bronchoscopy. The investigators found eosinophilia. Both of these studies provided insight into greater cell infiltration of the epithelium and submucosa the pathomechanism of adverse reactions associated with in the asthmatic subjects compared with healthy sub- SABA monotherapy and warned against the use of SABA jects. Additionally, eosinophils and intraepithelial mast monotherapy, but the recommendations from GINA cells were higher in the asthmatic group. A thickened K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 5 of 14 Fig. 4 Timeline for SABA position changes in asthma management according to the GINA guidelines 1995–2019 [36, 37]. ICS inhaled corticosteroids, LABA long acting beta2 agonist, RABA rapid acting beta2 agonist, SABA short acting beta2 agonist, SMART single inhaler maintenance and rescue therapy, MART maintenance and rescue therapy, BUD budesonide, BDP beclomethasone, FORM formoterol basement membrane was associated with more marked In the late 1990s, two big international epidemiologi- cell infiltration in the submucosa. The cells in BAL cal studies were carried out (ARIE [38] and Asthma in broadly reflected cell infiltration of the submucosa, and America [39]), which indicated the need for changes in the degree of bronchial responsiveness was correlated asthma management. They showed that, despite the pro - with ciliated cells in BAL and with intraepithelial cells in gress in pharmacological therapy and the updated rec- bronchial biopsies. ommendations for asthma management, most patients were symptomatic, with up to 50% feeling significantly The previous GINA recommendation impaired in their activities of daily living due to asthma, for intermittent and mild asthma management approximately 11–23% making emergency depart- Despite obvious evidence of airway inflammation in ment visits in the previous year, and 7–9% having severe patients with mild asthma, SABA held a strong position exacerbations that required hospitalization. Moreover, in the GINA recommendations from 1995 until 2019 patients relied too heavily on SABAs and did not use ICS (Fig.  4) [36, 37]. The only changes over the years con - as they should have (while 63% of patients used a SABA, cerned the recommended maximum number of SABA only 23% used an ICS). inhalations during the first step of treatment, which var - Since the publication of the first guidelines in 1995, ied from 1 inhalation per week in 1995 to 2 inhalations many important changes have been introduced to per week in 2006 and fewer than 2 inhalation per month improve asthma outcomes. In 2006, the severity classifi - in 2014. In 2002, formoterol, a long-acting β2-agonist cation was changed to assess control when making thera- with a rapid onset of action was recommended as a res- peutic decisions, and single inhaler maintenance and cue medication but only in patients receiving ICS. The reliever therapy (SMART) was recommended. The man - question then arises: Why was SABA not also consid- agement of intermittent and mild asthma was unchanged, ered as a rescue medication for use only in patients using however, and remained consistent from when SABAs ICS? In 2014, a fixed combination of ICS with formoterol were introduced for use approximately 50 years ago. (budesonide and beclomethasone) was recommended Moreover, later cross-sectional studies showed that, as a rescue medication from the third step of treatment despite the very important changes in GINA recom- in patients receiving such medications as a maintenance mendations, asthma control was still suboptimal in therapy but not during the first or second steps, where a approximately 50% (45–56, 5%) of patients. Severe exac- SABA was the only preferred rescue medication [36]. erbations were still common and had occurred in 44% of patients within the previous year; 24% of those patients Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 6 of 14 had needed an emergency department visit, and 12% most of these patients could not correctly identify drugs had been hospitalized [40]. Uncontrolled asthma was the for asthma prescribed by doctors. reason for a poor asthma-related quality of life (QoL), a There is one more interesting study from 1997 per - high risk of exacerbations and significant consumption of formed by Donahue et al. [45]. The investigators showed healthcare resources [41]. that SABA use was associated with an increased risk of It was a sign that there was a need for further changes hospitalization. The overall relative risk (RR) of hospi - in recommendations. talization among those who received inhaled steroids was low and was 0.5 (95% confidence interval [CI], 0.4–0.6) New concept in management of intermittent after adjusting for SABA dispensing. The steroid-asso - and mild asthma ciated protection was most marked among individu- The epidemiological data proved that mild, intermittent, als who received the largest amount of SABA, while the and persistent asthma are the most frequent forms of the group of patients using eight or more SABA inhalations disease and concern more than 50% of patients (ARIA), per day and ICS as maintenance therapy experienced which explains their great impact on the overall asthma a nearly 75% decrease in the risk of exacerbations com- burden. pared to patients using only SABA. A fixed combination of SABA/rapid acting beta2 agonists (RABA) and ICS as Risk of severe exacerbations in mild asthma a rescue medication therefore may protect against severe In 2007, Dusser et  al. [42] published a review show- exacerbations. ing that patients suffering from mild asthma quite often experience severe exacerbations at a frequency rang- History of the BUD‑FORM as needed concept ing from 0.12 to 0.77 per patient per year. Severe exac- In 2008, in their review on the position of BUD-FORM, erbations in mild asthma represent as many as 30–40% Kuna and Kupryś-Lipińska [46] proposed an extension of of asthma exacerbations requiring emergency consulta- SMART and the inclusion of BUD-FORM as the medica- tion. Even patients with mild symptoms meeting the cri- tion to be used on demand from the first step of therapy teria of asthma controlled by GINA are at risk of severe according to the GINA guidelines. BUD-FORM serving exacerbations (experiencing symptoms varying from 0 to as a rescue medication during the first and second steps 1–2 times per week). They constituted more than 70% of of treatment could be a smooth transition to SMART patient consults for acute asthma and patients with acute in the further steps. The idea of using BUD-FORM on near fatal asthma in emergency departments. demand as the preferred therapy for the first and second steps of treatment was based on the clinical experience of Risk of asthma exacerbation in patients overusing SABA the authors as well as the previous clinical studies and the or using them in monotherapy knowledge of patient preferences and behavior, which Later, Stanford et  al. [43] determined the magnitude were presented in the review. of the risk of asthma exacerbation depending on SABA Studies using formoterol or BUD-FORM as a res- demand. Based on two large databases, researchers cal- cue drug provided the most important support for this culated that the consumption of 3 or more SABA canis- concept. ters within the previous year increased the risk of asthma exacerbation. For adults, such a marker may be the use of Pharmacological basis of the BUD‑FORM as needed 2 or more SABA canisters in a shorter 3–6 month period. concept The use of an additional SABA canister resulted in a cor - In 1996, Schreurs et  al. [47] demonstrated the dose- responding increase in the risk of asthma exacerbation dependent effect of formoterol (6, 12 and 24  µg#) in the by 8% to 14% and 14% to 18% in children and adults, maintenance therapy of patients with moderate asthma. respectively. Compared to placebo, 6  μg formoterol b.i.d. was found In a survey conducted by Price et al. [44] in eight Asian to be the lowest effective dose for improving the morn - countries, only 14.5% of respondents taking exclusively ing (p = 0.008) and evening (p = 0.0041) peak expiratory rescue medications had controlled asthma, and two- flow (PEF). Increasing the dose from 6 to 24 μg b.i.d. pro - −1 thirds had experienced severe exacerbations in the previ- vided an additional effect of 18 L  min (p = 0.035) in ous year. Unfortunately, in this study, similar proportions the evening PEF. In 1998, Malolepszy et  al. [48] demon- of adverse events were also found in the group taking strated the effectiveness and safety of formoterol at high controller medications, which may be because respond- doses in the treatment of acute severe airway obstruction. ents confess that they fear the regular use of asthma Adult patients with asthma and COPD who had been drugs and then only take them occasionally; additionally, admitted to intensive care units with acute severe bron- choconstriction (FEV1 = 20–50% of the predicted value) K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 7 of 14 were randomized to receive 20 inhalations of either for- more beneficial than using RABA alone in patients with moterol (4.5 μg^) or terbutaline (0.5 mg) within the first intermittent asthma and signs of airway inflammation. 3 h of therapy, but all received 40 mg of methylpredniso- lone i.v. in the 90th min of therapy. High doses of formo- Patient preferences and commitment as an essential terol were equally as effective as terbutaline in improving element of therapy effectiveness supporting the concept lung function. Additionally, formoterol therapy resulted of BUD‑FORM as needed in significantly lower pulse rates than terbutaline therapy, For physicians working with patients, solving patents’ which confirmed the safety profile of formoterol admin - everyday problems and meeting expectations are essen- istered in high doses. Five years later, a similar study was tial elements of asthma management. Understanding the performed comparing formoterol with salbutamol in an factors that influence patient behavior may help to deter - emergency setting [49]. In this study, using 54 µg^ of for- mine the most effective regimen. Therefore, the results moterol compared to 3600  µg of salbutamol resulted in of the study on patients’ adherence to therapy are vitally greater acute lung function improvement over the 4-h important. assessment period. The Respiratory Patients Opinions Survey In 2001, Palmqvist et  al. [50] showed the rapid onset (RESPONSE) [54], performed in Europe, showed that of bronchodilation (within the first 3 min) after inhala - the majority of patients prefer to use fewer asthma drugs tion of BUD-FORM (160/4.5 µg^ one or two doses). This and to have just one inhaler. Further studies of patient effect was not observed after FLUT-SALM administra - behavior revealed that over half of patients tend to rely tion compared to placebo. on reliever medication [55] and thus underuse ICS [38]. Another group of investigators [51] confirmed the Studies show that fewer than 50% of patients adhere to immediate bronchodilation following BUD-FORM in the prescribed schema [56, 57]. Regardless of the fact that patients with methacholine-induced moderate-to-severe people forget to take drugs regularly, patients are also bronchoconstriction and demonstrated rapid improve- concerned about the side effects of long-term therapy ment of dyspnea (1 min after inhalation) as well as a and dependence [58] and therefore decrease the doses shorter recovery time to 85% baseline lung function themselves or even stop taking drugs when they feel bet- (approximately 3 min) than FLUT-SALM (approximately ter. A fixed combination of ICS with RABA as a reliever 9 min) or the placebo (30 min). therapy eliminates the risk of using RABA relievers alone and thus increases safety. Clinical evidence from first short term studies supporting Patients with chronic conditions tend to have a strong the BUD‑FORM as needed concept influence on the treatment process, regardless of the effi - In 2006, two very interesting studies on the use of BUD- cacy of the therapy. Therefore, asthma management must FORM as a rescue medication were published. In Bate- be a compromise between patient and physician prefer- man et  al. [52] study, budesonide-formoterol (with a ences. The goal for physicians is complete asthma control, total dose of 1280/36  µg^) and formoterol (with a total while from a patient’s perspective, limiting the influence dose of 36  µg^) provided similarly rapid relief of acute of asthma and its therapy on real life is most important. bronchoconstriction in patients with asthma who were The fixed ICS and formoterol combination has been previously refractory to SABA treatment. The second shown to improve both the safety and the effectiveness of study was SOMA, performed by Haahtela et  al. [53] asthma therapy as well as patients’ health-related quality The investigators compared the as-needed use of RABA of life. The usage of one inhaler with a simple and intui - (formoterol 4.5  µg^) with the as-needed use of a RABA tive regimen is the most preferred asthma therapy option and corticosteroid fixed combination (BUD-FORM by both patients and physicians. It also improves anti- 160/4.5  µg^) as the only medication in asthma patients inflammatory therapy in mild asthmatics, since patients’ with intermittent symptoms. The study population con - perception of ICS effectiveness is low and often results sisted of patients who had previously only used RABA as in the discontinuation of these drugs. Thus, when using a needed with FeNO > 20  ppb. Baseline FeNO was 60  ppb fixed dose combination product, with every rescue inha - and 59  ppb in the BUD-FORM and formoterol groups, lation, patients also receive anti-inflammatory treatment. respectively. During the 24 weeks of the study, FeNO was In 2008, the present authors emphasized that the fixed significantly reduced in patients receiving a combination combination of BUD-FORM as a reliever therapy elimi- of drugs from the fourth week of therapy until the end. nated the risk of SABA use as monotherapy, thus increas- The number of days of rescue medication use was signifi - ing patient safety. We also stressed that considering a cantly lower in the BUD-FORM group compared to the patient’s behavior and preferences is one of the ways to FORM group (21 days compared to 74 days). The authors improve a treatment’s effectiveness. concluded that the as-needed use of ICS-RABA may be Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 8 of 14 Fig. 5 Pro and con for using SABA and ICS‑FORM as relivers. SABA short acting beta2 agonist, ICS inhaled corticosteroids, FORM formoterol This innovative proposal was then criticized by review - options for the second step of treatment. The alternative ers, mainly due to the lack of registration of the drug for options include low-dose ICS whenever SABA is taken as this indication, although the benefits from using BUD- well as a leukotriene receptor antagonist. FORM as needed form the 1st step of therapy clearly out- What changes have caused these recommendations to weighed the doubts (Fig. 5.) appear? New GINA recommendation for mild asthmatics The proof of concept studies for the use At the time the 2019 GINA Report was published, nei- of ICS‑FORM as a reliever in first and second level ther BUD-FORM nor BDP-FORM had been registered therapy as on-demand relievers when not used in maintenance Over the last 10  years, several important clinical trials treatment; nonetheless, the GINA experts issued this rec- have been published. ommendation. For safety reasons, GINA no longer rec- In 2007, Papi et  al. [59] published the results of the ommends using SABAs as monotherapy. BEST study. This study showed that in patients with mild GINA experts recommend low-dose ICS-FORM as asthma, BDP-SALB (Salbutamol) 250/100 μg in a single needed (off label) as the preferred treatment option dur - inhaler, administered as needed, was as effective as the ing the first step of treatment for patients who suffer regular use of inhaled BDP (250 micrograms, twice daily) from asthma symptoms less than twice per month and and more effective than as needed SALB in improving who are not at risk of exacerbation. An alternative option morning PEF and in the prevention of exacerbations. is the use of low-dose ICS whenever SABA is taken. Martinez et al. [60] demonstrated in the TREXA study Maintenance use of low-dose ICS was recommended in that in children with mild persistent asthma, the most 2014 for patients with risk factors, but this therapy is no effective therapy to prevent exacerbations is regular, low- longer recommended due to the low rate of compliance dose ICS (BDP 40  μg 2 inhalations/day); however, ICS in these patients and the risk of exposing them to SABA- as a rescue medication along with SABA (BDP 80 μg for only treatment. each dose of SALB PRN) could be an effective strategy In addition to the other preferred options, low-dose for the prevention of exacerbations in children with well- ICS-FORM as needed and low-dose ICS and SABA as controlled mild asthma and is more effective than SABA needed were added by experts to the list of potential monotherapy. This new regimen allows children to avoid K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 9 of 14 daily inhaled corticosteroid treatments and their related by patients during the first step of therapy, but on the side-effects, such as growth impairment. other hand, these recommendations were much stricter Lazarinis et al. [61] demonstrated that combined BUD- and more inflexible during the second through fifth steps FORM (200/6 μg#) on demand improves asthma control of therapy. by reducing exercise-induced bronchoconstriction in the Experts also emphasize that the recommended changes same order of magnitude as regular budesonide (400 μg* are meant to counteract the trend of patients who rely once daily) treatment and terbutaline on demand, despite solely on rescue medications, which results in the dis- a substantially lower total steroid dose. Both these treat- continuation of ICS therapy because it is perceived as less ments were superior to terbutaline alone  on demand, effective in treating patients’ symptoms while also carry - which did not alter the bronchial response to exercise. ing risks of side effects. Patients using SABA as mono - A post hoc analysis of the START study results car- therapy have unconsciously increased their risk of severe ried out by Reddel et al. [62] showed that the use of low- exacerbations. Therefore, the need to track patterns of dose ICS (BUD 200 μg*/day in children or 400 μg*/day in patient behavior is a necessity to improve the adherence adults), even in patients with sporadic symptoms (zero to and safety of treatment (Fig. 5). one time per week), reduced the risk of exacerbating the disease by half compared to patients using only SABA. BUD‑FORM as needed for everyone or for patients Two studies published in 2018, SYGMA 1 and 2, seem with specific asthma phenotypes/endotypes to have been decisive for the change in GINA recommen- RABAs are considered the most effective drugs that dations. O’Byrne et  al. [63] (SYGMA 1) demonstrated reverse bronchospasm, and their choice does not require that in patients with mild asthma, a fixed combination the determination of asthma phenotypes or endotypes. of BUD-FORM (200/6  μg*) used as needed reduced There are studies mention above which show that for - the frequency of exacerbations by 64% compared to moterol is as effective and fast in bronchodilatation as SABA monotherapy. Moreover, the studies by O’Byrne salbutamol [49] and has good or even a better safety pro- (SYGMA 1) and Bateman (SYGMA 2) [64] both showed file [48]. The adding of BUD to FORM does not change that a BUD-FORM treatment regimen (200/6  μg* PRN) the bronchodilatory response [50] but guarantees taking protected mild asthmatics against exacerbations equally of ICS by patients who used relievers. The combination as effectively as low-dose ICS (BUD 200  μg* BID and of a low dose of BUD-FORM as a rescue medication is SABA as a rescue). preferred by GINA experts for treatment at the 1st and 2nd steps of treatment and for patients who use the same The reasons for changes in the GINA guidelines drug in maintenance therapy from step 3. Another com- The results of these studies coincided with the publica - bination—low dose of BDP-FORM can be also used as tion of alarming epidemiological data from England and reliever. SMART/MART therapy is especially recom- Wales, which showed the growing trend of deaths from mended for patients with asthma with the phenotype of asthma. In the last decade, the number of deaths due to frequent exacerbations, but it can be used in any patient asthma has increased there by 25%, reaching the highest who requires ICS-LABA [37]. number per year in this century [65]. However, neither BUD/BDP-FORM combinations are Since effective, safe medications are available and the the only recommended ICS-LABA by GINA experts, nor recommendations for how to effectively treat asthma are is BUD-FORM at the 1st and 2nd steps the only recom- commonly known, what is causing this increase? mended therapeutic option as described previously. If One of the problems seems to be the overuse of SABA other than ICS-FORM combined ICS-LABA is preferred, in monotherapy by patients with mild asthma. Therefore, SABA must be used as reliever. At 1st and 2nd step SABA for safety reasons, GINA no longer recommends treat- may be used but always with concurrent use ICS in one ment using only SABA monotherapy in any step. or separate inhalers [37]. The introduction of symptom-driven treatment that Leaving the classic regimens for asthma therapy is jus- combines RABA and ICS in the first step of therapy uni - tified by the availability of medical preparations and their fies the message (to providers and patients) of the prin - costs, by the patients’ habituation to the traditional treat- ciples of treating this disease, which had up to now been ment regimen and the choice of the suitable drug delivery contradictory. From the beginning, it has been com- system, by the lack of SMART/MART effectiveness in monly known that asthma is an inflammatory disease, certain patients, and finally by the possible but rare intol - but anti-inflammatory drugs were recommended only erance to formoterol. in the second step of therapy. Another problem was the From the above mentioned reasons, the biggest barrier ambiguous message given to patients: on one hand, the in popularizing BUD-FORM as a rescue medicine seems recommendations assumed freedom in the use of drugs to be the habit of patients and physicians holding to Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 10 of 14 traditional regimens of asthma therapy. And so, despite This approach to therapy was previously proposed by the availability of BUD-FORM in Poland and its reim- the authors in their review in 2008 [46]. bursement by the National Health Fund, one-third of Lack of clear indications for asthma treatment inten- patients using low dose BUD-FORM still use SABA as a sification may lead to uncertainty and limit the num - rescue [66]. ber of providers applying this treatment algorithm on a regular basis. Unmet needs in the GINA guidelines The second problem is the maintenance of SABA This chapter presents the personal views of the authors monotherapy in children during step one of treatment, regarding the needs for the development of asthma despite studies showing the beneficial effects of symp - guidelines tom-driven therapy with ICS in this age group and the Current changes to the GINA guidelines in the treatment popularity of this pattern with pediatricians. Declara- of patients with mild asthma are long-awaited changes tions on the shift from asthma being sheer bronchoc- with very strong evidence of efficacy, safety and patient onstriction to asthma as an inflammatory disease do acceptance [37]. not seem to apply to children. However, the new guidelines lack practical advice for Finally, the authors believe that the symptom-driven doctors and patients to seamlessly switch from the symp- approach in asthma therapy would be easier to imple- tom-driven therapy during the first and second steps of ment if the new approach was clearly separated from treatment to SMART therapy during the third through previously recommended treatments by modifying the fifth steps of treatment; furthermore, they do not clearly main GINA asthma management graph. This would state when to increase the maintenance dose of ICS dur- provide greater clarity regarding the new methods and ing SMART treatment. Perhaps by default, symptoms of would emphasize the flexibility of ICS doses, which uncontrolled asthma, as defined by GINA experts, should means a fluid rather than a rigid stepwise transition to be such a signal. the next level of therapy. As a reminder, the symptoms of uncontrolled asthma The authors’ proposed graphs can be found below: are daytime asthma symptoms appearing more fre- Fig.  6 (the new approach) and Fig.  7 (the conventional quently than twice a week, any nighttime waking due to approach). asthma, the need for reliever use due to asthma symp- And the last problem to think about for future is toms more than twice per week, and any limitation to whether biological therapies should be really at the end of activity due to asthma. the therapeutic ladder. In patients with severe asthma, the pathomorphological and pathophysiological changes may Fig. 6 Symptom‑ driven approach. ICS inhaled corticosteroids, FORM formoterol K uprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 11 of 14 Fig. 7 Conventional approach. ICS inhaled corticosteroids, LABA long acting beta2 agonist, SABA short acting beta2 agonis be irreversible. Earlier introduction of biological thera- and the results from clinical trials require years of analy- pies could prevent the development of severe asthma as sis. Therefore, we are witnessing an evolution rather than well as complications after OCS and high doses of ICS. a revolution in changing treatment patterns. Undoubt- It may also lead to a full remission of the disease as it was edly, an important lesson from the implementation of observed in anti-IgE therapy in children [67] and perhaps these asthma guidelines is that the careful observation of may be available in coming soon anti-TSLP or anti-IL-33 patients’ behavior can contribute to significant progress therapy. Due to the high costs of these therapies and the in the treatment of chronic diseases. The effectiveness of problematic route of administration, they may not gain treatment not only depends on the efficacy of the drug acceptance in mild asthma, but if every day good asthma itself and the systems for its administration, but it also control is interrupted by severe life-threatening attacks, depends on the patient’s acceptance and compliance. it may be worth considering anti-IgE in such asthmatics Treatment does not depend solely on the best medicine with an allergic background. being written on the prescription, but the one bought by the patient and used as recommended. The use of Summary SABA monotherapy in the treatment of chronic asthma Current changes in the asthma recommendations have is no doubt falling out of favor, but in order to completely been long-awaited and are focused on reducing the risk eliminate this treatment, the popularity of using com- of morbidity and mortality, which have been repeatedly bined preparations of ICS-RABA must be increased. emphasized by experts. One might wonder why these For those who are still unconvinced, new changes in changes were introduced so late, since it has been known the GINA guidelines, which are symptom-driven dur- for many years that the use of SABA monotherapy is ing the first and second steps of therapy together with associated with a serious risk of exacerbations and death. SMART treatment during the third through fifth steps, A fixed combination of ICS and RABA has been available create the most personalized asthma therapy we know, for many years, and it has been known that this combi- regardless of asthma phenotype and endotype, where nation increases the safety of patients, although there is the ICS dose is best-suited to asthma activity. It allows also an option to simultaneously use ICS and RABA from treatment with the lowest dose of ICS, which ensures a separate inhalers. One of the explanations for the delay low risk of side effects (which is extremely important for in changing the recommendations is that evidence from long-term treatment), while maintaining effectiveness to clinical trials is needed in order to make positive changes, ensure unhampered life activities and preventing severe Kuprys‑Lipinska et al. Clin Transl Allergy (2020) 10:19 Page 12 of 14 Availability of data and materials exacerbations. In addition, that is why, until the discovery All papers discussed in the review are accessible through medical databases of a drug that will cure asthma (which will be revolution- and are listed in the references. ary), the symptom-driven approach in asthma manage- Ethics approval and consent to participate ment, according to the authors, is the best therapeutic Not applicable. option and the most personalized option currently avail- able for the majority of patients. Consent for publication All authors provided written consent for the publication of this article. No personal patient data requiring consent for publication were used. Conclusions Competing interests IK‑L received personal fees for lectures from AstraZeneca, Chiesi, GSK, Nexter, 1. Many epidemiological, clinical and experimental data Novartis and Teva; PK received personal fees for lectures from Adamed, Allergopharma, Almirall, Astra‑ Zeneca, GSK, HAL, Meda, Pfizer, Polfarmex, have shown that SABA monotherapy and/or overuse Stallergen, Teva, and LekAM, and for lectures and advisory board activities are associated with a serious risk of exacerbations from Boehringer Ingelheim, Celon Pharma, Chiesi, FAES, MSD, Novartis, and and death. Polpharma. MK‑F received personal fees for lectures from AstraZeneca and Novartis. 2. Changes proposed in the 2019 GINA report (with- drawal of the recommendation for SABA in mono- Received: 31 October 2019 Accepted: 13 April 2020 therapy and the introduction of symptom-driven ICS-RABA therapy on 1st and 2nd step) are the most fundamental change to asthma therapy in the last 30 years. References 3. A fixed combination of ICS and RABA prevents 1. Global Initiative for Asthma. 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Clinical and Translational Allergy – Springer Journals

Published: Jun 3, 2020

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