asthma treatment essay

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Treatment strategies for asthma: reshaping the concept of asthma management

Alberto papi.

1 Section of Cardiorespiratory and Internal Medicine, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

7 Respiratory Unit, Emergency Department, University Hospital S. Anna, Via Aldo Moro 8, 44124 Ferrara, Italy

Francesco Blasi

2 Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

3 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

Giorgio Walter Canonica

4 Personalized Medicine Asthma & Allergy Clinic, Humanitas University & Istituto Clinico Humanitas, Milan, Italy

Luca Morandi

Luca richeldi.

5 Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy

Andrea Rossi

6 Respiratory Section, Department of Medicine, University of Verona, Verona, Italy

Associated Data

Not applicable.

Asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation. Asthma treatment is based on a stepwise and control-based approach that involves an iterative cycle of assessment, adjustment of the treatment and review of the response aimed to minimize symptom burden and risk of exacerbations. Anti-inflammatory treatment is the mainstay of asthma management. In this review we will discuss the rationale and barriers to the treatment of asthma that may result in poor outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life conditions and how these led to the GINA 2019 guidelines for asthma treatment and prevention will also be discussed.

Asthma, a major global health problem affecting as many as 235 million people worldwide [ 1 ], is a common, non-communicable, and variable chronic disease that can result in episodic or persistent respiratory symptoms (e.g. shortness of breath, wheezing, chest tightness, cough) and airflow limitation, the latter being due to bronchoconstriction, airway wall thickening, and increased mucus.

The pathophysiology of the disease is complex and heterogeneous, involving various host-environment interactions occurring at various scales, from genes to organ [ 2 ].

Asthma is a chronic disease requiring ongoing and comprehensive treatment aimed to reduce the symptom burden (i.e. good symptom control while maintaining normal activity levels), and minimize the risk of adverse events such as exacerbations, fixed airflow limitation and treatment side effects [ 3 , 4 ].

Asthma treatment is based on a stepwise approach. The management of the patient is control-based; that is, it involves an iterative cycle of assessment (e.g. symptoms, risk factors, etc.), adjustment of treatment (i.e. pharmacological, non-pharmacological and treatment of modifiable risk factors) and review of the response (e.g. symptoms, side effects, exacerbations, etc.). Patients’ preferences should be taken into account and effective asthma management should be the result of a partnership between the health care provider and the person with asthma, particularly when considering that patients and clinicians might aim for different goals [ 4 ].

This review will discuss the rationale and barriers to the treatment of asthma, that may result in poor patient outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life situations will also be discussed.

The treatment of asthma: where are we? Evolution of a concept

Asthma control medications reduce airway inflammation and help to prevent asthma symptoms; among these, inhaled corticosteroids (ICS) are the mainstay in the treatment of asthma, whereas quick-relief (reliever) or rescue medicines quickly ease symptoms that may arise acutely. Among these, short-acting beta-agonists (SABAs) rapidly reduce airway bronchoconstriction (causing relaxation of airway smooth muscles).

National and international guidelines have recommended SABAs as first-line treatment for patients with mild asthma, since the Global Initiative for Asthma guidelines (GINA) were first published in 1995, adopting an approach aimed to control the symptoms rather than the underlying condition; a SABA has been the recommended rescue medication for rapid symptom relief. This approach stems from the dated idea that asthma symptoms are related to bronchial smooth muscle contraction (bronchoconstriction) rather than a condition concomitantly caused by airway inflammation. In 2019, the GINA guidelines review (GINA 2019) [ 4 ] introduced substantial changes overcoming some of the limitations and “weaknesses” of the previously proposed stepwise approach to adjusting asthma treatment for individual patients. The concept of an anti-inflammatory reliever has been adopted at all degrees of severity as a crucial component in the management of the disease, increasing the efficacy of the treatment while lowering SABA risks associated with patients’ tendency to rely or over-rely on the as-needed medication.

Until 2017, the GINA strategy proposed a pharmacological approach based on a controller treatment (an anti-inflammatory, the pillar of asthma treatment), with a SABA as an additional rescue intervention. The reliever, a short-acting bronc hodilator, was merely an addendum , a medication to be used in case the real treatment (the controller) failed to maintain disease control: SABAs effectively induce rapid symptom relief but are ineffective on the underlying inflammatory process. Based on the requirement to achieve control, the intensity of the controller treatment was related to the severity of the disease, varying from low-dose ICS to combination low-dose ICS/long-acting beta-agonist (LABA), medium-dose ICS/LABA, up to high-dose ICS/LABA, as preferred controller choice, with a SABA as the rescue medication. As a result, milder patients were left without any anti-inflammatory treatment and could only rely on SABA rescue treatment.

Poor adherence to therapy is a major limitation of a treatment strategy based on the early introduction of the regular use of controller therapy [ 5 ]. Indeed, a number of surveys have highlighted a common pattern in the use of inhaled medication [ 6 ], in which treatment is administered only when asthma symptoms occur; in the absence of symptoms, treatment is avoided as patients perceive it as unnecessary. When symptoms worsen, patients prefer to use reliever therapies, which may result in the overuse of SABAs [ 7 ]. Indirect evidence suggests that the overuse of beta-agonists alone is associated with increased risk of death from asthma [ 8 ].

In patients with mild persistent disease, low-dose ICS decreases the risk of severe exacerbations leading to hospitalization and improves asthma control [ 9 ]. When low-dose ICS are ineffective in controlling the disease (Step 3 of the stepwise approach), a combination of low-dose ICS with LABA maintenance was the recommended first-choice treatment, plus as-needed SABA [ 3 , 10 ]. Alternatively, the combination low-dose ICS/LABA (formoterol) was to be used as single maintenance and reliever treatment (SMART). The SMART strategy containing the rapid-acting formoterol was recommended throughout GINA Steps 3 to 5 based on solid clinical-data evidence [ 3 ].

The addition of a LABA to ICS treatment reduces both severe and mild asthma exacerbation rates, as shown in the one-year, randomized, double-blind, parallel-group FACET study [ 11 ]. This study focused on patients with persistent asthma symptoms despite receiving ICS and investigated the efficacy of the addition of formoterol to two dose levels of budesonide (100 and 400 µg bid ) in decreasing the incidence of both severe and mild asthma exacerbations. Adding formoterol decreased the incidence of both severe and mild asthma exacerbations, independent of ICS dose. Severe and mild exacerbation rates were reduced by 26% and 40%, respectively, with the addition of formoterol to the lower dose of budesonide; the corresponding reductions were 63% and 62%, respectively, when formoterol was added to budesonide at the higher dose.

The efficacy of the ICS/LABA combination was confirmed in the post hoc analysis of the FACET study, in which patients were exposed to a combination of formoterol and low-dose budesonide [ 12 ]. However, such high levels of asthma control are not achieved in real life [ 5 ]. An explanation for this is that asthma is a variable condition and this variability might include the exposure of patients to factors which may cause a transient steroid insensitivity in the inflammatory process. This, in turn, may lead to an uncontrolled inflammatory response and to exacerbations, despite optimal controller treatment. A typical example of this mechanism is given by viral infections, the most frequent triggers of asthma exacerbations. Rhinoviruses, the most common viruses found in patients with asthma exacerbations, interfere with the mechanism of action of corticosteroids making the anti-inflammatory treatment transiently ineffective. A transient increase in the anti-inflammatory dose would overcome the trigger-induced anti-inflammatory resistance, avoiding uncontrolled inflammation leading to an exacerbation episode [ 13 – 15 ].

Indeed, symptoms are associated with worsening inflammation and not only with bronchoconstriction. Romagnoli et al. showed that inflammation, as evidenced by sputum eosinophilia and eosinophilic markers, is associated with symptomatic asthma [ 16 ]. A transient escalation of the ICS dose would prevent loss of control over inflammation and decrease the risk of progression toward an acute episode. In real life, when experiencing a deterioration of asthma control, patients self-treat by substantially increasing their SABA medication (Fig.  1 ); it is only subsequently that they (modestly) increase the maintenance treatment [ 17 ].

Mean use of SABA at different stages of asthma worsening. Patients have been grouped according to maintenance therapy shown in the legend. From [ 17 ], modified

As bronchodilators, SABAs do not control the underlying inflammation associated with increased symptoms. The “as required” use of SABAs is not the most effective therapeutic option in controlling a worsening of inflammation, as signaled by the occurrence of symptoms; instead, an anti-inflammatory therapy included in the rescue medication along with a rapid-acting bronchodilator could provide both rapid symptom relief and control over the underlying inflammation. Thus, there is a need for a paradigm shift, a new therapeutic approach based on the rescue use of an inhaled rapid-acting beta-agonist combined with an ICS: an anti-inflammatory reliever strategy [ 18 ].

The symptoms of an exacerbation episode, as reported by Tattersfield and colleagues in their extension of the FACET study, increase gradually before the peak of the exacerbation (Fig.  2 ); and the best marker of worsening asthma is the increased use of rescue beta-agonist treatment that follows exactly the pattern of worsening symptomatology [ 19 ]. When an ICS is administered with the rescue bronchodilator, the patient would receive anti-inflammatory therapy when it is required; that is, when the inflammation is uncontrolled, thus increasing the efficiency of the anti-inflammatory treatment.

Percent variation in symptoms, rescue beta-agonist use and peak expiratory flow (PEF) during an exacerbation. In order to allow comparison over time, data have been standardized (Day-14 = 0%; maximum change = 100%)

(From [ 19 ])

Barriers and paradoxes of asthma management

A number of barriers and controversies in the pharmacological treatment of asthma have prevented the achievement of effective disease management [ 20 ]. O’Byrne and colleagues described several such controversies in a commentary published in 2017, including: (1) the recommendation in Step 1 of earlier guidelines for SABA bronchodilator use alone, despite asthma being a chronic inflammatory condition; and (2) the autonomy given to patients over perception of need and disease control at Step 1, as opposed to the recommendation of a fixed-dose approach with treatment-step increase, regardless of the level of symptoms [ 20 ]. Other controversies outlined were: (3) a difficulty for patients in understanding the recommendation to minimize SABA use at Step 2 and switch to a fixed-dose ICS regimen, when they perceive SABA use as more effective; (4) apparent conflicting safety messages within the guidelines that patient-administered SABA monotherapy is safe, but patient-administered LABA monotherapy is not; and (5) a discrepancy as to patients’ understanding of “controlled asthma” and their symptom frequency, impact and severity [ 20 ].

Controversies (1) and (2) can both establish an early over-dependence on SABAs. Indeed, asthma patients freely use (and possibly overuse) SABAs as rescue medication. UK registry data have recently suggested SABA overuse or overreliance may be linked to asthma-related deaths: among 165 patients on short-acting relievers at the time of death, 56%, 39%, and 4% had been prescribed > 6, > 12, and > 50 SABA inhalers respectively in the previous year [ 21 ]. Registry studies have shown the number of SABA canisters used per year to be directly related to the risk of death in patients with asthma. Conversely, the number of ICS canisters used per year is inversely related to the rate of death from asthma, when compared with non-users of ICS [ 8 , 22 ]. Furthermore, low-dose ICS used regularly are associated with a decreased risk of asthma death, with discontinuation of these agents possibly detrimental [ 22 ].

Other barriers to asthma pharmacotherapy have included the suggestion that prolonged treatment with LABAs may mask airway inflammation or promote tolerance to their effects. Investigating this, Pauwels and colleagues found that in patients with asthma symptoms that were persistent despite taking inhaled glucocorticoids, the addition of regular treatment with formoterol to budesonide for a 12-month period did not decrease asthma control, and improved asthma symptoms and lung function [ 11 ].

Treatment strategies across all levels of asthma severity

Focusing on risk reduction, the 2014 update of the GINA guidelines recommended as-needed SABA for Step 1 of the stepwise treatment approach, with low-dose ICS maintenance therapy as an alternative approach for long-term anti-inflammatory treatment [ 23 ]. Such a strategy was only supported by the evidence from a post hoc efficacy analysis of the START study in patients with recently diagnosed mild asthma [ 24 ]. The authors showed that low-dose budesonide reduced the decline of lung-function over 3 years and consistently reduced severe exacerbations, regardless of symptom frequency at baseline, even in subjects with symptoms below the then-threshold of eligibility for ICS [ 24 ]. However, as for all post hoc analyses, the study by Reddel and colleagues does not provide conclusive evidence and, even so, their results could have questionable clinical significance for the management of patients with early mild asthma. To be effective, this approach would require patients to be compliant to regular twice-daily ICS for 10 years to have the number of exacerbations reduce by one. In real life, it is highly unlikely that patients with mild asthma would adhere to such a regular regimen [ 25 ].

The 2016 update to the GINA guidelines lowered the threshold for the use of low-dose ICS (GINA Step 2) to two episodes of asthma symptoms per month (in the absence of any supportive evidence for the previous cut-off). The objective was to effectively increase the asthma population eligible to receive regular ICS treatment and reduce the population treated with a SABA only, given the lack of robust evidence of the latter’s efficacy and safety and the fact that asthma is a variable condition characterized by acute exacerbations [ 26 ]. Similarly, UK authorities recommended low-dose ICS treatment in mild asthma, even for patients with suspected asthma, rather than treatment with a SABA alone [ 10 ]. However, these patients are unlikely to have good adherence to the regular use of an ICS. It is well known that poor adherence to treatment is a major problem in asthma management, even for patients with severe asthma. In their prospective study of 2004, Krishnan and colleagues evaluated the adherence to ICS and oral corticosteroids (OCS) in a cohort of patients hospitalized for asthma exacerbations [ 27 ]. The trend in the data showed that adherence to ICS and OCS treatment in patients dropped rapidly to reach nearly 50% within 7 days of hospital discharge, with the rate of OCS discontinuation per day nearly double the rate of ICS discontinuation per day (− 5.2% vs. − 2.7%; p < 0.0001 respectively, Fig.  3 ), thus showing that even after a severe event, patients’ adherence to treatment is suboptimal [ 27 ].

Use of inhaled (ICS) and oral (OCS) corticosteroids in patients after hospital discharge among high-risk adult patients with asthma. The corticosteroid use was monitored electronically. Error bars represent the standard errors of the measured ICS and OCS use

(From [ 27 ])

Guidelines set criteria with the aim of achieving optimal control of asthma; however, the attitude of patients towards asthma management is suboptimal. Partridge and colleagues were the first in 2006 to evaluate the level of asthma control and the attitude of patients towards asthma management. Patients self-managed their condition using their medication as and when they felt the need, and adjusted their treatment by increasing their intake of SABA, aiming for an immediate relief from symptoms [ 17 ]. The authors concluded that the adoption of a patient-centered approach in asthma management could be advantageous to improve asthma control.

The concomitant administration of an as-needed bronchodilator and ICS would provide rapid relief while administering anti-inflammatory therapy. This concept is not new: in the maintenance and reliever approach, patients are treated with ICS/formoterol (fast-acting, long-acting bronchodilator) combinations for both maintenance and reliever therapy. An effective example of this therapeutic approach is provided in the SMILE study in which symptomatic patients with moderate to severe asthma and treated with budesonide/formoterol as maintenance therapy were exposed to three different as-needed options: SABA (terbutaline), rapid-onset LABA (formoterol) and a combination of LABA and ICS (budesonide/formoterol) [ 28 ]. When compared with formoterol, budesonide/formoterol as reliever therapy significantly reduced the risk of severe exacerbations, indicating the efficacy of ICS as rescue medication and the importance of the as-needed use of the anti-inflammatory reliever.

The combination of an ICS and a LABA (budesonide/formoterol) in one inhaler for both maintenance and reliever therapy is even more effective than higher doses of maintenance ICS and LABA, as evidenced by Kuna and colleagues and Bousquet and colleagues (Fig.  4 ) [ 29 , 30 ].

Comparison between the improvements in daily asthma control resulting from the use of budesonide/formoterol maintenance and reliever therapy vs. higher dose of ICS/LABA + SABAZ and steroid load for the two regimens

(Data from [ 29 , 30 ])

The effects of single maintenance and reliever therapy versus ICS with or without LABA (controller therapy) and SABA (reliever therapy) have been recently addressed in the meta-analysis by Sobieraj and colleagues, who analysed 16 randomized clinical trials involving patients with persistent asthma [ 31 ]. The systematic review supported the use of single maintenance and reliever therapy, which reduces the risk of exacerbations requiring systemic corticosteroids and/or hospitalization when compared with various strategies using SABA as rescue medication [ 31 ].

This concept was applied to mild asthma by the BEST study group, who were the first to challenge the regular use of ICS. A pilot study by Papi and colleagues evaluated the efficacy of the symptom-driven use of beclomethasone dipropionate plus albuterol in a single inhaler versus maintenance with inhaled beclomethasone and as-needed albuterol. In this six-month, double-blind, double-dummy, randomized, parallel-group trial, 455 patients with mild asthma were randomized to one of four treatment groups: an as-needed combination therapy of placebo bid plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler; an as-needed albuterol combination therapy consisting of placebo bid plus 100 μg of albuterol; regular beclomethasone therapy, comprising beclomethasone 250 μg bid and 100 μg albuterol as needed); and regular combination therapy with beclomethasone 250 μg and albuterol 100 μg in a single inhaler bid plus albuterol 100 μg as needed.

The rescue use of beclomethasone/albuterol in a single inhaler was as efficacious as the regular use of inhaled beclomethasone (250 μg bid ) and it was associated with a lower 6-month cumulative dose of the ICS [ 32 ].

The time to first exacerbation differed significantly among groups ( p  = 0.003), with the shortest in the as-needed albuterol and placebo group (Fig.  5 ). Figure  5 also shows equivalence between the as-needed combination therapy and the regular beclomethasone therapy. However, these results were not conclusive since the study was not powered to evaluate the effect of the treatment on exacerbations. In conclusion, as suggested by the study findings, mild asthma patients may require the use of an as-needed ICS and an inhaled bronchodilator rather than a regular treatment with ICS [ 32 ].

Kaplan Meier analysis of the time to first exacerbation (modified intention-to-treat population). First asthma exacerbations are shown as thick marks. As-needed albuterol therapy = placebo bid plus 100 μg of albuterol as needed; regular combination therapy = 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler bid plus 100 μg of albuterol as needed; regular beclomethasone therapy = 250 μg of beclomethasone bid and 100 μg of albuterol as needed; as-needed combination therapy = placebo bid plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed

(From [ 32 ])

Moving forward: a new approach to the management of asthma patients

Nearly a decade after the publication of the BEST study in 2007, the use of this alternative therapeutic strategy was addressed in the SYGMA 1 and SYGMA 2 trials. These double-blind, randomized, parallel-group, 52-week phase III trials evaluated the efficacy of as-needed use of combination formoterol (LABA) and the ICS budesonide as an anti-inflammatory reliever in patients requiring GINA Step 2 treatment, with the current reliever therapy (e.g. as-needed SABA) or with low-dose maintenance ICS (inhaled budesonide bid ) plus as-needed SABA, administered as regular controller therapy [ 33 , 34 ].

The SYGMA 1 trial, which enrolled 3849 patients, aimed to demonstrate the superiority of the as-needed use of the combination budesonide/formoterol over as-needed terbutaline, as measured by the electronically-recorded proportion of weeks with well-controlled asthma [ 34 ]. The more pragmatic SYGMA 2 trial enrolled 4215 patients with the aim to demonstrate that the budesonide/formoterol combination is non-inferior to budesonide plus as-needed terbutaline in reducing the relative rate of annual severe asthma exacerbations [ 33 ]. Both trials met their primary efficacy outcomes. In particular, as-needed budesonide/formoterol was superior to as-needed SABA in controlling asthma symptoms (34.4% versus 31.1%) and preventing exacerbations, achieving a 64% reduction in exacerbations. In both trials, budesonide/formoterol as-needed was similar to budesonide maintenance bid at preventing severe exacerbations, with a substantial reduction of the inhaled steroid load over the study period (83% in the SYGMA 1 trial and 75% in the SYGMA 2 trial). The time to first exacerbation did not differ significantly between the two regimens; however, budesonide/formoterol was superior to SABA in prolonging the time to first severe exacerbation [ 33 , 34 ].

The double-blind, placebo-controlled design of the SYGMA trials does not fully address the advantages of anti-inflammatory reliever strategy in patients who often rely on SABAs for symptom relief, so to what extent the study findings could apply to real-life practice settings was unclear.

These limitations were overcome by the results of the Novel START study, an open-label, randomized, parallel-group, controlled trial designed to reflect real-world practice, which demonstrated the effectiveness in mild asthma of budesonide/formoterol as an anti-inflammatory reliever therapy [ 35 ].

In real-world practice, mild asthma patients are treated with an as-needed SABA reliever or with daily low-dose ICS maintenance therapy plus a SABA reliever. In the Novel START study, 668 patients with mild asthma were randomized to receive either as-needed albuterol 100 µg, two inhalations (SABA reliever as a continuation of the Step 1 treatment according to the 2017 GINA guidelines), budesonide 200 µg (ICS maintenance treatment) plus as-needed albuterol (Step 2 therapy of the GINA 2017 guidelines), or 200 µg/6 µg budesonide/formoterol as anti-inflammatory reliever therapy taken as-needed for a 52-week study period.

In this study, the rate of asthma exacerbations for budesonide/formoterol was lower compared with albuterol (51%) and similar to the twice-daily maintenance budesonide plus albuterol, despite a 52% reduction in the mean steroid dose with the single combination inhaler treatment [ 35 ]. In addition, severe exacerbation rate was lower with budesonide/formoterol as compared with as-needed albuterol and regular twice-daily budesonide. These data support the findings of the SYGMA 1 and 2 trials, highlighting the need for a critical re-examination of current clinical practice. Along with the results of the SYGMA trials, they provide convincing evidence of the advantages of the anti-inflammatory reliever strategy, particularly in real-life settings.

The SYGMA 1, SYGMA 2 and the novel START studies complete the picture of the treatment strategies for asthma at any degree of severity, including mild asthma. A growing body of evidence shows that an anti-inflammatory reliever strategy, when compared with all other strategies with SABA reliever, consistently reduces the rate of exacerbations across all levels of asthma severity (Fig.  6 ) [ 28 , 29 , 34 , 36 – 39 ].

Risk reduction of severe asthma attack of anti-inflammatory reliever versus SABA across all levels of asthma severity. Bud = budesonide; form = formoterol; TBH = turbohaler. Data from: 1: [ 36 ]; 2: [ 37 ]; 3: [ 38 ]; 4: [ 28 ]; 5: [ 29 ]; 6: [ 30 ]; 7: [ 34 ]

(Data source: [ 39 ])

This evidence set the ground (Fig.  7 ) for the release of the 2019 GINA strategy updates. The document provides a consistent approach towards the management of the disease and aims to avoid the overreliance and overuse of SABAs, even in the early course of the disease. The 2019 GINA has introduced key changes in the treatment of mild asthma: for safety reasons, asthmatic adults and adolescents should receive ICS-containing controller treatment instead of the SABA-only treatment, which is no longer recommended.

Timeline of key randomized controlled trials and meta-analyses providing the supporting evidence base leading to the Global Initiative for Asthma (GINA) 2019 guidelines. GINA global initiative for asthma, MART maintenance and reliever therapy, SMART single inhaler maintenance and reliever therapy

In Step 1 of the stepwise approach to adjusting asthma treatment, the preferred controller option for patients with fewer than two symptoms/month and no exacerbation risk factors is low-dose ICS/formoterol as needed. This strategy is indirectly supported by the results of the SYGMA 1 study which evaluated the efficacy and safety of budesonide/formoterol as needed, compared with as-needed terbutaline and budesonide bid plus as-needed terbutaline (see above). In patients with mild asthma, the use of an ICS/LABA (budesonide/formoterol) combination as needed provided superior symptom control to as-needed SABA, resulting in a 64% lower rate of exacerbations (p = 0.07) with a lower steroid dose (17% of the budesonide maintenance dose) [ 34 ]. The changes extend to the other controller options as well. In the 2017 GINA guidelines, the preferred treatment was as-needed SABA with the option to consider adding a regular low-dose ICS to the reliever. In order to overcome the poor adherence with the ICS regimen, and with the aim to reduce the risk of severe exacerbations, the 2019 GINA document recommends taking low-dose ICS whenever SABA is taken, with the daily ICS option no longer listed.

Previous studies including the TREXA study in children and adolescents [ 40 ], the BASALT study [ 41 ] and research conducted by the BEST study group [ 32 ] have already added to the evidence that a low-dose ICS with a bronchodilator is an effective strategy for symptom control in patients with mild asthma. A recently published study in African-American children with mild asthma found that the use of as-needed ICS with SABA provides similar asthma control, exacerbation rates and lung function measures at 1 year, compared with daily ICS controller therapy [ 42 ], adding support to TREXA findings that in children with well controlled, mild asthma, ICS used as rescue medication with SABA may be an efficacious step-down strategy [ 40 ].

In Step 2 of the stepwise approach, there are now two preferred controller options: (a) a daily low-dose ICS plus an as-needed SABA; and (b) as-needed low-dose ICS/formoterol. Recommendation (a) is supported by a large body of evidence from randomized controlled trials and observations showing a substantial reduction of exacerbation, hospitalization, and death with regular low-dose ICS [ 7 – 9 , 24 , 43 ], whereas recommendation (b) stems from evidence on the reduction or non-inferiority for severe exacerbations when as-needed low-dose ICS/formoterol is compared with regular ICS [ 33 , 34 ].

The new GINA document also suggests low-dose ICS is taken whenever SABA is taken, either as separate inhalers or in combination. This recommendation is supported by studies showing reduced exacerbation rates compared with taking a SABA only [ 32 , 40 ], or similar rates compared with regular ICS [ 32 , 40 , 41 ]. Low-dose theophylline, suggested as an alternative controller in the 2017 GINA guidelines, is no longer recommended.

Airway inflammation is present in the majority of patients with asthma, and although patients with mild asthma may have only infrequent symptoms, they face ongoing chronic inflammation of the lower airways and risk acute exacerbations. The GINA 2019 strategy recognizes the importance of reducing the risk of asthma exacerbations, even in patients with mild asthma (Steps 1 and 2) [ 4 ]. In this regard, the new recommendations note that SABA alone for symptomatic treatment is non-protective against severe exacerbation and may actually increase exacerbation risk if used regularly or frequently [ 4 ].

The reluctance by patients to regularly use an ICS controller means they may instead try and manage their asthma symptoms by increasing their SABA reliever use. This can result in SABA overuse and increased prescribing, and increased risk of exacerbations.

As part of the global SABINA (SABA use IN Asthma) observational study programme, a UK study examined primary care records to describe the pattern of SABA and ICS use over a 10-year period in 373,256 patients with mild asthma [ 44 ]. Results showed that year-to-year SABA prescribing was more variable than that of ICS indicating that, in response to fluctuations in asthma symptom control, SABA use was increased in preference to ICS use. Furthermore, more than 33% of patients were prescribed SABA inhalers at a level equivalent to around ≥ 3 puffs per week which, according to GINA, suggests inadequate asthma control.

The problem of SABA overuse is further highlighted by two studies [ 45 , 46 ], also as part of the SABINA programme. These analysed data from 365,324 patients in a Swedish cohort prescribed two medications for obstructive lung disease in any 12-month period (HERA).

The first study identified SABA overuse (defined as ≥ 3 SABA canisters a year) in 30% of patients, irrespective of their ICS use; 21% of patients were collecting 3–5 canisters annually, 7% were collecting 6–10, and 2% more than 11 [ 45 ]. Those patients who were overusing SABA had significantly more asthma exacerbations relative to those using < 3 canisters (20.0 versus 12.5 per 100 patient years; relative risk 1.60, 95% CI 1.57–1.63, p < 0.001). Moreover, patients overusing SABA and whose asthma was more severe (GINA Steps 3 and 4) had greater exacerbation risk compared with overusing patients whose asthma was milder (GINA Steps 1 and 2).

The second study found those patients using three or more SABA reliever canisters a year had an increased all-cause mortality risk relative to patients using fewer SABA canisters: hazard ratios after adjustment were 1.26 (95% CI 1.14–1.39) for 3–5 canisters annually, 1.67 (1.49–1.87) for 6–10 canisters, and 2.35 (2.02–2.72) for > 11 canisters, relative to patients collecting < 3 canisters annually [ 46 ].

The recently published PRACTICAL study lends further support to as-needed low-dose ICS/formoterol as an alternative option to daily low-dose ICS plus as-needed SABA, outlined in Step 2 of the guidelines [ 47 ]. In their one-year, open-label, multicentre, randomized, superiority trial in 890 patients with mild to moderate asthma, Hardy and colleagues found that the rate of severe exacerbations per patient per year (the primary outcome) was lower in patients who received as-needed budesonide/formoterol than in patients who received controller budesonide plus as-needed terbutaline (relative rate 0.69, 95% CI 0.48–1.00; p < 0.05). Indeed, they suggest that of these two treatment options, as-needed low-dose ICS/formoterol may be preferred over controller low-dose ICS plus as-needed SABA for the prevention of severe exacerbations in this patient population.

Step 3 recommendations have been left unchanged from 2017, whereas Step 4 treatment has changed from recommending medium/high-dose ICS/LABA [ 3 ] to medium-dose ICS/LABA; the high-dose recommendation has been escalated to Step 5. Patients who have asthma that remains uncontrolled after Step 4 treatment should be referred for phenotypic assessment with or without add-on therapy.

To summarise, the use of ICS medications is of paramount importance for optimal asthma control. The onset and increase of symptoms are indicative of a worsening inflammation leading to severe exacerbations, the risk of which is reduced by a maintenance plus as-needed ICS/LABA combination therapy. The inhaled ICS/bronchodilator combination is as effective as the regular use of inhaled steroids.

The efficacy of anti-inflammatory reliever therapy (budesonide/formoterol) versus current standard-of-care therapies in mild asthma (e.g. reliever therapy with a SABA as needed and regular maintenance controller therapy plus a SABA as-needed) has been evaluated in two randomized, phase III trials which confirmed that, with respect to as-needed SABA, the anti-inflammatory reliever as needed is superior in controlling asthma and reduces exacerbation rates, exposing the patients to a substantially lower glucocorticoid dose.

Conclusions

A growing body of evidence shows that anti-inflammatory reliever strategy is more effective than other strategies with SABA reliever in controlling asthma and reducing exacerbations across all levels of asthma severity. A budesonide/formoterol therapy exposes asthma patients to a substantially lower glucocorticoid dose while cutting the need for adherence to scheduled therapy.

Acknowledgements

The Authors thank Maurizio Tarzia and Gayle Robins, independent medical writers who provided editorial assistance on behalf of Springer Healthcare Communications. The editorial assistance was funded by AstraZeneca.

Abbreviations

Authors’ contributions.

AP, FB, GWC, LM, LR and AR contributed to writing. All authors read and approved the final manuscript.

No funding was received for this study. The editorial assistance was funded by AstraZeneca.

Availability of data and materials

Ethics approval and consent to participate, consent for publication, competing interests.

AP reports grants, personal fees, non-financial support and payment for advisory board membership, consultancy, payment for lectures, grants for research, and travel expenses reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and Teva, and personal fees and non-financial support from Menarini, Novartis, Zambon and Sanofi.

FB reports having received in the last three years research grants as well as lecture or advisory board fees from: Alk-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, Guidotti, Glaxo Smith Kline, Grifols, Menarini, Novartis, Sanofi, Valeas, Zambon.

GWC reports having received in the last 3 years research grants as well as lecture or advisory board fees from: A. Menarini, Alk-Abelló, AstraZeneca-Medimmune, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Hal Allergy, Merck Sharp & Dohme, Mundipharma, Novartis, Orion, Sanofi-Aventis, Sanofi Genzyme/Regeneron, Stallergenes-Greers, UCB Pharma, Uriach Pharma, Valeas.

LR Receipt of grants/research supports: Roche, Boehringer Ingelheim.

Receipt of honoraria or consultation fees: Boehringer Ingelheim, Roche, Biogen, FibroGen,

Sanofi-Aventis, Anthera, Promedior, ImmuneWorks, Asahi-Kasei, Bayer, Celgene, RespiVant,

Nitto, Bristol Myers Squibb, Prometic, Pliant Therapeutics, Toray, Global Blood Therapeutics,

Zambon, Veracyte, Acceleron, CSL Behring.

LM and AR reports no conflicts of interest in the last 3 years.

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Asthma treatment: 3 steps to better asthma control.

Follow this three-step approach to keep asthma symptoms under control and prevent asthma attacks.

The goals of asthma treatment are to limit symptoms, prevent asthma attacks and avoid side effects of asthma medicines. The following three steps can help you take control of your asthma treatment.

1. Follow your asthma action plan

Your health care team may work with you to create a written asthma action plan. This plan tells you how to make decisions every day and when to take your medicines. Following this plan is key to controlling your asthma.

A plan has three parts with color codes:

• Green. The green zone of the plan is for times you are feeling well and have no asthma symptoms. The plan tells you what dose of long-term control medicine to take every day. It also tells you how many puffs of a quick-relief inhaler to take before you exercise.
• Yellow. The yellow zone tells you what to do if you have symptoms. It explains when to use a quick-relief inhaler and how many puffs to take. It also describes what to do if your symptoms don't improve and when to call your care team.
• Red. The red zone tells you when to get emergency care if symptoms don't improve or if they worsen.

2. Use at-home lung tests

Your health care team may ask you to use a device that measures how well your lungs are working. This is called a lung function test.

Your asthma action plan includes instructions for when or how often you should do a lung function test. The plan also tells you what to do if the test shows your lungs aren't working well.

You may use one of these devices:

• Peak flow meter. This device measures how quickly you can force air out of your lungs. Peak flow readings are usually a percentage of how your lungs work at their best. This is called your personal best peak flow.
• Spirometer. A spirometer measures how much air your lungs can hold and how quickly you can breathe out. This measurement is called forced expiratory volume (FEV-1). Your FEV-1 measurement is compared with the typical FEV-1 for people who don't have asthma. As with your peak flow reading, this comparison is often given as a percentage. Your health care team will likely use this test during your office visits, but you may need to use a hand-held spirometer at home.

3. Keep an asthma diary

Keep an asthma diary every day. This information helps you keep track of your symptoms and helps you share accurate information with your health care team. Record the following information:

• Dose of long-term and quick-relief medicines you use each day.
• Description of symptoms.
• Severity and duration of symptoms.
• Time of day when symptoms occur.
• Possible triggers of symptoms, such as exercise or allergies.
• Difficulty with work, school, exercise or other day-to-day activities because of asthma symptoms.
• Results of a lung function test.
• Unscheduled appointments or urgent care for asthma.

Symptoms to record in your asthma diary include:

• Shortness of breath or coughing.
• Whistling sounds when you exhale, called wheezing.
• Disturbed sleep caused by shortness of breath, coughing or wheezing.
• Chest tightness or pain.
• Hay fever symptoms such as sneezing and runny nose.

Work with your health care team

You will likely meet with your care team regularly for checkups to see how you are doing. Bring your written asthma action plan and your asthma diary to every appointment. The information in your diary helps your asthma specialist know if your asthma is well controlled, poorly controlled or very poorly controlled.

Levels of asthma control in people 12 and older

If your asthma is well controlled, your provider may lower the dose of your medicines. If your asthma is poorly controlled or very poorly controlled, you may need to take different medicines or higher doses of medicine. These changes are recorded in your new asthma action plan.

You also may need to take steps to control triggers, such as increasing or changing allergy treatments. You may need to take steps to remove or avoid asthma triggers.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

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• Fanta CH. An overview of asthma management. https://www.uptodate.com/contents/search. Accessed May 8, 2023.
• Asthma care quick reference: Diagnosing and managing asthma. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthma_qrg_0_0.pdf. Accessed May 16, 2023.
• Asthma action plans. Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/actionplan.html. Accessed May 8, 2023.
• Learn More Breathe Better (LLMB): Monitoring your asthma. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/resources/lmbb-monitoring-your-asthma. Accessed May 16, 2023.
• Asthma: Diagnosis. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health/asthma/diagnosis. Accessed May 16, 2023.
• Learn More Breath Better (LLMB): Tips for talking to your health care provider about asthma. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/resources/lmbb-tips-talking-your-health-care-provider-about-asthma. Accessed May 16, 2023.

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• Published: 13 August 2021

Biological therapy for severe asthma

• Silvano Dragonieri   ORCID: orcid.org/0000-0003-1563-6864 1 &
• Giovanna Elisiana Carpagnano 1  

Asthma Research and Practice volume  7 , Article number:  12 ( 2021 ) Cite this article

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Around 5–10% of the total asthmatic population suffer from severe or uncontrolled asthma, which is associated with increased mortality and hospitalization, increased health care burden and worse quality of life. In the last few years, new drugs have been launched and several asthma phenotypes according to definite biomarkers have been identified. In particular, therapy with biologics has revolutionized the management and the treatment of severe asthma, showing high therapeutic efficacy associated with significant clinical benefits. To date, four types of biologics are licensed for severe asthma, i.e. omalizumab (anti-immunoglobulin E) antibody, mepolizumab and reslizumab (anti-interleukin [IL]-5antibody), benralizumab (anti-IL-5 receptor a antibody) and dupilumab (anti-IL-4 receptor alpha antibody). The aim of this article was to review the biologic therapies currently available for the treatment of severe asthma, in order to help physicians to choose the most suitable biologic agent for their asthmatic patients.

Since the beginning of this millennium, asthma assessment and management have been revolutionized. While some new therapeutic approaches have been suggested for mild asthmatics, the most relevant changes have occurred in severe asthma. Severe asthma accounts for the 5–10% of the global asthma population, with 3 to 5% being uncontrolled despite adherence to therapy and proper use of inhalers [ 1 ]. These subjects cannot achieve symptoms control despite maximal therapy with inhaled corticosteroids (ICS) and, quite often, maintenance oral corticosteroids (OCS) are necessary in an endeavor to avoid life-threatening exacerbations [ 2 ]. Although OCS courses remain essential for the management of acute exacerbations, their recurrent or continuous usage is associated with several complications, such as an increased risk of developing osteoporotic fractures and pneumonia [ 3 ]. Moreover, other conditions including cardiovascular and cerebrovascular events, renal dysfunction, diabetes mellitus type 2, humor alterations, obesity and sleep apneas are known to be associated with systemic corticosteroid exposure [ 3 ]. Additionally, many patients remain poorly controlled and show recurrent exacerbations despite a strict adherence to therapy [ 4 ].

The recent advances in our knowledge of the etiopathological mechanisms of different phenotypes and endotypes of severe asthma gave us very innovative therapies, such as biological drugs for severe asthma. These medications are mostly directed against molecules involved in the type 2 inflammatory pathway, thus modifying the natural course of the disease by reducing airways inflammation without the collateral damage associated with corticosteroids. Based on the above, the aim of this article was to review the biologic therapies currently available for the treatment of severe asthma, in order to help physicians to choose the most suitable biologic agent for their asthmatic patients.

Licensed medications for severe asthma

To date, there are five biologic molecules officially approved for use in selected severe asthmatic patients. The first of these is omalizumab, an anti-IgE monoclonal antibody acting through various mechanisms on allergic pathways (Table 1 ). Three more biologics for asthma, belonging to a different class, have been approved, i.e. mepolizumab, reslizumab and benralizumab. They all target the interleukin-5 (IL-5) pathway with the first two targeting the interleukin itself and the last one its receptor. Finally, dupilumab is a monoclonal antibody against the receptor of interleukin-4 (IL-4) which blocks the signaling pathways of IL-4 and IL-13.

BIOLOGICS TARGETING IgE

Omalizumab was the first targeted biologic therapy developed and licensed for severe asthma, being approved by the Food and Drugs Administration in 2003 [ 5 ]. It is a recombinant monoclonal Antibody which binds to IgE, thereby lowering blood IgE levels of up to 99% [ 6 ]. Moreover, It decreases expression of IgE receptor FCRI on inflammatory cells such as mast cells and basophils, thus helping to both mitigate the allergic response and strengthen the antiviral immune response, finally leading to prevent asthma exacerbations [ 7 ]. Omalizumab is approved in adults and children above 6 years old with IgE-driven moderate-to-severe persistent allergic asthma which remains uncontrolled despite GINA step 4/5 treatment, high levels of blood IgE, and documented sensitization to a perennial allergen [ 8 ]. Its dosage varies according to patient’s bodyweight and circulating IgE levels and it is administered subcutaneously every 14 or 28 days [ 9 ]. Although not necessary from a safety point of view, it is advisable to re-evaluate patients after the initial 16 weeks of treatment to assess the drug efficacy before continuing with omalizumab therapy [ 8 ].

The efficacy and safety of omalizumab are nowadays unquestionably recognized, with numerous studies demonstrating that this biological is generally well-tolerated, with no serious adverse effects reported [ 10 , 11 , 12 , 13 , 14 , 15 ]. Common side effects include injection site or diffuse rash, fever, nose bleeding, joint pain, gastro-intestinal disturbances, headache, dizziness and cold symptoms [ 10 , 11 , 12 , 13 , 14 , 15 ]. A Cochrane systematic review assessing 25 randomized controlled trials in patients with allergic asthma showed the efficacy of omalizumab in reducing asthma exacerbations, hospitalizations, and inhaled corticosteroid dosage [ 10 , 15 , 16 , 17 , 18 , 19 ].

During the last few years, a number of biomarkers for monitoring the efficacy of omalizumab therapy have been proposed, including total and antigen-specific IgE, blood eosinophil count and exhaled nitric oxide (FeNO) [ 20 , 21 ]. Surprisingly, total IgE did not appear to be a reliable predictor of response to omalizumab therapy, evidencing that our knowledge on this field is still limited [ 21 ]. Peripheral blood eosinophil count ≥300 cells/mL are linked to higher asthma severity and to a better response to omalizumab [ 22 , 23 ]. Furthermore, patients under omalizumab with higher blood eosinophil count have a higher chance to suffer from asthma exacerbations in case of omalizumab discontinuation [ 24 ]. Regarding FeNO, elevated values at baseline correlated with a better response to omalizumab with regard to exacerbations decrease [ 20 , 25 ]. Likewise, elevated levels of FeNO after suspension of long-term therapy with omalizumab may be a predictor of successive exacerbations [ 24 ].

Biologics targeting IL-5

IL-5 is a well-known regulator of the activation, differentiation, effector function, migration and survival and effector function of eosinophils [ 26 ]. Eosinophil levels associated with symptoms of asthma correlate with disease severity and increase the risk of asthma exacerbations, evidencing that this granulocyte type plays a key role in the pathophysiololgy of asthma [ 26 ]. Currently, licensed biologics against IL-5 pathways are mepolizumab, reslizumab, and benralizumab.

MEPOLIZUMAB

Mepolizumab is a monoclonal antibody directed against IL-5 which has been approved as an add-on treatment for patients ≥6 years old in Europe and for patients ≥12 years old in the USA. Mepolizumab was the first anti-IL-5 antibody approved for the treatment of severe asthma by the Food and Drugs Administration in 2015. Eligible subjects are those with severe eosinophilic asthma that remains uncontrolled despite GINA step 4/5 therapy, with blood eosinophil count of ≥150 cells/μl during the first administration or ≥ 300 cells/μl in the previous year and with at least 2 asthma exacerbations requiring systemic steroid course in the past year [ 27 , 28 ]. Mepolizumab is administered by a subcutaneous injection at a fixed dose of 100 mg every 28 days.

Several studies evaluating mepolizumab for uncontrolled eosinophilic asthma showed a markedly reduction with regard to number of exacerbations, systemic corticosteroid usage, emergency room accesses and hospital admissions, and a concurrent improvement of asthma controls and lung function parameters [ 29 , 30 , 31 , 32 , 33 ].

Furthermore, a number of studies revealed that mepolizumab has a positive long-term safety profile [ 34 , 35 , 36 ]. No reports of mepolizumab-associated anaphylaxis reactions were documented, as well as parasitic infections [ 34 , 35 , 36 ]. Common side effects include headache, injection site reaction, fatigue, flu symptoms, urinary tract infection, abdominal pain, itching, eczema, and muscle spasms [ 34 , 35 , 36 ].

Additionally, numerous investigations highlighted that the most important markers of response prediction to mepolizumab are the rate of previous exacerbation and baseline peripheral blood eosinophil count [ 29 , 32 , 37 , 38 , 39 ]. Indeed, a better clinical efficacy is directly proportional to a higher eosinophil count and to a higher rate of exacerbations [ 29 , 32 , 37 , 38 , 39 ]. Interestingly, mepolizumab effectiveness was not related to baseline IgE and to atopy [ 40 , 41 ] and earlier treatment with omalizumab is not a predictor for mepolizumab efficacy [ 42 , 43 , 44 ].

There is a lack of consensus about the duration of treatment before evaluating the effectiveness of mepolizumab. Actually, the GINA statement suggests that a 4-month trial may be adequate [ 8 ], whereas the NICE guidelines recommend that mepolizumab should not be discontinued before 12 months of therapy and that drug-responsiveness should be assessed every year [ 45 ].

Reslizumab is monoclonal antibody approved in 2016, which binds with high-affinity to IL-5 [ 46 ]. By an analogous mechanism of action to mepolizumab, reslizumab lowers circulating blood eosinophil levels [ 47 ]. It has been approved for patients ≥18 years old with severe eosinophilic asthma which remains uncontrolled despite therapy with high-doses of ICS plus another inhaler. Reslizumab is indicated in patients with ≥400 eosinophils/μl and history of asthma exacerbations in the previous 12 months [ 48 , 49 ]. Reslizumab is administered intravenously every 28 days at a weight-based dose of 3 mg/kg.

Similarly to mepolizumab, studies assessing reslizumab have shown a decreased number of asthma exacerbations and improved asthma control and lung function parameters in subjects with high blood eosinophil levels [ 47 , 50 ].

The safety profile of reslizumab has been evaluated for up to 24 months, revealing minor adverse effects without any reports of parasitic and opportunistic infections [ 51 ]. Most frequent side effects include cough, dizziness, itching, skin rash and fatigue [ 51 ].

However, despite its proven excellent clinical efficacy, intravenous formulation has a significant impact on the ease of administration compared to mepolizumab and/or benralizumab. Studies using reslizumab showed unsatisfactory results, without significant improvements in terms of acute exacerbations reduction or OCS lowering [ 52 ].

BENRALIZUMAB

Benralizumab is a monoclonal antibody approved in 2017 and directed against IL-5 receptor a (IL-5Ra) which induces eosinophil apoptosis via the antibody-dependent cell-mediated cytotoxicity (ADCC) involving natural killer cells, leading to peripheral blood eosinophil depletion [ 53 , 54 ]. Benralizumab acts like a competitive inhibitor to IL-5, binding with higher affinity to the a-subunit of IL-5Ra, which is expressed on mature (and precursors) eosinophils and basophils [ 55 ].

This biologic drug is licensed as an add-on treatment for uncontrolled severe eosinophilic asthma in patients ≥18 years with ≥300 blood eosinophils/μl [ 56 , 57 ]. A 30 mg dose of benralizumab is injected subcutaneously every 28 days for the first 3 administrations and afterwards every 56 days.

Large studies evaluating benralizumab in patients with moderate to severe asthma have shown a decrease in exacerbations number, improved lung function, and reduced use of OCS [ 53 , 54 , 58 ]. Combined analysis of these investigation have revealed that the best predictors of response to benralizumab are adult-onset asthma, more than 3 exacerbations in the previous year, nasal polyposis and pre-bronchodilator FVC < 65% of predicted [ 53 , 54 , 58 ].. The most common adverse effect were fever after the first injection, headache and pharyngitis [ 53 , 54 , 58 ].

Interestingly, based on its mechanism, benralizumab almost completely depletes blood eosinophils within 24 h of administration and a total depletion of airway eosinophils compared to that caused by mepolizumab [ 59 , 60 ]. Likewise, nasal eosinophils were totally suppressed after 6 months of therapy with benralizumab [ 61 ].

Recently, some concerns have been raised about the theoretical risks following an eosinophil depletion, especially with respect to host defense. However, these warnings were not confirmed, since it appears that there is adequate redundancy within human immune apparatus, which is not impaired by eosinophils depletion [ 62 ].

Biologics targeting IL-4 and IL-13

IL-4 and IL-13 are two interleukins which regulate and drive Type-2 inflammation. IL-4 increases the Th-2 cell population and B-cell isotype rearrangement of IgE as well as promoting eosinophilic transmigration through endothelium, whereas IL-13 plays an important role in asthma by promoting airway hyperresponsiveness, mucus secretion and airway remodeling [ 63 , 64 ]. Thus far, the only licensed drug acting on the two aforementioned ILs is dupilumab.

Dupilumab is a monoclonal antibody approved in 2018 which binds to the IL-4 receptor alpha-subunit, mutual to IL-4 and IL-13 receptors and inhibits both IL-4 and IL-13 pathways. Dupilumab is licensed as an add-on maintenance therapy in asthmatic patients GINA step 4/5 ≥ 12 years with type 2 inflammation characterized by increased blood eosinophils and/or raised FeNO. Dupilumab is administered subcutaneously at a starting dose of two injections of 200 mg each (total 400 mg), followed by one injection of 200 mg every 14 days, or at a starting dose of 600 mg (two injections of 300 mg each) followed by 300 mg every 14 days. The latter regimen is recommended for asthmatic subjects strictly dependent from OCS or with atopic dermatitis [ 65 ]. Dupilumab is also indicated for moderate to severe atopic dermatitis and for nasal polyposis.

A number of studies have demonstrated that therapy with dupilumab in severe asthmatics lowers the number of asthma exacerbations, improves lung function parameters and asthma control test scores, and lowers the use of OCS, irrespective of peripheral blood eosinophil count [ 66 , 67 , 68 , 69 ]. Indeed, a transitory increase of blood eosinophilia at the beginning of treatment with dupilumab has been observed although it may be due to blocked migration into tissues rather than hyperproduction [ 69 ]. Furthermore, reduced levels of T2 inflammation markers, including FeNO, serum levels of eotaxin-3, periostin and thymus and activation regulated chemokine (TARC) and total IgE, may serve as parameters for monitoring the efficacy of therapy with dupilumab [ 66 , 67 , 68 , 69 ]. The most common adverse reactions were injection site reactions, various types of infections, conjunctivitis and related conditions [ 66 , 67 , 68 , 69 ].

Biologics under development

Research for next-generation biologics is ongoing. Currently, other effector molecules are under the spotlight as new targets for perspective biological therapies, particularly the so-called alarmins [ 70 ]. These molecules are released by the airway epithelium against the harmful actions of germs, pollutants, allergens and cigarette smoke.

Tezepelumab is a human monoclonal antibody which binds to thymic stromal lymphopoietin (TSLP), an epithelium-derived alarmin that plays a relevant role in the pathogenesis of asthma, being an upstream effector T2-high pathobiologic pathways [ 71 , 72 , 73 ]. With the presence of tezepelumab, TLSP cannot bind to its receptor [ 74 ] hence inhibiting downstream signaling. A number of phase 2 and 3 trials have clearly shown that patients with severe uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo [ 75 , 76 ]. Concerning its safety profile, neither investigational tezepelumab-related anaphylactic reactions nor the detection of neutralizing antibodies were reported [ 75 , 76 ]. To date, license application for tezepelumab has been accepted and granted Priority Review for the treatment of asthma from the US Food and Drug Administration, whose regulatory decision is expected during the first quarter of 2022.

Ipetekimab is a monoclonal antibody targeting IL-33, another alarmin which associates with TSLP leading to an activation of T2-high inflammatory pathway in asthma [ 77 ]. Phase 2 studies with this biologic are ongoing, however preliminary results did not show adequate efficacy in severe asthmatics when associated with dupilumab or vs dupilumab alone [ 70 ].

Moreover, Tralokinumab and lebrokizumab are monoclonal antibodies both targeting IL-13 alone with disappointing results of phase 3 studies in terms of exacerbations reduction and OCS sparing in severe asthmatics [ 78 ].

Finally, regarding Th2-low asthma, mainly characterized by a neutrophilic airways inflammation, efforts are focusing on its pathogenic cascade involving cytokines such as IL-1beta, IL-17 and IL-23. Several monoclonal antibodies against the aforementioned interleukins such as canakinumab (anti IL-1beta), brodalumab (anti IL-17 receptor) and risankizumab (anti IL-23) are under evaluation with phase 1–2 trials showing controversial results [ 79 , 80 , 81 ].

Which biologic should I choose for my asthmatic patient?

When choosing a biologic medication for their patients with severe uncontrolled asthma, clinicians should always take into account the asthma endotype, clinical biomarkers, and patient-focused aspects (Fig 1 ).

Algorithm for Selecting Ideal Biologic Treatment for severe uncontrolled asthma

Omalizumab should always be the first biological option in allergic non-eosinophilic severe asthmatics, with high levels of blood IgE, and with at least a documented positivity to a perennial aeroallergen. Contrariwise, patients with a non-allergic eosinophilic phenotype should be treated with an anti-IL-5 biological drug. Finally, anti- IL-4/IL-13 should be reserved to patients with severe eosinophilic type 2 asthma OCS dependent [ 8 ].

Given to the a lack of comparison studies, to date there are no recommendations about the selection of appropriate anti IL-5 biologic drug among those available. Hence, the choice is empirical and possibly shared between physician and patient.

According to GINA guidelines, a (at least) 4-month trial should be carried to evaluate asthma control. In the event of poor asthma control, a switch to a different biological treatment can be attempted if the patient meets the eligibility criteria.

Nevertheless, the right time and the right modality of switching from one biologic to another and the treatment time are still unknown. Large studies focused on biological drug switch in patients with severe asthma are ongoing and will help physicians to ease therapeutic strategies.

Conclusions

Severe asthma accounts for a small proportion of total asthma cases, but impose a heavy burden on health care system. Recent revelations of the T2 inflammatory pathways and the development of monoclonal antibodies acting on the T2 cascade has completely revolutionized the management of severe asthma, by introducing new, life-improving treatment options for this class of patients. This paves the way for a biomarker-driven personalized medicine. Strictly following GINA recommendations, the categorization of T2 molecular targets has allowed the identification of patients with severe asthma who would likely respond to specific biological molecules. However, the most suitable biological option for severe asthmatics with overlapping phenotypes is still unclear, thus requiring further discriminatory and predicting biomarkers which may allow a better patient selection.

Availability of data and materials

Not applicable.

Abbreviations

interleukin

inhaled corticosteroids

oral corticosteroids

immunoglobulin E

fractional exhaled nitric oxide

forced vital capacity

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Dragonieri, S., Carpagnano, G.E. Biological therapy for severe asthma. asthma res and pract 7 , 12 (2021). https://doi.org/10.1186/s40733-021-00078-w

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Treatment strategies for asthma: reshaping the concept of asthma management

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• Giorgio Walter Canonica 4 ,
• Luca Morandi 1 , 7 ,
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Asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation. Asthma treatment is based on a stepwise and control-based approach that involves an iterative cycle of assessment, adjustment of the treatment and review of the response aimed to minimize symptom burden and risk of exacerbations. Anti-inflammatory treatment is the mainstay of asthma management. In this review we will discuss the rationale and barriers to the treatment of asthma that may result in poor outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life conditions and how these led to the GINA 2019 guidelines for asthma treatment and prevention will also be discussed.

Asthma, a major global health problem affecting as many as 235 million people worldwide [ 1 ], is a common, non-communicable, and variable chronic disease that can result in episodic or persistent respiratory symptoms (e.g. shortness of breath, wheezing, chest tightness, cough) and airflow limitation, the latter being due to bronchoconstriction, airway wall thickening, and increased mucus.

The pathophysiology of the disease is complex and heterogeneous, involving various host-environment interactions occurring at various scales, from genes to organ [ 2 ].

Asthma is a chronic disease requiring ongoing and comprehensive treatment aimed to reduce the symptom burden (i.e. good symptom control while maintaining normal activity levels), and minimize the risk of adverse events such as exacerbations, fixed airflow limitation and treatment side effects [ 3 , 4 ].

Asthma treatment is based on a stepwise approach. The management of the patient is control-based; that is, it involves an iterative cycle of assessment (e.g. symptoms, risk factors, etc.), adjustment of treatment (i.e. pharmacological, non-pharmacological and treatment of modifiable risk factors) and review of the response (e.g. symptoms, side effects, exacerbations, etc.). Patients’ preferences should be taken into account and effective asthma management should be the result of a partnership between the health care provider and the person with asthma, particularly when considering that patients and clinicians might aim for different goals [ 4 ].

This review will discuss the rationale and barriers to the treatment of asthma, that may result in poor patient outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life situations will also be discussed.

The treatment of asthma: where are we? Evolution of a concept

Asthma control medications reduce airway inflammation and help to prevent asthma symptoms; among these, inhaled corticosteroids (ICS) are the mainstay in the treatment of asthma, whereas quick-relief (reliever) or rescue medicines quickly ease symptoms that may arise acutely. Among these, short-acting beta-agonists (SABAs) rapidly reduce airway bronchoconstriction (causing relaxation of airway smooth muscles).

National and international guidelines have recommended SABAs as first-line treatment for patients with mild asthma, since the Global Initiative for Asthma guidelines (GINA) were first published in 1995, adopting an approach aimed to control the symptoms rather than the underlying condition; a SABA has been the recommended rescue medication for rapid symptom relief. This approach stems from the dated idea that asthma symptoms are related to bronchial smooth muscle contraction (bronchoconstriction) rather than a condition concomitantly caused by airway inflammation. In 2019, the GINA guidelines review (GINA 2019) [ 4 ] introduced substantial changes overcoming some of the limitations and “weaknesses” of the previously proposed stepwise approach to adjusting asthma treatment for individual patients. The concept of an anti-inflammatory reliever has been adopted at all degrees of severity as a crucial component in the management of the disease, increasing the efficacy of the treatment while lowering SABA risks associated with patients’ tendency to rely or over-rely on the as-needed medication.

Until 2017, the GINA strategy proposed a pharmacological approach based on a controller treatment (an anti-inflammatory, the pillar of asthma treatment), with a SABA as an additional rescue intervention. The reliever, a short-acting bronc hodilator, was merely an addendum , a medication to be used in case the real treatment (the controller) failed to maintain disease control: SABAs effectively induce rapid symptom relief but are ineffective on the underlying inflammatory process. Based on the requirement to achieve control, the intensity of the controller treatment was related to the severity of the disease, varying from low-dose ICS to combination low-dose ICS/long-acting beta-agonist (LABA), medium-dose ICS/LABA, up to high-dose ICS/LABA, as preferred controller choice, with a SABA as the rescue medication. As a result, milder patients were left without any anti-inflammatory treatment and could only rely on SABA rescue treatment.

Poor adherence to therapy is a major limitation of a treatment strategy based on the early introduction of the regular use of controller therapy [ 5 ]. Indeed, a number of surveys have highlighted a common pattern in the use of inhaled medication [ 6 ], in which treatment is administered only when asthma symptoms occur; in the absence of symptoms, treatment is avoided as patients perceive it as unnecessary. When symptoms worsen, patients prefer to use reliever therapies, which may result in the overuse of SABAs [ 7 ]. Indirect evidence suggests that the overuse of beta-agonists alone is associated with increased risk of death from asthma [ 8 ].

In patients with mild persistent disease, low-dose ICS decreases the risk of severe exacerbations leading to hospitalization and improves asthma control [ 9 ]. When low-dose ICS are ineffective in controlling the disease (Step 3 of the stepwise approach), a combination of low-dose ICS with LABA maintenance was the recommended first-choice treatment, plus as-needed SABA [ 3 , 10 ]. Alternatively, the combination low-dose ICS/LABA (formoterol) was to be used as single maintenance and reliever treatment (SMART). The SMART strategy containing the rapid-acting formoterol was recommended throughout GINA Steps 3 to 5 based on solid clinical-data evidence [ 3 ].

The addition of a LABA to ICS treatment reduces both severe and mild asthma exacerbation rates, as shown in the one-year, randomized, double-blind, parallel-group FACET study [ 11 ]. This study focused on patients with persistent asthma symptoms despite receiving ICS and investigated the efficacy of the addition of formoterol to two dose levels of budesonide (100 and 400 µg bid ) in decreasing the incidence of both severe and mild asthma exacerbations. Adding formoterol decreased the incidence of both severe and mild asthma exacerbations, independent of ICS dose. Severe and mild exacerbation rates were reduced by 26% and 40%, respectively, with the addition of formoterol to the lower dose of budesonide; the corresponding reductions were 63% and 62%, respectively, when formoterol was added to budesonide at the higher dose.

The efficacy of the ICS/LABA combination was confirmed in the post hoc analysis of the FACET study, in which patients were exposed to a combination of formoterol and low-dose budesonide [ 12 ]. However, such high levels of asthma control are not achieved in real life [ 5 ]. An explanation for this is that asthma is a variable condition and this variability might include the exposure of patients to factors which may cause a transient steroid insensitivity in the inflammatory process. This, in turn, may lead to an uncontrolled inflammatory response and to exacerbations, despite optimal controller treatment. A typical example of this mechanism is given by viral infections, the most frequent triggers of asthma exacerbations. Rhinoviruses, the most common viruses found in patients with asthma exacerbations, interfere with the mechanism of action of corticosteroids making the anti-inflammatory treatment transiently ineffective. A transient increase in the anti-inflammatory dose would overcome the trigger-induced anti-inflammatory resistance, avoiding uncontrolled inflammation leading to an exacerbation episode [ 13 , 14 , 15 ].

Indeed, symptoms are associated with worsening inflammation and not only with bronchoconstriction. Romagnoli et al. showed that inflammation, as evidenced by sputum eosinophilia and eosinophilic markers, is associated with symptomatic asthma [ 16 ]. A transient escalation of the ICS dose would prevent loss of control over inflammation and decrease the risk of progression toward an acute episode. In real life, when experiencing a deterioration of asthma control, patients self-treat by substantially increasing their SABA medication (Fig.  1 ); it is only subsequently that they (modestly) increase the maintenance treatment [ 17 ].

Mean use of SABA at different stages of asthma worsening. Patients have been grouped according to maintenance therapy shown in the legend. From [ 17 ], modified

As bronchodilators, SABAs do not control the underlying inflammation associated with increased symptoms. The “as required” use of SABAs is not the most effective therapeutic option in controlling a worsening of inflammation, as signaled by the occurrence of symptoms; instead, an anti-inflammatory therapy included in the rescue medication along with a rapid-acting bronchodilator could provide both rapid symptom relief and control over the underlying inflammation. Thus, there is a need for a paradigm shift, a new therapeutic approach based on the rescue use of an inhaled rapid-acting beta-agonist combined with an ICS: an anti-inflammatory reliever strategy [ 18 ].

The symptoms of an exacerbation episode, as reported by Tattersfield and colleagues in their extension of the FACET study, increase gradually before the peak of the exacerbation (Fig.  2 ); and the best marker of worsening asthma is the increased use of rescue beta-agonist treatment that follows exactly the pattern of worsening symptomatology [ 19 ]. When an ICS is administered with the rescue bronchodilator, the patient would receive anti-inflammatory therapy when it is required; that is, when the inflammation is uncontrolled, thus increasing the efficiency of the anti-inflammatory treatment.

(From [ 19 ])

Percent variation in symptoms, rescue beta-agonist use and peak expiratory flow (PEF) during an exacerbation. In order to allow comparison over time, data have been standardized (Day-14 = 0%; maximum change = 100%)

Barriers and paradoxes of asthma management

A number of barriers and controversies in the pharmacological treatment of asthma have prevented the achievement of effective disease management [ 20 ]. O’Byrne and colleagues described several such controversies in a commentary published in 2017, including: (1) the recommendation in Step 1 of earlier guidelines for SABA bronchodilator use alone, despite asthma being a chronic inflammatory condition; and (2) the autonomy given to patients over perception of need and disease control at Step 1, as opposed to the recommendation of a fixed-dose approach with treatment-step increase, regardless of the level of symptoms [ 20 ]. Other controversies outlined were: (3) a difficulty for patients in understanding the recommendation to minimize SABA use at Step 2 and switch to a fixed-dose ICS regimen, when they perceive SABA use as more effective; (4) apparent conflicting safety messages within the guidelines that patient-administered SABA monotherapy is safe, but patient-administered LABA monotherapy is not; and (5) a discrepancy as to patients’ understanding of “controlled asthma” and their symptom frequency, impact and severity [ 20 ].

Controversies (1) and (2) can both establish an early over-dependence on SABAs. Indeed, asthma patients freely use (and possibly overuse) SABAs as rescue medication. UK registry data have recently suggested SABA overuse or overreliance may be linked to asthma-related deaths: among 165 patients on short-acting relievers at the time of death, 56%, 39%, and 4% had been prescribed > 6, > 12, and > 50 SABA inhalers respectively in the previous year [ 21 ]. Registry studies have shown the number of SABA canisters used per year to be directly related to the risk of death in patients with asthma. Conversely, the number of ICS canisters used per year is inversely related to the rate of death from asthma, when compared with non-users of ICS [ 8 , 22 ]. Furthermore, low-dose ICS used regularly are associated with a decreased risk of asthma death, with discontinuation of these agents possibly detrimental [ 22 ].

Other barriers to asthma pharmacotherapy have included the suggestion that prolonged treatment with LABAs may mask airway inflammation or promote tolerance to their effects. Investigating this, Pauwels and colleagues found that in patients with asthma symptoms that were persistent despite taking inhaled glucocorticoids, the addition of regular treatment with formoterol to budesonide for a 12-month period did not decrease asthma control, and improved asthma symptoms and lung function [ 11 ].

Treatment strategies across all levels of asthma severity

Focusing on risk reduction, the 2014 update of the GINA guidelines recommended as-needed SABA for Step 1 of the stepwise treatment approach, with low-dose ICS maintenance therapy as an alternative approach for long-term anti-inflammatory treatment [ 23 ]. Such a strategy was only supported by the evidence from a post hoc efficacy analysis of the START study in patients with recently diagnosed mild asthma [ 24 ]. The authors showed that low-dose budesonide reduced the decline of lung-function over 3 years and consistently reduced severe exacerbations, regardless of symptom frequency at baseline, even in subjects with symptoms below the then-threshold of eligibility for ICS [ 24 ]. However, as for all post hoc analyses, the study by Reddel and colleagues does not provide conclusive evidence and, even so, their results could have questionable clinical significance for the management of patients with early mild asthma. To be effective, this approach would require patients to be compliant to regular twice-daily ICS for 10 years to have the number of exacerbations reduce by one. In real life, it is highly unlikely that patients with mild asthma would adhere to such a regular regimen [ 25 ].

The 2016 update to the GINA guidelines lowered the threshold for the use of low-dose ICS (GINA Step 2) to two episodes of asthma symptoms per month (in the absence of any supportive evidence for the previous cut-off). The objective was to effectively increase the asthma population eligible to receive regular ICS treatment and reduce the population treated with a SABA only, given the lack of robust evidence of the latter’s efficacy and safety and the fact that asthma is a variable condition characterized by acute exacerbations [ 26 ]. Similarly, UK authorities recommended low-dose ICS treatment in mild asthma, even for patients with suspected asthma, rather than treatment with a SABA alone [ 10 ]. However, these patients are unlikely to have good adherence to the regular use of an ICS. It is well known that poor adherence to treatment is a major problem in asthma management, even for patients with severe asthma. In their prospective study of 2004, Krishnan and colleagues evaluated the adherence to ICS and oral corticosteroids (OCS) in a cohort of patients hospitalized for asthma exacerbations [ 27 ]. The trend in the data showed that adherence to ICS and OCS treatment in patients dropped rapidly to reach nearly 50% within 7 days of hospital discharge, with the rate of OCS discontinuation per day nearly double the rate of ICS discontinuation per day (− 5.2% vs. − 2.7%; p < 0.0001 respectively, Fig.  3 ), thus showing that even after a severe event, patients’ adherence to treatment is suboptimal [ 27 ].

(From [ 27 ])

Use of inhaled (ICS) and oral (OCS) corticosteroids in patients after hospital discharge among high-risk adult patients with asthma. The corticosteroid use was monitored electronically. Error bars represent the standard errors of the measured ICS and OCS use

Guidelines set criteria with the aim of achieving optimal control of asthma; however, the attitude of patients towards asthma management is suboptimal. Partridge and colleagues were the first in 2006 to evaluate the level of asthma control and the attitude of patients towards asthma management. Patients self-managed their condition using their medication as and when they felt the need, and adjusted their treatment by increasing their intake of SABA, aiming for an immediate relief from symptoms [ 17 ]. The authors concluded that the adoption of a patient-centered approach in asthma management could be advantageous to improve asthma control.

The concomitant administration of an as-needed bronchodilator and ICS would provide rapid relief while administering anti-inflammatory therapy. This concept is not new: in the maintenance and reliever approach, patients are treated with ICS/formoterol (fast-acting, long-acting bronchodilator) combinations for both maintenance and reliever therapy. An effective example of this therapeutic approach is provided in the SMILE study in which symptomatic patients with moderate to severe asthma and treated with budesonide/formoterol as maintenance therapy were exposed to three different as-needed options: SABA (terbutaline), rapid-onset LABA (formoterol) and a combination of LABA and ICS (budesonide/formoterol) [ 28 ]. When compared with formoterol, budesonide/formoterol as reliever therapy significantly reduced the risk of severe exacerbations, indicating the efficacy of ICS as rescue medication and the importance of the as-needed use of the anti-inflammatory reliever.

The combination of an ICS and a LABA (budesonide/formoterol) in one inhaler for both maintenance and reliever therapy is even more effective than higher doses of maintenance ICS and LABA, as evidenced by Kuna and colleagues and Bousquet and colleagues (Fig.  4 ) [ 29 , 30 ].

(Data from [ 29 , 30 ])

Comparison between the improvements in daily asthma control resulting from the use of budesonide/formoterol maintenance and reliever therapy vs. higher dose of ICS/LABA + SABAZ and steroid load for the two regimens

The effects of single maintenance and reliever therapy versus ICS with or without LABA (controller therapy) and SABA (reliever therapy) have been recently addressed in the meta-analysis by Sobieraj and colleagues, who analysed 16 randomized clinical trials involving patients with persistent asthma [ 31 ]. The systematic review supported the use of single maintenance and reliever therapy, which reduces the risk of exacerbations requiring systemic corticosteroids and/or hospitalization when compared with various strategies using SABA as rescue medication [ 31 ].

This concept was applied to mild asthma by the BEST study group, who were the first to challenge the regular use of ICS. A pilot study by Papi and colleagues evaluated the efficacy of the symptom-driven use of beclomethasone dipropionate plus albuterol in a single inhaler versus maintenance with inhaled beclomethasone and as-needed albuterol. In this six-month, double-blind, double-dummy, randomized, parallel-group trial, 455 patients with mild asthma were randomized to one of four treatment groups: an as-needed combination therapy of placebo bid plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler; an as-needed albuterol combination therapy consisting of placebo bid plus 100 μg of albuterol; regular beclomethasone therapy, comprising beclomethasone 250 μg bid and 100 μg albuterol as needed); and regular combination therapy with beclomethasone 250 μg and albuterol 100 μg in a single inhaler bid plus albuterol 100 μg as needed.

The rescue use of beclomethasone/albuterol in a single inhaler was as efficacious as the regular use of inhaled beclomethasone (250 μg bid ) and it was associated with a lower 6-month cumulative dose of the ICS [ 32 ].

The time to first exacerbation differed significantly among groups ( p  = 0.003), with the shortest in the as-needed albuterol and placebo group (Fig.  5 ). Figure  5 also shows equivalence between the as-needed combination therapy and the regular beclomethasone therapy. However, these results were not conclusive since the study was not powered to evaluate the effect of the treatment on exacerbations. In conclusion, as suggested by the study findings, mild asthma patients may require the use of an as-needed ICS and an inhaled bronchodilator rather than a regular treatment with ICS [ 32 ].

(From [ 32 ])

Kaplan Meier analysis of the time to first exacerbation (modified intention-to-treat population). First asthma exacerbations are shown as thick marks. As-needed albuterol therapy = placebo bid plus 100 μg of albuterol as needed; regular combination therapy = 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler bid plus 100 μg of albuterol as needed; regular beclomethasone therapy = 250 μg of beclomethasone bid and 100 μg of albuterol as needed; as-needed combination therapy = placebo bid plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed

Moving forward: a new approach to the management of asthma patients

Nearly a decade after the publication of the BEST study in 2007, the use of this alternative therapeutic strategy was addressed in the SYGMA 1 and SYGMA 2 trials. These double-blind, randomized, parallel-group, 52-week phase III trials evaluated the efficacy of as-needed use of combination formoterol (LABA) and the ICS budesonide as an anti-inflammatory reliever in patients requiring GINA Step 2 treatment, with the current reliever therapy (e.g. as-needed SABA) or with low-dose maintenance ICS (inhaled budesonide bid ) plus as-needed SABA, administered as regular controller therapy [ 33 , 34 ].

The SYGMA 1 trial, which enrolled 3849 patients, aimed to demonstrate the superiority of the as-needed use of the combination budesonide/formoterol over as-needed terbutaline, as measured by the electronically-recorded proportion of weeks with well-controlled asthma [ 34 ]. The more pragmatic SYGMA 2 trial enrolled 4215 patients with the aim to demonstrate that the budesonide/formoterol combination is non-inferior to budesonide plus as-needed terbutaline in reducing the relative rate of annual severe asthma exacerbations [ 33 ]. Both trials met their primary efficacy outcomes. In particular, as-needed budesonide/formoterol was superior to as-needed SABA in controlling asthma symptoms (34.4% versus 31.1%) and preventing exacerbations, achieving a 64% reduction in exacerbations. In both trials, budesonide/formoterol as-needed was similar to budesonide maintenance bid at preventing severe exacerbations, with a substantial reduction of the inhaled steroid load over the study period (83% in the SYGMA 1 trial and 75% in the SYGMA 2 trial). The time to first exacerbation did not differ significantly between the two regimens; however, budesonide/formoterol was superior to SABA in prolonging the time to first severe exacerbation [ 33 , 34 ].

The double-blind, placebo-controlled design of the SYGMA trials does not fully address the advantages of anti-inflammatory reliever strategy in patients who often rely on SABAs for symptom relief, so to what extent the study findings could apply to real-life practice settings was unclear.

These limitations were overcome by the results of the Novel START study, an open-label, randomized, parallel-group, controlled trial designed to reflect real-world practice, which demonstrated the effectiveness in mild asthma of budesonide/formoterol as an anti-inflammatory reliever therapy [ 35 ].

In real-world practice, mild asthma patients are treated with an as-needed SABA reliever or with daily low-dose ICS maintenance therapy plus a SABA reliever. In the Novel START study, 668 patients with mild asthma were randomized to receive either as-needed albuterol 100 µg, two inhalations (SABA reliever as a continuation of the Step 1 treatment according to the 2017 GINA guidelines), budesonide 200 µg (ICS maintenance treatment) plus as-needed albuterol (Step 2 therapy of the GINA 2017 guidelines), or 200 µg/6 µg budesonide/formoterol as anti-inflammatory reliever therapy taken as-needed for a 52-week study period.

In this study, the rate of asthma exacerbations for budesonide/formoterol was lower compared with albuterol (51%) and similar to the twice-daily maintenance budesonide plus albuterol, despite a 52% reduction in the mean steroid dose with the single combination inhaler treatment [ 35 ]. In addition, severe exacerbation rate was lower with budesonide/formoterol as compared with as-needed albuterol and regular twice-daily budesonide. These data support the findings of the SYGMA 1 and 2 trials, highlighting the need for a critical re-examination of current clinical practice. Along with the results of the SYGMA trials, they provide convincing evidence of the advantages of the anti-inflammatory reliever strategy, particularly in real-life settings.

The SYGMA 1, SYGMA 2 and the novel START studies complete the picture of the treatment strategies for asthma at any degree of severity, including mild asthma. A growing body of evidence shows that an anti-inflammatory reliever strategy, when compared with all other strategies with SABA reliever, consistently reduces the rate of exacerbations across all levels of asthma severity (Fig.  6 ) [ 28 , 29 , 34 , 36 , 37 , 38 , 39 ].

(Data source: [ 39 ])

Risk reduction of severe asthma attack of anti-inflammatory reliever versus SABA across all levels of asthma severity. Bud = budesonide; form = formoterol; TBH = turbohaler. Data from: 1: [ 36 ]; 2: [ 37 ]; 3: [ 38 ]; 4: [ 28 ]; 5: [ 29 ]; 6: [ 30 ]; 7: [ 34 ]

This evidence set the ground (Fig.  7 ) for the release of the 2019 GINA strategy updates. The document provides a consistent approach towards the management of the disease and aims to avoid the overreliance and overuse of SABAs, even in the early course of the disease. The 2019 GINA has introduced key changes in the treatment of mild asthma: for safety reasons, asthmatic adults and adolescents should receive ICS-containing controller treatment instead of the SABA-only treatment, which is no longer recommended.

Timeline of key randomized controlled trials and meta-analyses providing the supporting evidence base leading to the Global Initiative for Asthma (GINA) 2019 guidelines. GINA global initiative for asthma, MART maintenance and reliever therapy, SMART single inhaler maintenance and reliever therapy

In Step 1 of the stepwise approach to adjusting asthma treatment, the preferred controller option for patients with fewer than two symptoms/month and no exacerbation risk factors is low-dose ICS/formoterol as needed. This strategy is indirectly supported by the results of the SYGMA 1 study which evaluated the efficacy and safety of budesonide/formoterol as needed, compared with as-needed terbutaline and budesonide bid plus as-needed terbutaline (see above). In patients with mild asthma, the use of an ICS/LABA (budesonide/formoterol) combination as needed provided superior symptom control to as-needed SABA, resulting in a 64% lower rate of exacerbations (p = 0.07) with a lower steroid dose (17% of the budesonide maintenance dose) [ 34 ]. The changes extend to the other controller options as well. In the 2017 GINA guidelines, the preferred treatment was as-needed SABA with the option to consider adding a regular low-dose ICS to the reliever. In order to overcome the poor adherence with the ICS regimen, and with the aim to reduce the risk of severe exacerbations, the 2019 GINA document recommends taking low-dose ICS whenever SABA is taken, with the daily ICS option no longer listed.

Previous studies including the TREXA study in children and adolescents [ 40 ], the BASALT study [ 41 ] and research conducted by the BEST study group [ 32 ] have already added to the evidence that a low-dose ICS with a bronchodilator is an effective strategy for symptom control in patients with mild asthma. A recently published study in African-American children with mild asthma found that the use of as-needed ICS with SABA provides similar asthma control, exacerbation rates and lung function measures at 1 year, compared with daily ICS controller therapy [ 42 ], adding support to TREXA findings that in children with well controlled, mild asthma, ICS used as rescue medication with SABA may be an efficacious step-down strategy [ 40 ].

In Step 2 of the stepwise approach, there are now two preferred controller options: (a) a daily low-dose ICS plus an as-needed SABA; and (b) as-needed low-dose ICS/formoterol. Recommendation (a) is supported by a large body of evidence from randomized controlled trials and observations showing a substantial reduction of exacerbation, hospitalization, and death with regular low-dose ICS [ 7 , 8 , 9 , 24 , 43 ], whereas recommendation (b) stems from evidence on the reduction or non-inferiority for severe exacerbations when as-needed low-dose ICS/formoterol is compared with regular ICS [ 33 , 34 ].

The new GINA document also suggests low-dose ICS is taken whenever SABA is taken, either as separate inhalers or in combination. This recommendation is supported by studies showing reduced exacerbation rates compared with taking a SABA only [ 32 , 40 ], or similar rates compared with regular ICS [ 32 , 40 , 41 ]. Low-dose theophylline, suggested as an alternative controller in the 2017 GINA guidelines, is no longer recommended.

Airway inflammation is present in the majority of patients with asthma, and although patients with mild asthma may have only infrequent symptoms, they face ongoing chronic inflammation of the lower airways and risk acute exacerbations. The GINA 2019 strategy recognizes the importance of reducing the risk of asthma exacerbations, even in patients with mild asthma (Steps 1 and 2) [ 4 ]. In this regard, the new recommendations note that SABA alone for symptomatic treatment is non-protective against severe exacerbation and may actually increase exacerbation risk if used regularly or frequently [ 4 ].

The reluctance by patients to regularly use an ICS controller means they may instead try and manage their asthma symptoms by increasing their SABA reliever use. This can result in SABA overuse and increased prescribing, and increased risk of exacerbations.

As part of the global SABINA (SABA use IN Asthma) observational study programme, a UK study examined primary care records to describe the pattern of SABA and ICS use over a 10-year period in 373,256 patients with mild asthma [ 44 ]. Results showed that year-to-year SABA prescribing was more variable than that of ICS indicating that, in response to fluctuations in asthma symptom control, SABA use was increased in preference to ICS use. Furthermore, more than 33% of patients were prescribed SABA inhalers at a level equivalent to around ≥ 3 puffs per week which, according to GINA, suggests inadequate asthma control.

The problem of SABA overuse is further highlighted by two studies [ 45 , 46 ], also as part of the SABINA programme. These analysed data from 365,324 patients in a Swedish cohort prescribed two medications for obstructive lung disease in any 12-month period (HERA).

The first study identified SABA overuse (defined as ≥ 3 SABA canisters a year) in 30% of patients, irrespective of their ICS use; 21% of patients were collecting 3–5 canisters annually, 7% were collecting 6–10, and 2% more than 11 [ 45 ]. Those patients who were overusing SABA had significantly more asthma exacerbations relative to those using < 3 canisters (20.0 versus 12.5 per 100 patient years; relative risk 1.60, 95% CI 1.57–1.63, p < 0.001). Moreover, patients overusing SABA and whose asthma was more severe (GINA Steps 3 and 4) had greater exacerbation risk compared with overusing patients whose asthma was milder (GINA Steps 1 and 2).

The second study found those patients using three or more SABA reliever canisters a year had an increased all-cause mortality risk relative to patients using fewer SABA canisters: hazard ratios after adjustment were 1.26 (95% CI 1.14–1.39) for 3–5 canisters annually, 1.67 (1.49–1.87) for 6–10 canisters, and 2.35 (2.02–2.72) for > 11 canisters, relative to patients collecting < 3 canisters annually [ 46 ].

The recently published PRACTICAL study lends further support to as-needed low-dose ICS/formoterol as an alternative option to daily low-dose ICS plus as-needed SABA, outlined in Step 2 of the guidelines [ 47 ]. In their one-year, open-label, multicentre, randomized, superiority trial in 890 patients with mild to moderate asthma, Hardy and colleagues found that the rate of severe exacerbations per patient per year (the primary outcome) was lower in patients who received as-needed budesonide/formoterol than in patients who received controller budesonide plus as-needed terbutaline (relative rate 0.69, 95% CI 0.48–1.00; p < 0.05). Indeed, they suggest that of these two treatment options, as-needed low-dose ICS/formoterol may be preferred over controller low-dose ICS plus as-needed SABA for the prevention of severe exacerbations in this patient population.

Step 3 recommendations have been left unchanged from 2017, whereas Step 4 treatment has changed from recommending medium/high-dose ICS/LABA [ 3 ] to medium-dose ICS/LABA; the high-dose recommendation has been escalated to Step 5. Patients who have asthma that remains uncontrolled after Step 4 treatment should be referred for phenotypic assessment with or without add-on therapy.

To summarise, the use of ICS medications is of paramount importance for optimal asthma control. The onset and increase of symptoms are indicative of a worsening inflammation leading to severe exacerbations, the risk of which is reduced by a maintenance plus as-needed ICS/LABA combination therapy. The inhaled ICS/bronchodilator combination is as effective as the regular use of inhaled steroids.

The efficacy of anti-inflammatory reliever therapy (budesonide/formoterol) versus current standard-of-care therapies in mild asthma (e.g. reliever therapy with a SABA as needed and regular maintenance controller therapy plus a SABA as-needed) has been evaluated in two randomized, phase III trials which confirmed that, with respect to as-needed SABA, the anti-inflammatory reliever as needed is superior in controlling asthma and reduces exacerbation rates, exposing the patients to a substantially lower glucocorticoid dose.

Conclusions

A growing body of evidence shows that anti-inflammatory reliever strategy is more effective than other strategies with SABA reliever in controlling asthma and reducing exacerbations across all levels of asthma severity. A budesonide/formoterol therapy exposes asthma patients to a substantially lower glucocorticoid dose while cutting the need for adherence to scheduled therapy.

Availability of data and materials

Not applicable.

Abbreviations

Global Initiative for Asthma

Inhaled corticosteroids

Long-acting beta-agonists

Oral corticosteroids

Short-acting beta-agonists

Single inhaler maintenance and reliever treatment

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Acknowledgements

The Authors thank Maurizio Tarzia and Gayle Robins, independent medical writers who provided editorial assistance on behalf of Springer Healthcare Communications. The editorial assistance was funded by AstraZeneca.

No funding was received for this study. The editorial assistance was funded by AstraZeneca.

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Section of Cardiorespiratory and Internal Medicine, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

Alberto Papi & Luca Morandi

Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

Francesco Blasi

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

Personalized Medicine Asthma & Allergy Clinic, Humanitas University & Istituto Clinico Humanitas, Milan, Italy

Giorgio Walter Canonica

Università Cattolica del Sacro Cuore, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy

Luca Richeldi

Respiratory Section, Department of Medicine, University of Verona, Verona, Italy

Andrea Rossi

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AP, FB, GWC, LM, LR and AR contributed to writing. All authors read and approved the final manuscript.

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AP reports grants, personal fees, non-financial support and payment for advisory board membership, consultancy, payment for lectures, grants for research, and travel expenses reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and Teva, and personal fees and non-financial support from Menarini, Novartis, Zambon and Sanofi.

FB reports having received in the last three years research grants as well as lecture or advisory board fees from: Alk-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, Guidotti, Glaxo Smith Kline, Grifols, Menarini, Novartis, Sanofi, Valeas, Zambon.

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Papi, A., Blasi, F., Canonica, G.W. et al. Treatment strategies for asthma: reshaping the concept of asthma management. Allergy Asthma Clin Immunol 16 , 75 (2020). https://doi.org/10.1186/s13223-020-00472-8

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Asthma And Its Treatment

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Introduction

Asthma is a complex heterogeneous disease, characterised by chronic airway inflammation and recurrent, episodic respiratory exacerbations, namely wheezing, breathlessness, chest tightness and coughing, particularly at night (Kaufman, 2011). Danvers et al (2019) describe asthma as being the most prevalent chronic condition affecting children within the United Kingdom (UK), with 374 child deaths (14 years and under) being reported between 2001 and 2016 (Asthma UK, 2020a). Remarkably, Asthma UK (2020b) claims that two-thirds of the aforementioned fatalities could be prevented if better asthma control measures were implemented (Leyshon, 2011). Kai, who is at the heart of this assignment, is a fourteen-year-old male, diagnosed with asthma, attention-deficit/hyperactivity disorder (AD/HD) and a mild learning disability (MLD). Due to the severe risks associated with asthma, Kai’s ‘nocturnal cough’ has been selected as the principal focus of the care plan. Over 12 weeks, the implementation of four evidence-based interventions aim to reduce the overall frequency (1-2 episodes a week, to 1-2 a month) and severity of Kia’s nocturnal cough. To do that, the following interventions will be employed; the creation of a therapeutic relationship, medication administration technique, peak expiratory flow (PEF)/medication monitoring and smoking cessation referral. Throughout, recognition of Kai’s behavioural and learning needs will be discussed, by considering how they may impact his adherence to the plan, and his life at both home and school.

Development of a therapeutic relationship

Crotty and Doody (2015), recommend that the formation of a therapeutic, nurse-patient relationship, should be considered a prerequisite when striving for high quality of care outcomes. This is congruent with Rogers (2004), who states that the adoption of a person-centred approach often maximises therapeutic value and adherence. Significantly, the distractible, disorganised and impulsive nature of Kai’s AD/HD, means that forming relationships is often difficult (NICE, 2018a). Therefore, in an attempt to facilitate meaningful conversations with Kai, it is paramount to create a safe environment, through congruence and trust (Rogers, 2004). Engaging Kia in this manner, allows healthcare practitioners to assume the role of active listener and attentive partner, thus unambiguously comprehending Kai’s individualist needs (Crotty and Doody, 2015). Prioritising Kai’s preferences and concerns, ensures a truly personalised care plan. Challenges arise when deciding which communication strategy to employ. Greenhalgh and Heath (2010), advise caution, suggesting that designating a specific model for building client relationships is unpragmatic. There is no ‘one-fits-all approach’, which reiterates the importance of sound clinical judgement and its subsequent application in practice (NMC, 2019). Evidently, building a therapeutic relationship can be time-consuming. Moreover, Stothard (2017) revealed that asthma patients with MLD, need longer consultations than those without MLD. When patients were afforded more time, reductions in the use of emergency healthcare resources were reported. Crucially, through empathetic guidance, Kia and his family may be better equipped to recognise how his conditions interact and influence his interpersonal relationships. Specifically, his neurodevelopment, and mental health, now and in the future (Wenderlich et al, 2019).

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Inhaler Devices Technique/Suitability

A classical feature of asthma is inflammation and bronchoconstriction of the respiratory airways, due to an overzealous immuno-response (Barber and Robertson, 2015); often triggered by allergen exposure or other mechanisms, resulting in airflow obstruction (NICE, 2018b). In accordance with NICE guidelines (2017), Kai has been prescribed short-acting-beta-2-agonist (SABA) medication, namely Salbutamol, in an attempt to reverse these effects. Despite being the mainstay of treatment, Finkelstein et al (2009), asserts that individual responses to SABA’s are variable and difficult to predict. Significantly, Khan et al (2017), found that the proliferation of nocturnal symptoms could be associated with fluctuations in beta-2-adrenergic receptor sensitivity at night (Khan et al, 2017). Therefore, to address the issue of reducing Kai’s nocturnal cough, every effort needs to be made to ensure optimised medication delivery, to the required site of action (Usmani, 2019). The Thoracic Society and Scottish Intercollegiate Guidelines Network (BTS/SIGN) (2011), recommend that inhaled asthma medication should not be prescribed without inhaler patients being competent in their use. Thus, it is paramount to ensure training is provided to Kai, with his technique being regularly assessed, to reaffirm its effective use. Additionally, Rollnick et al (2005), outlines the importance of encouraging patients to explore their views and goals regarding treatment. Crucially, determining what an acceptable device looks like to Kai, and whether it suits his needs is imperative. Moreover, adopting a patient-centred approach avoids practitioners making assumptions about Kai’s capacity to use a particular device (Leyshon, 2011). Striking a balance between accommodating Kai’s choices and the impact his AD/HD and MLD might have on device operation is key. Responding to Kai’s individual preferences, in accordance with section 2 of the NMC code (2018), will likely improve his medication adherence and compliance over the long term (Fletcher et al, 2005; Kaplan and Price, 2020). Likewise, to promote positive behaviour change, Kai’s care plan must be underpinned by realistic timeframes. Analysis by Lully et al (2009), discovered that on average, habit formation took 66 days (but ranged from 18-254 days). Therefore, the proposed 12-week plan falls within these recommended parameters.

Peak Expiratory Flow (PEF) and Medication Monitoring

Kai’s nocturnal cough is indicative of poorly controlled asthma (Leyshon, 2011). Moreover, to limit the severity and frequency of future ‘attacks’, it is vital that we make every attempt to explore potential underlying causes. Conceivably, Kai may experience adherence challenges, or may not be aware of his triggers. According to NICE (2009), non-adherence falls into two distinct categories; intentional (intrinsic motives/beliefs) and unintentional (barriers outside of the patient’s control). Therefore, to develop a wholly unique personal asthma action plan (PAAP) (Newell et al, 2015), objective data must be collated (Holmes, 2017). NICE (2009), propose the use of a medication and symptom diary, in conjunction with PEF charting. Despite its limitations, PEF is a simple, economical test that can be used to monitor lung function in asthma patients (Booker, 2007; Asthma UK, 2016a). However, due to asthmatic variability, it is not possible to gauge a ‘normal’ PEF score with a single assessment. Booker (2007) recommends that serial PEF readings be recorded morning and evening, for a period of no less than 2-3 weeks. Scores can then be used to assess diurnal and nocturnal variability (BTS/SIGN, 2019), providing objective data that underpins Kai’s PAAP. Significantly, the detail at which Kai is required to monitor his condition may present problems. Potential solutions exist through smartphone asthma applications (Huckvale et al, 2015). Interestingly, in 2019, 96% of 16-24 years old in the UK owned a smartphone (O’Dea, 2019). Asthma UK (2016b) view this kind of connectedness in data collection, as an opportunity that could greatly enhance clinical care outcomes, whilst supporting individuals in self-management. Notwithstanding Kai being the focus of the care plan, consideration must be given as to how Kai’s conditions impact life at home and school. Where appropriate, families should be engaged in his treatment, ensuring a holistic support network for all involved (UKAP, 2019).

Smoking Cessation Referral

Smoking is a leading cause of preventable death in the UK and has huge economic costs to the National Health Service (NHS) (Bauld et al, 2009). Worryingly, Boulet et al (2006) report that smoking among asthma patients is relatively common, with a prevalence similar to that of the general population. Moreover, it is argued that smoking could be viewed as the most important modifiable risk factor associated with improving asthma control (Asthma UK, 2018), due primarily to its toxic and proinflammatory effects (Boulet et al, 2006). Similarly, smoking has been found to interfere with the pharmacotherapeutic responses to corticosteroids, thus increasing symptom severity (Spears et al, 2013). Most adolescents would like to stop smoking (Asthma UK, 2018), but with relapse rates being high (Harvey and Chadi, 2016), employing a strategy that engages Kai when considering his long-term outcomes is crucial. Smoking Cessation Services (SCS) are an intervention advocated by NICE (2018) as an effective framework for assisting adolescents, like Kai, to stop smoking. Furthermore, being mindful of Kai’s personal needs and preferences may enhance the chances of him agreeing to SCS referral (NCSCT, 2010). Engaging Kai, by asking, “Why do you smoke?” and “Have you thought about giving up?”, open up dialogue, allowing us to understand his reasons for smoking; for example, does he do it to ‘fit in’ with his peers at school? Equally, it is important to consider intrinsic and extrinsic barriers that may impede Kai’s adherence to an SCS programme. For instance, Bauld et al (2009), report that socioeconomic factors are a strong driver in SCS outcomes. Notably, Kai’s mother has failed to attend appointments in the past, citing ‘transport issues’ as a reason. Summarily, having captured Kai’s information, it must then be delivered to SCS. To do this, NHS guidelines recommend the use of the SBAR communication tool (NHS, 2018), which supports the prompt transfer of accurate patient information to relevant departments.

Asthma is a highly complex, chronic disease that is widespread among the UK populous (Asthma, 2020a). With poor symptom control comes an increased risk of severe exacerbations and/or death (Leyshon, 2011). The primary approach employed in improving health outcomes for asthma suffers focuses on symptom control, through the implementation of varying pharmacological (NICE, 2017), and non-pharmacological interventions (NICE, 2018). Consequently, Kai’s care plan has been constructed in a way that utilises various approaches, to reduce the frequency and severity of his nocturnal symptoms over a period of 12-weeks. Firstly, Kai’s care plan considers his unique behavioural and learning needs, through the development of a ‘nurse-patient’ relationship. Despite Kai being the focus of the plan, it recognised that a collaborative effort is essential; hence the inclusion of Kai’s family throughout the planning and treatment process. In accordance with NICE (2017), immediate assessment of Kai’s inhaler technique is deemed critical, in ensuring optimised medication delivery for acute symptom relief. Capturing PEF measures and medication usage data over a 12-week period, allows for the objective assessment of both the efficacy of his prescription drugs and his symptom control. Moreover, the serious detrimental effects smoking has on Kai’s health has not been overlooked. A SCS referral allows for behavioural specialists to fully explore Kai’s reasons for smoking and his readiness to stop.

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Home — Essay Samples — Nursing & Health — Asthma — Asthma: Causes, Pathophysiology, and Treatment

Asthma: Causes, Pathophysiology, and Treatment

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Introduction, pathophysiology, classification, management and treatment, lifestyle modification, medications, drug used to treat asthma, ipratropium bromide.

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FASENRA approved for treatment of children aged 6 to 11 with severe asthma

Additional indication for pediatric patients with severe eosinophilic asthma

AstraZeneca’s FASENRA ® (benralizumab) is now approved by the US Food and Drug Administration (FDA) for add-on maintenance treatment for patients with severe asthma aged 6 to 11 with an eosinophilic phenotype. 1 FASENRA was first approved in 2017 as an add-on maintenance for the treatment of severe eosinophilic asthma (SEA) in patients aged 12 and older. 1

This additional indication for FASENRA was supported by evidence from TATE, an open-label, multinational, non-randomized, parallel assignment Phase III trial, as well as adequate and well-controlled trials in adult and adolescent populations. 2 In the TATE study, FASENRA met the primary endpoints, demonstrating pharmacokinetics (PK) and pharmacodynamics (PD) in children aged 6 to 11 years old with SEA were consistent with those seen in prior trials. The safety and tolerability of FASENRA in the trial was also consistent with the known profile of the medicine. 2 The recommended dose for FASENRA is 30 mg for patients 6 years and older who weigh 35 kg or more. For patients aged 6 to 11 who weigh less than 35 kg, a new 10 mg dose will be available. 1 FASENRA is administered by subcutaneous injection every 4 weeks for the first 3 doses, and then every 8 weeks.

Lynda Mitchell, MA, CAE, CEO, of the Allergy & Asthma Network, said: “We welcome additional treatment options for children living with severe asthma, a condition that remains complicated to manage, further helping to address the unmet need in this patient population and reducing the burden of disease for the broader asthma community.”

Asthma is the most common chronic childhood disease and can cause serious symptoms such as coughing, wheezing and difficulty breathing. 3 Children with severe asthma and their families face a significant burden, including impaired school performance, substantially higher healthcare resource use and a poorer quality of life. 4 Severe asthma is a debilitating type of asthma that can be complicated and challenging to treat. 4   

Liz Bodin, Vice President, US Respiratory & Immunology, AstraZeneca said: “We’re proud that FASENRA has helped more than 100,000 patients in the US to date. Expanding options for children whose quality of life has been drastically impacted by severe eosinophilic asthma with the help of FASENRA is an exciting step in our mission to revolutionize asthma care.”

FASENRA is currently approved as an add-on maintenance treatment for patients aged 6 and older with SEA in the US. 1

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Known hypersensitivity to benralizumab or excipients.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred after administration of FASENRA. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., days). Discontinue in the event of a hypersensitivity reaction.

Acute Asthma Symptoms or Deteriorating Disease

FASENRA should not be used to treat acute asthma symptoms, acute exacerbations, or acute bronchospasm.

Reduction of Corticosteroid Dosage

Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with FASENRA. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.

Parasitic (Helminth) Infection

It is unknown if FASENRA will influence a patient’s response against helminth infections. Treat patients with pre-existing helminth infections before initiating therapy with FASENRA. If patients become infected while receiving FASENRA and do not respond to anti-helminth treatment, discontinue FASENRA until infection resolves.

ADVERSE REACTIONS  

The most common adverse reactions (incidence ≥ 5%) include headache and pharyngitis.

Injection site reactions (e.g., pain, erythema, pruritus, papule) occurred at a rate of 2.2% in patients treated with FASENRA compared with 1.9% in patients treated with placebo.

USE IN SPECIFIC POPULATIONS  

A pregnancy exposure registry monitors pregnancy outcomes in women exposed to FASENRA during pregnancy. To enroll call 1-877-311-8972 or visit www.mothertobaby.org/Fasenra.

The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies such as benralizumab are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy.

FASENRA is indicated for the add-on maintenance treatment of patients with severe asthma aged 6 years and older, and with an eosinophilic phenotype.

• FASENRA is not indicated for treatment of other eosinophilic conditions
• FASENRA is not indicated for the relief of acute bronchospasm or status asthmaticus

Please read full Prescribing Information , including Patient Information and Instructions for Use .

You may report side effects related to AstraZeneca products .

TATE Phase III Trial TATE was an open-label, Phase III trial evaluating the safety of FASENRA in children aged 6 to 11 years with severe eosinophilic asthma. The trial evaluated the PK, PD and safety of FASENRA administered subcutaneously in 28 children in the US and Japan aged 6 to 11 years, in addition to 2 patients aged 12 to 14 years in Japan with severe eosinophilic asthma over 48 weeks. 2

FASENRA met the primary endpoints in the trial, demonstrating PK, PD, and safety in children aged 6 to 11 years old with SEA were consistent with those seen in prior trials.

FASENRA is a monoclonal antibody that binds directly to IL-5 receptor alpha on eosinophils and attracts natural killer cells to induce rapid and near-complete depletion of blood and tissue eosinophils in most patients via apoptosis (programmed cell death). 5,6

FASENRA (benralizumab) is currently approved in more than 80 countries, including the US, EU, and Japan, and is approved for self-administration in the US, EU and other countries. 7-10 FASENRA has been prescribed to over 100,000 patients in the US. 11

FASENRA is in development for other diseases including chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps and hypereosinophilic syndrome. 12-14

FASENRA was developed by AstraZeneca and is in-licensed from BioWa, Inc., a wholly-owned subsidiary of Kyowa Kirin Co., Ltd., Japan.

AstraZeneca in Respiratory & Immunology Respiratory & Immunology, part of BioPharmaceuticals, is one of AstraZeneca’s main disease areas and is a key growth driver for the Company.

AstraZeneca is an established leader in respiratory care with a 50-year heritage. The Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death. The Company’s early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.

With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Company’s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including systemic lupus erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZeneca’s ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.

AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca .

Brendan McEvoy        +1 302 885 2677 Jillian Gonzales          +1 302 885 2677        

US Media Mailbox: [email protected]            

• FASENRA US prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761070Orig1s020correctedlbl.pdf . [Last accessed April 2024].
•  Wedner HJ, Fujisawa T, Guilbert TW, et al on behalf of the TATE Investigators. Benralizumab in children with severe eosinophilic asthma: pharmacokinetics and long-term safety (TATE study). Pediatri Allergy Immunol 2024;35:e14092.
• World Health Organization. Asthma. Available at: https://www.who.int/news-room/fact-sheets/detail/asthma. [Last accessed April 2024].
• Castagnoli R, Marseglia A, Brambilla I, Marseglia GL, Licari A. Severe uncontrolled asthma in children: practical approach on diagnosis and management. Minerva Pediatr . 2020;72(3):196-205.
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Asthma: Evidence-Based Pharmacological Treatment Research Paper

Pathophysiology, genomic issues, literature review, data collection, clinical guideline for asthma management, treatment approaches, follow-up treatment and referrals.

Asthma is typically defined as a chronic disease that affects the patient’s airways, impeding the process of breathing (National Heart, Lung, and Blood Institute, 2014). The understanding of how asthma is developed and by what factors it is triggered has been altered significantly over the past few years. At present, the pathophysiology of the disease is rather intricate since several conditions have been identified as the leading causes of asthma.

For instance, “Bronchospasms, edema, excessive mucus, and epithelial and muscle damage” (Lynn & Kushto-Reese, 2015, p. 49) are typically viewed as the key contributors to asthma development in patients (Lynn & Kushto-Reese, 2015). Each of the conditions listed above causes the development of bronchoconstriction with bronchospasms, therefore, making airways narrow (Lynn & Kushto-Reese, 2015). As a result, the premises for an asthma attack are created (see Appendix A).

It should be borne in mind, though, that the degree of disease variation in patients hinges on not the symptoms but the age thereof, as a recent study indicates (Kudo, Ishigatsubo, & Aoki, 2013). For instance, in children under 6, the development of the disease is typically preceded by the asthma-like symptoms that manifest themselves roughly at the age of three (Centers for Disease Control and Prevention, 2017).

A deficit in lung function can be observed in the identified group of patients at the age of 11-16. The force expiratory volume, however, remains consistent. The observations mentioned above are strikingly different from the ones carried out in a group of children that developed asthma after the age of three. Particularly, the specified patients did not show the propensity toward the development of lung function deficit (National Heart, Lung, and Blood Institute, 2014).

Asthma is currently viewed as a disease induced by both environmental and genetic factors. Therefore, understanding the genomic characterization of the disease is crucial to its management. Genome-wide association studies (GWASs) carried out lately indicate that the PGAP3 gene, or PERLD1, defines the development of asthma in patients (Li et al., 2013).

It should be noted, though, that there are uncertainties in the current research on the subject of genomes and asthma. For instance, a recent analysis of the issue shows that, while PGAP3 has a tangible effect on the development of allergic reactions to specific elements, it is GSDMB that determines the propensity toward the disease development in patients: “STARD3/PGAP3 may act on the allergic component of asthma while the GSDMB/ORMDL3/GSDMA locus may mediate its effect by a shared mechanism acting on most forms of asthma” (Lavoie-Charland, Berube, Boulet, & Bosse, 2016, p. 909). Therefore, there are at least two genomes that possibly cause the development of asthma in patients (Lavoie-Charland et al., 2016).

A whole-blood expression quantitative trait loci (eQTL) used in the research conducted by aaa showed that the functional variants of 17q12-21 are also associated with the development of allergic reactions toward a set of specific irritants (Andiappan et al., 2016). It is remarkable, though, that 17q12-21 affects the development of allergic asthma yet not rhinitis (Andiappan et al., 2016). Particularly, there is a connection between the genes at 17q12-21 and the polymorphism rs8076131 (Andiappan et al., 2016).

It should be borne in mind, though, that rs8076131 is not the only polymorphism that is associated with asthma. The article written by Schedel et al. (2015) shows that rs4065275, as well as the group of polymorphisms within ORMDL3, in general, is linked directly to the TH2 cytokines levels and, therefore, affects the susceptibility to asthma, especially among children (Schedel et al., 2015). However, further studies of the identified connection, as well as how the genomes in question affect the development of the disease, is required.

Seeing that asthma cannot be cured completely, the current approaches to managing it are aimed primarily at reducing the symptoms (e.g., coughing, shortness of breath, etc.) and improving the patients’ quality of life. At present, active engagement of patients and, if needed, their parents or legal guardians in the process of managing the disorder is viewed as a necessity. For the people that are capable of taking care of themselves, the promotion of patient independence is considered a crucial step in addressing the adverse effects of asthma successfully (Jain et al., 2014).

Two primary types of asthma treatment are utilized presently. These are short-term relievers (bronchodilators, particularly, dry powder inhalers and nebulizers (Daley-Yates, Mehta, Chan, Despa, & Louey, 2014)) and long-term disease control medications (Loymans et al., 2014).

Among the former, corticosteroids that are administered orally or intravenously are typically listed. Short-term relievers, which include bronchodilators, are used for three primary goals, i.e., the relaxation of the smooth muscle by stimulating beta-2 receptors, prevention of the cholinergic nerves activation, and cessation of the phosphodiesterase (PDE) enzymes’ functioning so that the further dilation of the bronchial airways could be possible (Normansell & Welsh, 2015). Long-term medication, in turn, also include corticosteroids (e.g., budesonide, beclomethasone, fluticasone, etc.). Apart from corticosteroids, leukotriene modifiers (zileuton, montelukast, etc.) are used to reduce the threat of an asthma attack (Lajqi, Ilazi, Kastrati, & Islami, 2015).

To gather the essential information about asthma, its development, and treatment, as well as other issues associated with the disease, an overview of the recent studies and the databases that contained the general information about asthma was required. Therefore, a literature review was used as the primary approach to data collection and its further interpretation so that it could be utilized in the study. As a result, a comprehensive review of the available information became possible.

Searching for the relevant data required using specific keywords. It should be noted, though, that the information about different aspects of the disease had to be utilized in the research. Therefore, different sets of keywords were used for each of the search processes.

Table 1. Keywords used in the Search Process.

In the course of the search, ResearchGate and NCBI were used as the key databases for locating the essential information. The two resources were selected because they provide academic, peer-reviewed, and credible articles. Less trustworthy databases were discarded.

Electronic Clinical Tools

No electronic clinical tools were utilized in the research. Since there was no need for a quantitative study, including the information from HER provided by local healthcare facilities did not seem necessary. Instead, an all-embracive analysis of the articles obtained from scholarly databases was conducted.

At present, the U.S. standards for asthma management are defined by the guide provided by the NCBI in 2007 (National Heart, Lung, and Blood Institute, 2007). Even though the identified resource is comparatively old, it remains the basis for the diagnosis and management of asthma. The guide provides detailed information about the nature of the problem, its pathophysiology, and the available treatment methods.

The guide places an especially strong emphasis on the importance of patient education as the path to successful management of the disease: “Asthma self-management education should be integrated into all aspects of asthma care, and it requires repetition and reinforcement” (National Heart, Lung, and Blood Institute, 2007, p. 93). The identified guideline should be improved and followed closely nowadays by introducing social media into the process of patient education as the means of keeping the target population updated on the latest information and promoting cooperation between a nurse and the community.

For instance, engaging asthma patients in a dialogue by encouraging them to participate in Facebook discussions of the problem and responding to the information posted by the healthcare services will be a crucial step on the way to improving the management of asthma. Furthermore, a range of myths about asthma will be debunked. As a result, patients will feel empowered for developing independence in identifying asthma-related symptoms and searching for the assistance of healthcare experts (Panzera et al., 2013).

As stressed above, the complete treatment of asthma is impossible at present; instead, its consistent management is used to improve the quality of the patient’s life (Jain et al., 2014). Therefore, an approach to handling the disorder in a long-term perspective needs to be considered. Furthermore, one must keep in mind that there are treatment strategies for three stages of asthma development (i.e., the so-called green, yellow, and red zones) (Yin et al., 2012). For this purpose, the stepwise approach must be used (Inoue et al., 2017). A common treatment framework implies carrying out the following steps:

• Identifying the severity of the problem (i.e., either a green, yellow, or red zone stage);
• Providing the patient with a quick-relief medication, if necessary (Albuterol, Levalbuterol, Metaproterenol, or Terbutaline) (U.S. National Library of Medicine, 2017);
• Expectorating the secretions of the patient so that the further aggravation of the problem could be avoided;
• Maintaining the airway clean so that the necessary medications could be administered to the patient;
• Continuing to provide long-term medications such as dry powder inhalers and nebulizers (1-2 puffs a day) if the short-term medication is efficient;
• Educating the patient about the symptoms, the necessity to avoid the allergens, the need to use the provided medications (1-2 puffs of nebulizers per day), etc. (Inoue et al., 2017).

Alternative treatment approaches may involve the use of fluid therapy (in case of a patient experiences dehydration) and pharmacologic therapy, which allows determining the patient’s response to medications (Bendjelid, Rex, Scheeren, & Critchley, 2015). However, the plan outlined above creates premises for all-embracive management of asthma and, thus, should be viewed as the superior one.

Best Approach: Selection and Rationale

As stressed above, the framework involving the classification of the asthma attack severity and the identification of the patient’s age (i.e., the stepwise approach) allows for the best results. The reason for choosing the specified strategy as the most efficient one is that it helps determine the patients’ needs fast and accurately. As a result, the chances for a patient outcome increase greatly (Inoue et al., 2017).

The use of fluid therapy, while also being quite effective, cannot be seen as an independent strategy for managing asthma since it does not include the comprehensive model that can be used to assist any asthma patient. Instead, it can only be utilized in specific cases of certain asthma severity. Therefore, it cannot be viewed as the ultimate tool for handling asthma cases (Bendjelid et al., 2015).

Consequently, the stepwise approach must be considered the most effective tool. It produces an immediate result and contributes to a massive improvement in the patient’s condition. Furthermore, the identified framework helps monitor asthma in patients of any age, from newborns to adults. The fact that the strategy allows for a minimum of adverse effects should also be considered one of its primary advantages (Inoue et al., 2017). Thus, it should be used as the basis for handling asthma cases.

The further management of the case involves educating the patient about asthma and its management. Particularly, independence must be encouraged. The patient must be able to identify the symptoms that may pose a threat to their well-being and contact the healthcare services. Patient referrals must be considered a necessity in case of an asthma episode exacerbation. Subsequent tests carried out by an immunologist are obligatory for the further analysis of the problem and the identification of the possible treatment options. Furthermore, patient education must follow the treatment process so that further instances of asthma could be addressed efficiently.

Andiappan, A. K., Sio, Y. Y., Lee, B., Suri, B. K., Matta, S. A., Lum, J., … Chew, F. T. (2016). Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis. Journal of Allergy and Clinical Immunology, 137 (3), 758-766. Web.

Asthma: Practice essentials, background, anatomy . (2017). Web.

Bendjelid, K., Rex, S., Scheeren, T., & Critchley, L. (2015). Year in review in journal of clinical monitoring and computing 2014: Cardiovascular and hemodynamic monitoring. Journal of Clinical Monitoring and Computing, 29 (2), 203-207. Web.

Centers for Disease Control and Prevention. (2017). Learn how to control asthma . Web.

Daley-Yates, P. T., Mehta, R., Chan, R. H., Despa, S. X., & Louey, M. D. (2014). Pharmacokinetics and pharmacodynamics of fluticasone propionate and salmeterol delivered as a combination dry powder from a capsule-based inhaler and a multidose inhaler in asthma and COPD patients. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 27 (4), 279-289. Web.

Inoue, H., Nagase, T., Morita, S., Yoshida, A., Jinnai, T., & Ichinose, M. (2017). Prevalence and characteristics of asthma–COPD overlap syndrome identified by a stepwise approach. International Journal of Chronic Obstructive Pulmonary Disease, 12 (1), 1803-1810. Web.

Jain, V. V., Allison, R., Beck, S. J., Jain, R., Mills, P. K., Mccurley, J. W., … Peterson, M. W. (2014). Impact of an integrated disease management program in reducing exacerbations in patients with severe asthma and COPD. Respiratory Medicine, 108 (12), 1794-1800. Web.

Kudo, M., Ishigatsubo, Y., & Aoki, I. (2013). Pathology of asthma. Frontiers in Microbiology, 4 (263), 1-16. Web.

Lajqi, N., Ilazi, A., Kastrati, B., & Islami, H. (2015). Comparison of Glucocorticoid (Budesonide) and Antileukotriene (Montelukast) effect in patients with bronchial asthma determined with body plethysmography. Acta Informatica Medica, 23 (6), 347-351. Web.

Lavoie-Charland, E., Berube, J. C., Boulet, L. P., & Bosse, Y. (2016). Asthma susceptibility variants are more strongly associated with clinically similar subgroups. Journal of Asthma, 53 (9), 907-13. Web.

Li, L., Kabesch, M., Bouzigon, E., Demenais, F., Farrall, M., Moffatt, M. F., … Liang, L. (2013). Using eQTL weights to improve power for genome-wide association studies: A genetic study of childhood asthma. Frontiers in Genetics, 4 (103), 1-14. Web.

Loymans, R. J., Gemperli, A., Cohen, J., Rubinstein, S. M., Sterk, P. J., Reddel, H. K., … Riet, G. T. (2014). Comparative effectiveness of long term drug treatment strategies to prevent asthma exacerbations: Network meta-analysis. BMJ, 348 (1), 1-16. Web.

Lynn, S. J., & Kushto-Reese, K. (2015). Understanding asthma pathophysiology, diagnosis, and management Learn about new research findings and current treatment strategies for this common disorder. American Nurse Today, 10 (7), 49-51.

National Heart, Lung, and Blood Institute. (2007). Guidelines for the diagnosis and management of asthma (EPR-3): Full report . Web.

National Heart, Lung, and Blood Institute. (2014). What is asthma? Web.

Normansell, R., & Welsh, E. (2015). Asthma can take over your life but having the right support makes that easier to deal with. Informing research priorities by exploring the barriers and facilitators to asthma control: A qualitative analysis of survey data. Asthma Research and Practice, 1 (1), 11-21. Web.

Panzera, A. D., Schneider, T. K., Martinasek, M. P., Lindenberger, J. H., Couluris, M., Bryant, C. A., & Mcdermott, R. J. (2013). Adolescent asthma self-management: Patient and parent-caregiver perspectives on using social media to improve care. Journal of School Health, 83 (12), 921-930. Web.

Schedel, M., M., S., Gaertner, V. D., Toncheva, A. A., Depner, M., Binia, A., … Kabesch, M. (2015). Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. Journal of Allergy and Clinical Immunology, 136 (4), 758-768. Web.

U.S. National Library of Medicine. (2017). Asthma – Quick-relief drugs . Web.

Yin, H. S., Gupta, R. S., Tomopoulos, S., Wolf, M. S., Mendelsohn, A. L., Antler, L., … Dreyer, B. P. (2012). Readability, suitability, and characteristics of asthma action plans: Examination of factors that may impair understanding. Pediatrics, 131 (1), 118-128. Web.

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IvyPanda . "Asthma: Evidence-Based Pharmacological Treatment." January 23, 2024. https://ivypanda.com/essays/asthma-evidence-based-pharmacological-treatment/.

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Ozempic Hurts the Fight Against Eating Disorders

I t’s impossible to escape the soaring popularity of Ozempic and similar drugs these days—daily headlines, celebrity “success” stories, and apparent ease in procuring prescriptions (even Costco sells them now) abound. But the cumulative effect of all of this has many experts in the eating disorder field worried about how this might affect their patients. This makes sense—even for those without eating disorders, these drugs can feel both triggering and enticing. After all, research tells us about 90% of women are dissatisfied with their bodies. This sounds like a quick fix.

Then, I started hearing reports—first anecdotal, then published —that some doctors were prescribing weight loss drugs like Ozempic to their patients with eating disorders. As in, to help treat them.

As a journalist who has extensively researched the harms of eating disorders and the barriers to recovery—and as a woman who had suffered from eating disorders on and off for much of my own life—I thought I must have misunderstood. Yes, we as a society are in the midst of Ozempic Fever—and by “fever,” I’m referring to excitement, rather than a possible side effect of the drug (which it is). Researchers are continuing to find new potential applications for these drugs, initially developed to treat type 2 diabetes. In March, the FDA approved a new indication for the weight-loss drug Wegovy (which has the same active ingredient as Ozempic), allowing it to be used as a treatment to reduce the risk for heart attack and stroke. Ozempic, a diabetes drug, used off-label for weight loss, is also being studied to treat anxiety and depression , polycystic ovary syndrome, substance abuse, Alzheimer’s , and now—eating disorders.

Read More: Ozempic Exposed the Cracks in the Body Positivity Movement

It’s early days and research hasn’t yet caught up with the enthusiasm.  But our cultural misunderstanding of eating disorders, even by well-meaning practitioners, could exacerbate the illnesses for those who suffer from them—and have dire consequences.

The new class of weight loss drugs mimics the body’s GLP-1 hormone , stimulating insulin production, and lowering blood sugar levels, helpful to those with type 2 diabetes. The drugs also curb appetite and slow the speed that food moves into the small intestine—you feel full more quickly and eat less. Many patients without eating disorders who take these drugs, have reported a reduction of “food noise” in their minds—referring to obsessive thoughts and preoccupation with food. (Though, as philosopher Kate Manne wisely posited in a recent New York Times piece , isn’t “food noise,” simply, hunger?)

For folks suffering from binge eating disorder (BED) or bulimia nervosa (BN), a drug that decreases appetite may seem to make sense. Both illnesses are characterized by eating large amounts of food, eating until uncomfortably full, and feeling distress around that (bulimia is distinguished by purging after a binge).

Binge eating often emerges as part of a cycle of restriction—dieting, fasting, or eliminating entire food groups—like carbs, for example. “Many people struggling with BED view the binge episodes as the problem and the restriction as something to strive for,” said Alexis Conason, a psychologist specializing in the treatment of binge eating disorder. “When people with BED take a GLP-1 medication that dampens their appetite, many are excited that they can be ‘better’ at restriction and consume very little throughout the day.” Subsequently, Conason adds, there is a dangerous potential for BED to then morph into anorexia, starving oneself with possibly life-threatening complications.

Eating disorders are complex illnesses that aren’t yet fully understood, even by experts in the field. Underneath the behaviors around food is often an intricate web of trauma, anxiety, and even genetic predisposition, all set against the backdrop of a culture that prizes thinness . Low weight is frequently (incorrectly) conflated with good health, and people in larger bodies are often subjected to bullying, negative stereotypes, and discrimination in the workplace .

Read More: Ozempic Gets the Oprah Treatment in a New TV Special

Emerging research strongly supports that for many, eating disorders are brain-based illnesses and in most cases, there exists a co-morbidity like anxiety, mood disorders, or substance abuse.

“GLP-1’s can’t help someone deal with their stress, anxiety, [and] trauma-history,” said psychologist Cynthia Bulik, one of the world’s leading eating disorder researchers, and Founding Director of the University of North Carolina Center of Excellence of Eating Disorders. “All of that background distress—fundamental distress that might be driving the BED in the first place—is temporarily bypassed by removing the desire to eat.”

Nearly 30 million Americans will have an eating disorder in their lifetime, but only about 6% of those are medically diagnosed as “underweight,” according to the National Association of Anorexia Nervosa and Associated Disorders. This means that a person may exhibit all of the diagnostic hallmarks of anorexia, for example, extreme restriction and even malnourishment, but still present as average weight or even overweight. They may even be told by a physician to lose weight, despite the fact that they are already going to dangerous extremes to chase that “goal.”

“We tend to think that everyone in a larger body with an eating disorder must have BED and everyone in a smaller body must have anorexia, but this couldn’t be further from the truth,” said Conason. “So many people with BED seek help in weight loss settings instead of seeking eating disorder treatment; many view the problem as their weight and think they need more help sticking to their diet” when in reality, an end to the restriction would more likely regulate their eating.

It’s much easier to get weight loss treatment than help for an eating disorder. There is no standard of care for eating disorders in this country and treatment is unregulated. While there are some promising, evidenced-based treatments (cognitive behavioral therapy for adults, and family-based treatment for children and teens), they don’t work for everyone. If a person is fortunate to be diagnosed and receive adequate treatment, relapses are common and full recovery can be elusive.

Further, these drugs are often intended to be taken for a person’s entire life. “When they go off the drug, or can’t access it due to supply problems, the urge to binge comes right back and they have not developed any psychological (or) behavioral skills to manage the urge,” Bulik told me. Just like with a diet, any lost weight will likely be regained when a person stops taking the drugs. Weight fluctuations, themselves ,may increase a person’s risk of chronic illnesses like type 2 diabetes, according to multiple studies.

“The focus on weight and erasing the desire to eat could indeed do harm,” cautioned Bulik. “The potential for abuse is high and will become higher with new preparations that don’t require an injection … Remember, these drugs are ‘for life.’ Stop them, and everything comes rushing back.”

The long-term side effects of GLP-1’s are not yet known. But the harms of eating disorders are: eating disorders have one of the highest mortality rates of any mental illness (second only to opioid overdose). People with eating disorders are more likely to attempt suicide, and during COVID-19, emergency room visits and inpatient admissions for eating disorders at pediatric hospitals skyrocketed, particularly for young women. According to the CDC, emergency room visits for 12-17 year old girls who suffer from eating disorders doubled during the pandemic. Those numbers, as shown by recent studies , have not returned to pre-pandemic levels.

An even greater concern is that the gaps in comprehensive care for eating disorders invite experimental, potentially harmful treatments and leave patients vulnerable. GLP-1’s may seem like a short-term “fix,” but they won’t graze the deeper issues nor will they diminish the eating disorder crisis in this country. And it is a crisis—every year, eating disorders cost the U.S. more than $65 billion .

I know too well that if a doctor advises their patient with an eating disorder “here’s something to make you eat less” most patients would happily oblige. That’s part of the pathology of the illness. It’s the eating disorder talking. Ideally, it wouldn’t be your doctor’s voice, too.

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