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Diagnosis and Management of Asthma in Adults : A Review

  • 1 Division of Allergy and Clinical Immunology, University of Texas Medical Branch, Galveston
  • 2 Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston
  • 3 Division of Pulmonary Critical Care and Sleep, Department of Internal Medicine, University of Texas Medical Branch, Galveston
  • Correction Incorrect Dosage Information in Table JAMA
  • Original Investigation Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists for Uncontrolled Asthma Diana M. Sobieraj, PharmD; William L. Baker, PharmD; Elaine Nguyen, PharmD, MPH; Erin R. Weeda, PharmD; Craig I. Coleman, PharmD; C. Michael White, PharmD; Stephen C. Lazarus, MD; Kathryn V. Blake, PharmD; Jason E. Lang, MD, MPH JAMA
  • Original Investigation Use of Inhaled Corticosteroids and Long-Acting β-Agonists for Asthma Exacerbations Diana M. Sobieraj, PharmD; Erin R. Weeda, PharmD; Elaine Nguyen, PharmD, MPH; Craig I. Coleman, PharmD; C. Michael White, PharmD; Stephen C. Lazarus, MD; Kathryn V. Blake, PharmD; Jason E. Lang, MD, MPH; William L. Baker, PharmD JAMA
  • Original Investigation Effect of Nebulized Magnesium vs Placebo Added to Albuterol Among Children With Refractory Acute Asthma Suzanne Schuh, MD; Judy Sweeney, RN, BScN; Maggie Rumantir, MD; Allan L. Coates, MDCM, BEng; Andrew R. Willan, PhD; Derek Stephens, MSc, BSc; Eshetu G. Atenafu, MSc; Yaron Finkelstein, MD; Graham Thompson, MD; Roger Zemek, MD; Amy C. Plint, MD, MSc; Jocelyn Gravel, MD, MSc; Francine M. Ducharme, MD, MSc; David W. Johnson, MD; Karen Black, MD, MSc; Sarah Curtis, MD; Darcy Beer, MD; Terry P. Klassen, MD, MSc; Darcy Nicksy, BSc, PhM; Stephen B. Freedman, MDCM, MSc; Pediatric Emergency Research Canada (PERC) Network JAMA

Importance   Asthma affects about 7.5% of the adult population. Evidence-based diagnosis, monitoring, and treatment can improve functioning and quality of life in adult patients with asthma.

Observations   Asthma is a heterogeneous clinical syndrome primarily affecting the lower respiratory tract, characterized by episodic or persistent symptoms of wheezing, dyspnea, and cough. The diagnosis of asthma requires these symptoms and demonstration of reversible airway obstruction using spirometry. Identifying clinically important allergen sensitivities is useful. Inhaled short-acting β 2 -agonists provide rapid relief of acute symptoms, but maintenance with daily inhaled corticosteroids is the standard of care for persistent asthma. Combination therapy, including inhaled corticosteroids and long-acting β 2 -agonists, is effective in patients for whom inhaled corticosteroids alone are insufficient. The use of inhaled long-acting β 2 -agonists alone is not appropriate. Other controller approaches include long-acting muscarinic antagonists (eg, tiotropium), and biological agents directed against proteins involved in the pathogenesis of asthma (eg, omalizumab, mepolizumab, reslizumab).

Conclusions and Relevance   Asthma is characterized by variable airway obstruction, airway hyperresponsiveness, and airway inflammation. Management of persistent asthma requires avoidance of aggravating environmental factors, use of short-acting β 2 -agonists for rapid relief of symptoms, and daily use of inhaled corticosteroids. Other controller medications, such as long-acting bronchodilators and biologics, may be required in moderate and severe asthma. Patients with severe asthma generally benefit from consultation with an asthma specialist for consideration of additional treatment, including injectable biologic agents.

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McCracken JL , Veeranki SP , Ameredes BT , Calhoun WJ. Diagnosis and Management of Asthma in Adults : A Review . JAMA. 2017;318(3):279–290. doi:10.1001/jama.2017.8372

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  • Published: 15 August 2020

Treatment strategies for asthma: reshaping the concept of asthma management

  • Alberto Papi 1 , 7 ,
  • Francesco Blasi 2 , 3 ,
  • Giorgio Walter Canonica 4 ,
  • Luca Morandi 1 , 7 ,
  • Luca Richeldi 5 &
  • Andrea Rossi 6  

Allergy, Asthma & Clinical Immunology volume  16 , Article number:  75 ( 2020 ) Cite this article

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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 ].

figure 1

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.

figure 2

(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 ].

figure 3

(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 ].

figure 4

(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 ].

figure 5

(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 ].

figure 6

(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.

figure 7

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.

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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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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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Overcoming Barriers to the Effective Management of Severe Asthma in Italy

Pierluigi paggiaro.

1 Department of Surgery, Medicine, Molecular Biology, and Critical Care, University of Pisa, Pisa, Italy

Simona Barbaglia

2 Associazione Nazionale Pazienti “Respiriamo Insieme”, Padova, Italy

Stefano Centanni

3 Department of Health Sciences, Università degli Studi di Milano, Milan, Italy

4 Respiratory Unit, ASST Santi Paolo e Carlo, Milan, Italy

Davide Croce

5 Center for Health Economics, Social and Health Care Management, LIUC-Università Cattaneo, Castellanza, Italy

Enrico Desideri

6 Fondazione Innovazione e Sicurezza in Sanità, Rome, Italy

Saffi Giustini

7 Italian General Practitioners’ Association “SIMG”, Florence, Italy

8 Local Health Unit of Montale, Pistoia, Italy

Claudio Micheletto

9 Cardio-Thoracic Department, Respiratory Unit, Integrated University Hospital, Verona, Italy

Antonino Musarra

10 Allergy Unit, National Healthcare System, Reggio Calabria, Italy

Nicola Scichilone

11 Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo, Italy

12 Dirigente UOD 06 Politica del Farmaco e Dispositivi, Naples, Italy

Maria Teresa Zedda

13 General Practice, Cagliari, Italy

Giorgio Walter Canonica

14 Personalized Medicine Asthma & Allergy Clinic, Humanitas University and Research Hospital-IRCCS, Milan, Italy

Introduction

People with severe asthma (SA) often have poor disease control and quality of life, and are at high risk of exacerbations, lung function decline and asthma-related death. The present expert opinion article aimed to identify unmet needs in the management of SA in Italy, and propose possible solutions to address these needs.

At five multidisciplinary events in Italy, attendees identified factors that interfered with the effective management of SA and suggested how these barriers could be overcome. A core group of 12 Italian experts (pulmonologists, general practitioners, allergists, payers and patients) identified the main issues and proposed possible solutions based on the results from the meetings and relevant articles from the literature.

Results and Conclusions

We reviewed the gap between real-world practice and guidelines, oral corticosteroid overuse, SA-related mortality, and barriers to effective SA treatment. Common themes were lack of awareness about SA among both patients and clinicians, and lack of networking/information exchange between those involved in the treatment of SA. Participants agreed on the need to implement patient education and create multidisciplinary groups of specialists to improve SA management through multidisciplinary educational initiatives, meetings with local experts, development of a flow chart for referral/connection with local experts and specialized centers. Clinical instruments that might help specialists improve SA management included referral networks, integrated care pathways, phenotyping and treatment algorithms, exacerbation tracking, and examination of electronic medical records for patients with uncontrolled asthma. The following actions need to be implemented in Italy: i) maximize the use of advanced therapies, eg, biologics; ii) increase/improve education for physicians and patients; iii) improve multidisciplinary communication and care coordination; iv) introduce regional and local protocols for SA diagnosis and treatment; and v) change the structure of healthcare services to reduce specialist waiting times and facilitate access to biologic therapies.

Asthma is a chronic respiratory disease characterized by airway inflammation and airflow obstruction. 1 Asthma affects more than 300 million people worldwide, of whom between 3.5% and 10.0% are believed to have severe asthma. 2–5 Several definitions of severe asthma have been proposed over the years. 6 Currently, it is defined as asthma that requires high-dose anti-inflammatory therapy to achieve disease control, or asthma that remains uncontrolled despite such therapy. 3 , 6 Severe asthma is a heterogeneous condition and its natural history is poorly understood. 1 , 3 , 7 A range of factors, including genetic predisposition, medical history, comorbidities, and smoking, appear to play a role in the development of severe asthma. 3

According to the European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines, 3 severe asthma is defined as the condition that requires regular use of high doses of inhaled corticosteroids (ICS) in combination with a second controller and/or systemic corticosteroids to be controlled, or that remains uncontrolled despite such treatment. 3 , 14 The 2020 Global Initiative for Asthma (GINA) recommendations define this condition as difficult-to-treat asthma, while severe asthma is a subset of difficult-to-treat disease that remains uncontrolled despite treatment with maximal optimized therapy or that worsens if such treatment is withdrawn. 1 These definitions assume that the differential diagnosis of asthma has been established, that comorbidities have been optimally treated, and that environmental factors and poor adherence or inhaler technique have been excluded as reasons for lack of control. 14 Therefore, the definition of severe asthma requires repeated observations of ongoing symptoms in patients whose treatment has been optimized.

Severe asthma imposes a substantial burden on the patient, the healthcare system and society at large. Patients with severe asthma are more likely to have poorly controlled symptoms, decreased lung function and exacerbations than patients with mild or moderate asthma. 3 Furthermore, patients with severe asthma, especially those with comorbidities or high peripheral eosinophil levels, often use systemic corticosteroids at high doses and frequencies, and therefore are at increased risk of developing corticosteroid-related adverse events. 8 , 9 Severe asthma also has a negative effect on the patients’ emotional wellbeing, their relationships with friends and family, and on their career. 10 , 11 Although severe asthma affects a minority of patients, it is responsible for most of the costs associated with this disease. 12 , 13

The aim of the present expert opinion article was to identify unmet needs in the management of severe asthma in Italy, and to propose possible solutions for addressing these needs in the context of the Italian Health Service.

In 2018 and 2019, five macroregional events and one multidisciplinary group meeting were held, at which panels of Italian experts, including pulmonologists, general practitioners (GPs), allergists, National Health Service (NHS) payers and representatives of patients’ associations, discussed the diagnosis and treatment of patients with severe asthma. The meetings were organized according to geographic location, with participants from: Lombardy and Trentino-Alto Adige; Piedmont, Liguria and Aosta Valley; Sicily, Calabria and Basilicata; Lazio, Tuscany and Sardinia; and Campania and Apulia. Attendees were local allergists, pulmonologists, and GPs known to be experienced in the management of severe asthma. Attendees were invited to participate independently of the sponsoring pharmaceutical company, based on the physicians’ publication history, reputation and curriculum vitae. During the meetings, panels of experts (total n=58) and attendees (total n=127) were asked to identify the barriers that, in their opinion, interfered with the effective management of severe asthma and to suggest how these barriers could be overcome. At the end of the meetings, the attendees and panel of experts were asked to complete a written survey (n=86), designed to identify the impact of various barriers on patients with severe asthma. This survey was performed by an external Italian agency (Sentrix Global Health Communications Srl) well experienced in observational surveys, working in agreement with the current European regulations about the privacy of the collected opinions. This company is maintaining a copy of all documents. According to Italian regulations, this type of consultative research activity (similar to demoscopic assessment) does not require Ethics committee approval. Attendees were fully informed about the nature of the survey and the anonymity of the survey results in their invitation to the meeting. Consent to participate was implicit in their attendance at the meeting. The authors of the present manuscript had access only to anonymous mean or median data.

In order to place the information gathered from the expert meetings in context, a review of relevant literature was conducted. Results from the macroregional events and relevant articles were discussed by the multidisciplinary group of 12 Italian experts, including pulmonologists, GPs, allergists, NHS payers and representatives of patients’ associations. Based on this discussion and after reaching a general consensus, the main issues were identified and possible solutions were proposed.

No statistical analysis was necessary, considering the descriptive nature of the article.

Based on the results of the literature review and the discussions at the macroregional events, the following issues were identified.

Gap Between Real-World Practice and Guideline Recommendations

Recommended management of severe asthma.

According to the GINA guidelines, 1 the recommended approach to the management of difficult-to-treat asthma includes several steps: i) evaluation of the patient’s adherence to the recommended treatment and the correct use of inhalers, considering the possibility of switching to ICS-formoterol as maintenance and reliever therapy; ii) verification that the diagnosis of asthma has been performed correctly considering the typical asthma symptoms and risk factors, as well as demonstration of a variable airway obstruction; iii) evaluation and appropriate management of any comorbidities potentially responsible for poor asthma control; iv) avoidance or minimization of the trigger factors (eg allergen exposure, environmental or occupational pollutants, and smoking); and v) optimization of treatment with currently available inhaled drugs (ie, ICS, long-acting β2-agonist, long-acting muscarinic antagonist). If the patient remains uncontrolled at the end of this complex process of assessment (which may require several weeks or months to complete), then he or she should be considered to have severe uncontrolled asthma and should undergo the following steps: i) pheno-endotyping of asthma that takes into consideration clinical history, comorbidities and biomarkers; ii) in the case of a type 2 pattern of inflammation, treatment with biologic drugs should be considered. The biologic agents that are currently available for the treatment of severe asthma are monoclonal antibodies that target immunoglobulin E (omalizumab), interleukin (IL)-5 (mepolizumab), IL-5 receptor α (benralizumab), or the IL-4 receptor (dupilumab). 15 While these agents provide a highly effective treatment option for many patients with severe asthma, 16–19 their high cost means that they should be reserved for those most likely to benefit. Unfortunately, very few treatment options (and in particular, no biologic drugs) are currently available for patients with severe asthma who have non-type 2 inflammation, and these patients have a poor prognosis. In these patients, low-dose oral corticosteroids (OCS) can be considered as second-line add-on therapy, although special attention is needed to minimize adverse effects. 1

After a treatment has been started, frequent assessment of its efficacy in terms of improving symptoms, reducing the exacerbation rate, and improving pulmonary function and quality of life should be performed in order to verify that the treatment is appropriate and to determine whether it should be continued. However, if the efficacy of the treatment regimen is inadequate, a switch to another alternative may be required.

Management of Severe Asthma in Real-World Practice

There is reason to believe that guideline recommendations are not followed in real-world clinical practice. 20 , 21 In a study that included 107 Italian GPs and 995 patients with asthma, 28.8% of patients received treatment that adhered to the 2009 GINA guidelines. 20 In this study, the use of guideline-compliant treatment was significantly associated with disease control. 20

Studies consistently find that asthma is poorly controlled in a large proportion of patients. 22 , 23 The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study provided important insights into the epidemiology and outcomes of patients aged >6 years with severe or difficult-to-treat asthma. 24 The TENOR I study included 807 patients with very poorly controlled asthma, as defined in the 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines; only a small proportion of these patients showed improvement over 24 months, with 62.2% of children (6–11 years old) and 75.0% of adolescents and adults (≥12 years old) having consistently very poorly controlled asthma during follow up. 24 Subsequently, the TENOR II study, which followed 341 patients from the TENOR 1 study for >10 years, showed that the majority of patients continued to have very poorly controlled asthma during this long-term follow-up period. 25

Poor disease control in patients with asthma is associated with a number of adverse outcomes, such as increased risk of unscheduled office visits, OCS bursts, emergency room visits and hospitalizations, and worsening quality of life and general health status. 26 , 27 Data from the Italian Severe Asthma Registry support these findings, and show that an increased rate of exacerbations, lung function decline, and corticosteroid-induced morbidity and mortality are associated with poor control of severe asthma in Italian patients. 7 , 28

Overuse of Oral Corticosteroids

A major issue in the management of asthma, and particularly severe asthma, is the overuse of OCS treatment. 14 The GINA guidelines have always listed low-dose OCS as an option for add-on therapy in patients with severe asthma, but from 2014, low-dose OCS was recommended as a second-line therapy in this setting, with biologic therapy being the preferred option. 15 In addition, from 2019, the GINA guidelines noted that physicians should consider the adverse effects of low-dose OCS when prescribing them for severe asthma. 16 The adverse events known to be associated with OCS include hypertension, osteoporosis and bone fracture, cataract and glaucoma, diabetes, respiratory infections, reduced growth velocity in children, and hypothalamic-pituitary-adrenal axis suppression. 13 A study of long-term medical records from 24,117 adult patients with asthma treated with systemic corticosteroids who were matched with an equal number of patients with no systemic corticosteroid exposure showed that systemic corticosteroids were associated with a significantly higher risk of osteoporosis and bone fracture, pneumonia, cardio- or cerebrovascular disease, cataracts, sleep apnea, renal impairment, depression or anxiety, type 2 diabetes, and bodyweight gain. 17 The risk of these adverse events increased in a dose-dependent manner. 17 Two systematic literature reviews reported similar findings, and also provided evidence that a higher dose and duration of systemic corticosteroid treatment are associated with increased healthcare costs. 18 , 19

OCS are widely used in patients with severe asthma in Italy. For example, in a study of 437 consecutive patients with severe asthma from the Severe Asthma Network in Italy (SANI), 64.1% were prescribed OCS. 20 Another study conducted in a cohort of Italian patients with severe asthma, who were identified using the Health Search Database from GPs, found that 76.1% received OCS at the time of diagnosis. 21 In Italy, the annual healthcare costs per patient due to OCS-related adverse events have been estimated at €1957.50 for severe asthma, compared with €1350.96 for mild or moderate asthma. 13 Based on an estimated 199,980 patients with severe asthma in Italy, the total annual healthcare costs associated with OCS-related adverse events were calculated to be €242.7 million. 13 , 20 The adverse events and costs of OCS explain why, since 2019, the GINA guidelines have recommended that these agents should be used only as a second-line option for patients with severe asthma who do not respond to, or are unable to take, other options such as biologic agents. 1 , 16

Preventable Mortality

Although deaths due to asthma declined in most countries by approximately 50% between 2001–2005 and 2011–2015, it is estimated that in 2016 there were 420,000 asthma-related deaths worldwide. 2 Many asthma-related deaths are believed to be preventable and result from a lack of appropriate treatment. 22–24 In the United Kingdom (UK), approximately 40% of asthma-related deaths are thought to have occurred in patients with severe asthma. 24 Furthermore, long-term OCS use in these patients is associated with an increased risk of mortality. 25 , 26

Barriers to Effective Management of Severe Asthma

The GINA guidelines emphasize the importance of patients’ goals and satisfaction in the effective management of asthma. 1 Recently, a group of academics, patient advocates, and representatives from professional organizations developed a Charter for the Care of Patients with Severe Asthma, with the goal of improving the quality of care for this condition. 27 The charter includes six principles that are intended to outline what patients with severe asthma should expect from treatment and what should constitute a basic standard of care ( Table 1 ). 27 Nevertheless, a number of barriers prevent patients achieving optimal care. 28–34

Charter to Improve Patient Care in Severe Asthma

Note: Data from Menzies-Gow et al. 27

Barriers to Severe Asthma Diagnosis and Management in Italy

The barriers to effective diagnosis and management of severe asthma in Italy that were identified during the five multidisciplinary meetings are presented in Table 2 . These barriers were classified based on whether they impacted mostly GPs and specialists, patients and caregivers, or healthcare providers, and whether they related to diagnosis, management, or follow-up. Two common themes emerged from the discussion: i) lack of awareness about severe asthma among both patients and clinicians, and ii) lack of networking and information exchange between those involved in the treatment of severe asthma. The findings of the short survey that was conducted to explore the impact of specific barriers are presented in Table 3 .

Barriers to Effective Management of Severe Asthma in Italy According to Various Stakeholders

Abbreviations: GP, general practitioner; OCS, oral corticosteroids.

The Impact of Various Barriers to Effective Management of Severe Asthma (Survey Results)

Abbreviation: OCS, oral corticosteroids.

Possible Solutions

The measures suggested by participants for addressing the various barriers are listed in Table 4 . All participants agreed on the need to create a multidisciplinary group of specialists in order to improve the management of patients with severe asthma and to implement patient education. This should be achieved by educational initiatives for multidisciplinary teams, meetings with local experts, instruments for the creation of a flow chart for referral or connection with local experts, and sessions to improve knowledge in specialized centers. Several clinical instruments are believed to be useful for specialists in improving the management of severe asthma: referral networks, integrated care pathways, phenotyping and treatment algorithms, tracking of exacerbations, and examination of electronic medical records for patients with uncontrolled asthma. Multidisciplinary networks and specific routes of referral should be organized and implemented in clinical practice in each area of Italy.

Suggestions for Overcoming the Barriers to Effective Management of Severe Asthma

Expert Opinion on Addressing Barriers to Effective Management of Severe Asthma in the Context of the Italian Health Service

We suggest several solutions to improve disease control, reduce the risks associated with poor asthma control, optimize healthcare resource utilization, and implement the Charter in the context of the Italian Health Service. These potential solutions take into consideration the results of discussions held during the macroregional events.

  • Considering that the use of OCS is often associated with adverse events, therapeutic strategies that reduce the need for OCS, while also achieving asthma control, should be adopted. 7 , 35 The biologic therapies targeting the IL-5/IL-5Rα and IL-4 pathways have been shown to reduce the maintenance dose of OCS in patients with severe asthma. 36–39
  • Better adherence to treatment guidelines, particularly with respect to ICS, should be encouraged. 16 , 40 , 41
  • Medical education should focus on the correct application of asthma treatment guidelines in order to overcome unnecessary prescriptions. Patients should be informed about the correct inhaler technique and provided with medical information to enable them to understand the nature of their condition and treatments. 1 An improvement in communication and care coordination between GPs and specialists may help to increase diagnostic and treatment capacities in primary care, improve referral, promote better use of specialist asthma centers, and ensure the more timely and appropriate prescription of biologic therapy. Many patients with asthma overestimate the extent of their asthma control. 42 Therefore, central to the primary care management of asthma is a thorough understanding by GPs of what constitutes asthma control, so that all patients who are not achieving control can be promptly identified and the reasons for poor control identified. Patient adherence should be thoroughly investigated, and patients should be evaluated for attitudes and beliefs that may be negatively impacting adherence, as well as other factors, such as depression, anxiety, or substance abuse. 28 , 33
  • Regional health systems should introduce better diagnostic and therapeutic pathways, and GPs and specialists should be provided with diagnostic algorithms designed specifically for severe asthma. There should be dedicated treatment pathways for patients with severe asthma, ideally involving referral to a specialist center, where these patients can be managed by a multidisciplinary team experienced in complex asthma management. Such centers are best placed to ensure that patients undergo phenotypic assessment and receive prompt treatment with the most appropriate agent for their asthma.
  • Healthcare is publicly funded in Italy and organized regionally, which can lead to differences in healthcare access between regions. The Charter described above recommends consistent and universal access to healthcare for all patients with severe asthma, which requires a coordinated approach overseen at the national level. Therefore, a Population Health Management approach should be introduced to improve clinical and financial outcomes in severe asthma. Individual patients should be monitored and data should be aggregated. Relevant clinical data should be shared by GPs, specialists and hospitals. The use of population-level data with treatment outcomes is expected to produce actionable analytics for providers that would help improve efficiency and patient care at a regional and local level. Effective division of labor, between specialists who are responsible for planning therapeutic interventions and GPs who are in charge of follow-up, should be promoted. Specialists should not be concentrated in single centers, but should move according to patients’ needs.
  • Minimal requirements for asthma centers should be formulated.
  • Payers should be involved in improving healthcare system organization and reducing waiting times for specialist consultation.
  • Pharmacoeconomic analyses should be performed to support all initiatives in this field to identify the most cost-effective approaches to comprehensive patient care.

Managing Severe Asthma Patients During the COVID-19 Pandemic

Beginning in early 2020, the world has been facing a new pandemic caused by the SARS-CoV-2 virus (COVID-19), which causes severe acute respiratory syndrome. Patients with asthma are at risk of experiencing exacerbations triggered by COVID-19 infection. 43 GINA, 44 the UK National Institute for Health and Care Excellence (NICE), 45 and the Italian Associazione Allergologi Immunologi Italiani Territoriali e Ospedalieri (AAITO) 46 and Societa’ Italiana di Allergologia, Asma ed Immunologia Clinica (SIAAIC) 47 guidelines recommend that i) patients should avoid accessing hospitals to reduce their risk of becoming infected; ii) patients should continue to receive ICS, OCS, or biologic therapies as prescribed and treatment interruptions should be avoided; and iii) if possible, patients should self-administer treatments at home after receiving appropriate training and written instructions. 44 , 45 Thus, patients with severe asthma who are receiving biologic treatments should continue the treatment by self-administration, whenever possible. 44–47

The COVID-19 pandemic will have a profound impact on modern medicine and is already reshaping the patient–physician relationship. A number of measures can be implemented to protect patients with asthma, as described in an article detailing the experience of physicians at the Allergy Clinic of the Humanitas Research Hospital in Milan, Italy. 48 COVID-19-free zones were established to reduce within-hospital transmission. Before entering these zones, patients were screened for signs of active infection, underwent hand sanitization procedures, and were provided with surgical masks. Patients with severe or uncontrolled asthma were instructed to arrive for their scheduled appointments at predetermined times and to maintain social distancing. On the other hand, patients with mild-to-moderate symptoms or well-controlled disease were transitioned to a telemedicine service that included phone, video, and email consultations. Patients were asked to self-administer biologic drugs that were delivered to their homes. 48 Hospitals treating patients with asthma should implement these or similar measures, depending on local circumstances, in order to maintain disease control in patients with asthma and reduce the risk of exacerbations that may necessitate hospitalization. 43

Conclusions

In Italy, as in other European countries, severe asthma places a significant burden on patients, healthcare systems, and society. Therefore, it is important to ensure effective management of this condition, which is hindered by several unmet needs. These include poor disease control and adherence to clinical practice guidelines, treatment-related adverse events, and adverse health outcomes, which may include asthma-related death in some cases. In order to address these unmet needs in Italy and to meet the Charter for patient care, it is necessary to implement a series of actions: i) decrease the burden of inappropriate OCS usage by maximizing the use of advanced therapies, such as biologic drugs; ii) increase education efforts targeted at physicians and patients; iii) improve multidisciplinary communication and care coordination, to accelerate referral and severe asthma diagnosis and pheno-endotyping; iv) introduce diagnostic and therapeutic protocols for severe asthma at the regional or local level; and v) establish cost-effective structural changes to healthcare services, reducing waiting times for specialist consultation and facilitating access to targeted biologic therapies.

Acknowledgments

The authors thank Laura Brogelli, who drafted the outline on behalf of Springer Healthcare Communications and Georgii Filatov of Springer Healthcare Communications who developed the first draft. This editorial support was funded by AstraZeneca.

Funding Statement

The macroregional events were funded by AstraZeneca. The expert panel meeting was funded by AstraZeneca as part of the manuscript development.

Abbreviations

AAITO, Associazione Allergologi Immunologi Italiani Territoriali e Ospedalieri; ATS, American Thoracic Society; COVID-19, SARS-CoV-2 virus; ERS, European Respiratory Society; GINA, Global Initiative for Asthma; GP, general practitioner; ICS, inhaled corticosteroids; IL, interleukin; OCS, oral corticosteroids; NHS, National Health Service; NICE, National Institute for Health and Care Excellence; SANI, Severe Asthma Network in Italy; SIAAIC, Società Italiana di Allergologia, Asma ed Immunologia Clinica; TENOR, The Epidemiology and Natural History of Asthma, Outcomes and Treatment Regimens; UK, United Kingdom.

Data Sharing Statement

Survey data are available from the corresponding author [PP] on request.

Author Contributions

All authors have participated in the PRECISION project, an AstraZeneca organized and funded program to promote the management of severe asthma around the world. All authors were members of the expert panel that reviewed the literature and the outcomes of the macroregional events, and developed the summary of recommendations. Dr. Paggiaro reviewed the manuscript and prepared the final version of the article. All Authors contributed in the conception of the reported work and in the literature analysis, critically revised and approved all the drafts, agreed on the target journal, approved the final version and agreed to take responsibility and be accountable for the contents of the article.

Dr. Paggiaro has received institutional and personal grants for research and education from ALK-Abellò, AstraZeneca, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Mundipharma, Novartis, and Sanofi. Dr. Trama reports grants from Fisioair Srl, grants from K. Link srl, grants from Mediacom Srl, grants from Boehringer Ingelheim, grants from Beneventi srl, outside the submitted work. Dr. Croce has received personal grants for research and education from AbbVie, Allergan, Astellas, Bayer, Becton Dickinson, Dompè, General Electric Healthcare, Gilead Science, Glaxo Smith Kline, Italfarmaco, MSD, Pfizer, Sanofi, Shire, Takeda, and ViiV Healthcare. Dr. Canonica has received research grants, been a speaker, or received advisory board fees from Menarini, Alk-Abellò, Allergy Therapeutics, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Hal Allergy, Mylan, Merck, Merck Sharp & Dome, Mundipharma, Novartis, Regeneron, Roche, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes-Greer, UCB Pharma, Uriach Pharma, Valeas, and Vibor-Pharma. Dr. Barbaglia has no conflicts of interest to declare. Dr. Centanni has received institutional grants for research and education from AstraZeneca, Chiesi, Valeas and Boehringer Ingelheim and personal fees from Glaxo Smith Kline, Novartis, Chiesi, Menarini, AstraZeneca, Valeas, Boehringer Ingelheim, Guidotti Malesci. Dr. Desideri has no conflicts of interest to declare. Dr. Giustini has no conflicts of interest to declare. Dr. Micheletto has been a speaker, or received advisory board fees from AstraZeneca, Glaxo Smith Kline, Sanofi, Novartis, Menarini, Guidotti, Chiesi, Zambon, Berlin Chemie. Dr. Musarra has received advisory board fees from Glaxo Smith Kline, AstraZeneca, Sanofi Genzyme and Mylan. Dr. Scichilone has no conflicts of interest to declare. Dr. Zedda has received institutional and personal grants for research and education from AstraZeneca, Guidotti, Menarini. The authors report no other conflicts of interest in this work.

  • Research article
  • Open access
  • Published: 03 April 2020

Relationship between the Asthma Control Test (ACT) and other outcomes: a targeted literature review

  • Bas C. P. van Dijk   ORCID: orcid.org/0000-0002-7343-4438 1 ,
  • Henrik Svedsater 2 ,
  • Andreas Heddini 3 ,
  • Linda Nelsen 4 ,
  • Janita S. Balradj 1 &
  • Cathelijne Alleman 1  

BMC Pulmonary Medicine volume  20 , Article number:  79 ( 2020 ) Cite this article

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The Asthma Control Test (ACT) has been used to assess asthma control in both clinical trials and clinical practice. However, the relationships between ACT score and other measures of asthma impact are not fully understood. Here, we evaluate how ACT scores relate to other clinical, patient-reported, or economic asthma outcomes.

A targeted literature search of online databases and conference abstracts was performed. Data were extracted from articles reporting ACT score alongside one or more of: Asthma Control Questionnaire (ACQ) score; rescue medication use; exacerbations; lung function; health−/asthma-related quality of life (QoL); sleep quality; work and productivity; and healthcare resource use (HRU) and costs.

A total of 1653 publications were identified, 74 of which were included in the final analysis. Of these, 69 studies found that improvement in ACT score was related to improvement in outcome(s), either as correlation or by association. The level of evidence for each relationship differed widely between outcomes: substantial evidence was identified for relationships between ACT score and ACQ score, lung function, and asthma-related QoL; moderate evidence was obtained for relationships between ACT score and rescue medication use, exacerbations, sleep quality, and work and productivity; limited evidence was identified for relationships between ACT score and general health-related QoL, HRU, and healthcare costs.

Conclusions

Findings of this review suggest that the ACT is an appropriate measure for overall asthma impact and support its use in clinical trial settings.

GlaxoSmithKline plc. study number HO-17-18170.

Peer Review reports

Asthma is a common and treatable disease that can impact heavily on health-related quality of life (HRQoL) [ 1 ]. Medical experts agree that the level of asthma control is a key feature when determining the best asthma treatment required [ 1 , 2 ]. Developed by asthma experts, the Asthma Control Test (ACT) provides a numerical score to assess the control of asthma [ 3 ]. It comprises five questions regarding aspects of asthma control relevant to patients. The ACT assesses frequency of shortness of breath, night-time/early awakenings, rescue medication use, overall asthma control, and loss of productivity. Each question is answered on a 5-point scale, with a total score ranging from 5 to 25; higher scores indicate improved asthma control [ 2 , 3 ]. A score of ≥ 20 indicates “well-controlled” asthma, while a score < 20 indicates asthma that is “not well controlled”. The ACT provides patients with asthma and their doctors and nurses with a useful measure to help determine the level of treatment required [ 2 , 3 ]. It has been tested extensively in patients with asthma [ 4 ], clinically validated against spirometry and specialist assessment [ 3 ], and is recognized by the National Institutes of Health since its 2007 asthma guidelines [ 2 ]. Despite its clinical utility, a need remains to assess the link between ACT score and asthma treatment benefits and outcomes, and its suitability as an endpoint in clinical trials. Previous studies have used the ACT as a measure of response to treatment [ 5 , 6 ], including a recent Phase III study that was not published in time to be included in this review [ 7 ]. The aim of the current study was to assess the extent to which ACT score is correlated, or associated, with other important clinical, patient-reported, and economic asthma outcomes.

A targeted literature search of the EMBASE, MEDLINE, EconLit, and Cochrane databases was performed, in addition to searching the relevant conference abstract repositories of the American Thoracic Society (ATS), European Respiratory Society (ERS), and American College of Chest Physicians (CHEST). Articles published before February 9th, 2017 were captured in the EMBASE, MEDLINE and EconLit database searches, while searches of the Cochrane database and conference repositories reviewed articles and congress abstracts published prior to January 21st, 2017. The details of the search strategy are included in Fig. 1 .

figure 1

Flow diagram of search strategy and targeted literature review approach. a Articles published before February 9th, 2017 were captured in the EMBASE, MEDLINE and EconLit database searches. b The Cochrane database search reviewed articles published prior to January 21st, 2017. c Conference abstract repositories searched were the American Thoracic Society (ATS), European Respiratory Society (ERS) and American College of Chest Physicians (ACCP) CHEST. d Conference databases were searched for the last three editions of the conference in question (i.e. 2015–2017 or 2014–2016), up to January 21st, 2017. e Studies could have reported on multiple outcomes. ACT : Asthma Control Test; HRQoL : health-related quality of life; QoL : quality of life

Identified publications were initially screened for eligibility by title and abstract, and full-text articles of all eligible studies were then assessed. Eligible studies included human studies investigating adult patients (≥ 18 years old) with a primary asthma diagnosis. Articles reporting the results of observational studies, clinical trials, longitudinal/cross-sectional studies and other studies reporting relationships between ACT score and other outcomes of interest were included, while letters, editorials, notes, and review articles were excluded.

Articles that met predefined inclusion criteria were retained for full text review i.e. articles were included if they reported the results of studies investigating a relationship between ACT score and/or asthma severity and one or more of identified outcomes of interest: symptom control, use of rescue medication, exacerbations, pulmonary function, HRQoL/utilities, sleep quality, productivity and activity levels, and resource use and costs.

Following identification of articles eligible for full-text review, the number of articles assessing each relationship, as well as the strength, significance, and direction of those relationships, was quantified. We also evaluated the extent to which the tested relationships differed per ACT score and/or asthma severity.

Articles describing a statistical relationship between two continuous variables were defined as reporting a “correlation”; statistical tests used in these studies included Pearson’s chi-square test and the Spearman correlation test. Those that instead reported a trend between subgroups or over time, assessed by covariance tests, regression analysis, or empirical observation, were defined as reporting “associations”; in other words, these are assessments of the extent to which two measures co-vary in an expected manner (i.e. an improvement of one measure should represent an improvement in another outcome measure).

Data for each outcome of interest were extracted from the targeted studies by means of a formalized extraction grid. Bibliographic and methodologic details of the study, basic population characteristics, and ACT scores at baseline and later if applicable were extracted. For each outcome of interest that was examined for a relationship with ACT score, the following were included: a description of the outcome and its value; time of measurement (baseline/later); change from baseline; method used to test relationship and the outcome of the test; significance level (range, 95% confidence interval, or p -value); statistical significance of relationship (yes/no); and the direction of the relationship (positive/negative).

Data availability

All publications identified in the targeted literature review were available from public databases (EMBASE, MEDLINE, EconLit, and the Cochrane Library), and can be accessed there or on the articles’ respective journal websites. Conference abstracts were available from the abstract repositories of the professional organizations that arranged the conferences in question (the ATS, ERS, and CHEST). Relevant data were extracted from these publications, but no new data were generated within the course of this literature review. Accordingly, no databases or data repositories were created. The protocol for this literature review is not publicly available.

The targeted literature search identified 1653 publications (1401 in EMBASE, MEDLINE, and EconLit; 116 in Cochrane databases; and 136 in conference abstracts), of which 67 were duplicates. Of the 1586 unduplicated publications screened, 239 were reviewed in full and 74 were included in the final analysis (Fig. 1 ). The analysis found that in 68 publications an improvement in ACT score was correlated or associated with improvements in key outcomes of interest (Table 1 ). Studies assessing symptom control, healthcare resource use, or lung function were among the most commonly identified; fewer studies assessing QoL, sleep, and productivity were found. Asthma severity was not frequently reported.

ACT score and asthma symptom control

In total, seven publications reported ACT and Asthma Control Questionnaire (ACQ) data (Table 1 ) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Six publications found strong and consistent correlations between improvement in ACT score and improvement in ACQ score [ 8 , 9 , 10 , 11 , 12 , 13 ], with five of the publications assessing the statistical significance of the correlations. All five of these reports found statistically significant relationships between ACT and ACQ scores ( p  < 0.05) [ 8 , 9 , 10 , 11 , 12 ]. Schuler et al. [ 12 ] reported that the ACQ-7 had a strong positive correlation, with a moderate correspondence with ACT score (Cohen’s kappa κ = 0.56). Zhou et al. [ 13 ] reported strong correlations between improvement in ACT score and improvement in both the ACQ-7 (all items) (Spearman correlation coefficient, r  = − 0.687; robust correlation, r  = − 0.865) and the ACQ-6 (excluding spirometry; Spearman correlation coefficient, r  = − 0.491; robust correlation, r  = − 0.637), although statistical significance was not tested. A further publication reported a similarly moderate effect with the same measure of concordance (κ = 0.52) as Schuler et al., without testing for significance [ 14 ].

ACT score and rescue medication use

Almost all of the 10 publications reporting on ACT score and rescue medication use [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] found a relationship between worsening ACT scores and increasing short-acting beta agonist (SABA) or rescue inhaler use (Table 1 ). Weak but statistically significant correlations between ACT score and the number of SABA inhalers dispensed were identified in two publications ( ρ  = − 0.33, p  = 0.001 in both); these studies may have been reporting on the same population [ 15 , 16 ]. One study reported strong relationships between risk of excess SABA use and both ACT score and change in ACT score; a 2-point worsening in ACT score led to a 46% increased risk of excess SABA use [ 22 ]. Another publication showed that the odds of having ≥6 SABA inhaler dispensings increased markedly at lower ACT scores over a continuous range of ACT scores [ 23 ].

Three publications reported SABA use by asthma control subgroup, and demonstrated trends between lower ACT score and higher rescue inhaler use [ 18 , 20 , 24 ], with one study performing a regression analysis ( r  = 0.51, p  < 0.001) [ 18 ].

Only one study was identified that evaluated the relationship between ACT score and rescue medication-free days. Improvement was evaluated by both a change from baseline and the proportion of patients who achieved asthma control, similar to the Salford Lung Study trial design [ 25 ]. The results suggested that improvement in ACT score was related to improvement in rescue medication-free days [ 19 ].

ACT score and asthma exacerbations

Ten studies reported on the relationship between improvement in ACT score and reduction in asthma exacerbations (Table 1 ) [ 17 , 22 , 23 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].

Across the studies, there was some variation in the definitions used to characterize an exacerbation. However, these definitions were generally comparable, specifying an exacerbation as a worsening in asthma symptoms that required one or more of oral/systemic corticosteroid use, hospitalization, or an emergency healthcare visit.

Two of the studies tested for correlations between improvement in ACT score and reduction in asthma exacerbations, resulting in small but significant correlation coefficients of − 0.129 and − 0.349, respectively ( p  < 0.01) [ 26 , 27 ].

In the other eight publications, fewer exacerbations were observed in patients with higher ACT scores [ 17 , 22 , 23 , 28 , 29 , 30 , 31 , 32 ], with seven of these publications reporting a statistically significant relationship between higher ACT score and lower numbers of exacerbations in patients split into the various ACT subgroups [ 22 , 23 , 28 , 29 , 30 , 31 , 32 ].

ACT score and lung function

Twenty-five articles were identified which assessed the relationship between ACT score and lung function. Of these, eight publications did not fully meet the predefined inclusion criteria and were therefore subsequently excluded from data extraction.

There is a strong body of evidence supporting a relationship between improvement in ACT score and improvement in lung function, particularly with respect to forced expiratory volume in 1 s (FEV 1 ; Table 1 ). In total, 17 publications detailing studies that met the inclusion criteria reported lung function measurements [ 3 , 11 , 13 , 15 , 18 , 27 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], with some reporting multiple outcomes (e.g. FEV 1 and forced vital capacity [FVC]) [ 15 , 27 , 36 , 38 ].

Of the 14 publications reporting FEV 1 , seven reported statistically tested correlations between improvement in ACT score and improvement in FEV 1 [ 3 , 15 , 27 , 34 , 35 , 36 , 37 ]. Of these, five demonstrated statistically significant correlations, with coefficients ranging from 0.177 to 0.518, as calculated by different methods [ 3 , 34 , 35 , 36 , 37 ]. This evidence was supported by the remaining seven studies, which tested the relationships between ACT score and FEV 1 by linear regression, analysis of variance (ANOVA), or in subgroups of patients categorized according to ACT score or FEV 1 [ 11 , 13 , 18 , 38 , 39 , 40 , 43 ]; of these seven articles, six reported statistically significant relationships [ 11 , 13 , 38 , 39 , 40 , 43 ].

Three articles tested for a statistical correlation between improved asthma control as measured by increased ACT score and improvement in FVC [ 15 , 33 , 36 ], with only one demonstrating a notable relationship (correlation coefficient, ρ  = 0.26, p  = 0.01) [ 36 ]. The one publication that assessed FVC without a correlation test also reported a strong relationship ( p  = 0.000) [ 42 ].

ACT score and QoL

A total of seven articles reported HRQoL in asthma patients [ 28 , 34 , 44 , 45 , 46 , 47 , 48 ], all of which showed strong positive relationships between improvement in ACT score and improvement in Asthma Quality of Life Questionnaire (AQLQ) score (Table 1 ). All seven studies published statistically significant results, five from correlation tests [ 28 , 34 , 44 , 45 , 46 ], and two derived from regression analyses [ 47 , 48 ].

In total, seven studies reported general HRQoL in ACT subgroups, measuring HRQoL by the Short Form (12-item) Health Survey (SF-12) or the EuroQol five dimensions questionnaire (EQ-5D) [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. In both questionnaires, a higher score indicates improved QoL.

For SF-12, a consistent trend was observed that individual physical and/or mental component scores were lower for the groups with asthma that was “not well controlled”. Statistically significant differences in individual SF-12 domain scores between patients with uncontrolled/not well-controlled versus controlled asthma (ACT score thresholds varied) were observed in three (physical component) [ 49 , 53 , 54 ] and two (mental component) studies [ 49 , 52 ], respectively.

Guilbert et al. [ 54 ] performed bivariate and multivariate analyses on the relationship between asthma control (“well-controlled” [ACT score > 19] vs. “not well-controlled” [ACT score ≤ 19]) and SF-12 physical domain score, observing a negative relationship between ACT score ≤ 19 and SF-12 score. The mean differences in SF-12 scores between patients with “not well-controlled” and “well-controlled” asthma were − 7.0 and − 3.4 for the bivariate and multivariate analyses, respectively (both p  < 0.001) [ 54 ].

Additionally, one study reported a significant difference in EQ-5D between patients with “not well-controlled” (ACT score < 20) and “well-controlled” (ACT score ≥ 20) asthma (EQ-5D scores, 0.7 vs. 0.9; p  < 0.0001) [ 50 ]. This finding is of particular interest, given that the EQ-5D system may lack sensitivity which often does not correlate with underlying clinical measures [ 56 , 57 ].

ACT score and sleep quality

In total, six articles reported on aspects of sleep quality, including instruments that measured daytime sleepiness and obstructive sleep apnea [ 45 , 58 , 59 , 60 , 61 , 62 ]; three of these studies utilized multiple sleep quality instruments (Table 1 ) [ 58 , 60 , 62 ].

Of the four studies using the Pittsburgh Sleep Quality Index (PSQI) [ 45 , 58 , 60 , 62 ], two reported notable, statistically significant correlations between improvement in ACT score and improvement in sleep quality (r = − 0.315, p  < 0.001 and r = − 0.620, p  < 0.001, respectively) [ 45 , 58 ]. Additionally, Lv et al. [ 60 ] found that poor sleep quality, assessed by PSQI, was related to lower ACT score using regression analyses (β = − 0.87, p  = 0.045).

A statistically significant relationship was also demonstrated between improvement in ACT score and improvement in sleep quality measured using the Medical Outcomes Study (MOS) Sleep Scale. Compared with patients who had an ACT score ≥ 20, those with a score < 20 had significantly higher scores in all components of the MOS Sleep Scale (all p  < 0.001, F-values 19.1–109.0), corresponding to poorer sleep quality [ 61 ].

A relationship between the level of asthma control, as measured by ACT score, and improvement in sleep quality, as measured by the Sleep-5 questionnaire, was also reported, but the relationship was not tested for statistical significance [ 59 ].

Two studies reported that patients with lower ACT scores tended to have higher (worse) Epworth Sleepiness Scale scores, although no statistical analysis was performed [ 58 , 62 ].

Regression analyses (unadjusted and adjusted) were performed in one study to determine the relationship between asthma control (measured by the ACT) and the Berlin Questionnaire for obstructive sleep apnea [ 60 ].

ACT score and productivity and activity levels

Out of a total of seven articles, five reported on the relationship between improvement in ACT score and improvement in productivity, as measured by the Work Productivity and Activity Impairment questionnaire (WPAI) (Table 1 ) [ 49 , 51 , 53 , 55 , 63 ]. One study reported a negative correlation between ACT score and WPAI score (correlation varied between − 0.707 and − 0.750, statistical significance not reported) [ 63 ]. The other four studies reported higher work impairment in patients whose asthma was not well controlled (ACT score < 20), compared with those with well-controlled asthma (ACT score ≥ 20) [ 49 , 51 , 53 , 55 ]. However, only one of these found that relationship to be statistically significant [ 49 ].

Two studies reported on the relationship between the level of asthma control, as measured by ACT score, and improvement in productivity using other measures (i.e. the Effort-Reward-Imbalance questionnaire, the Sheehan Disability Scale, and the Impact on Work Productivity Index [IMPALA]) [ 56 , 57 ]. Of these, one study reported a statistically significant relationship between the subgroup with improved asthma control and productivity measured by the Sheehan Disability Scale and IMPALA [ 57 ].

ACT score and resource use and costs

In total, 17 publications reported on the relationship between ACT score and HRU (Table 1 ) [ 47 , 49 , 51 , 53 , 54 , 55 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ].

One study reported a non-significant relationship between improvement in ACT score and both the ratio of maintenance to reliever medication dispensed, and inhaler nebulization rates [ 66 ].

A total of 16 studies examined relationships between reduction in unscheduled care and ACT score improvement from “not well controlled” to “well-controlled” asthma [ 47 , 49 , 51 , 53 , 54 , 55 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. Statistically significant results were reported for unscheduled outpatient clinic visits by two studies [ 54 , 74 ], for emergency department visits by five studies [ 54 , 55 , 71 , 74 , 75 ], for hospitalizations by three studies [ 55 , 71 , 72 ], for ‘urgent health care utilization’ by one study [ 69 ] and use of inhaled corticosteroids by one study [ 67 ].

In total, six studies reported on costs [ 50 , 65 , 70 , 76 , 77 , 78 ], of which five reported relationships between asthma control subgroup and direct medical costs [ 50 , 65 , 70 , 76 , 77 ], and three with indirect medical costs [ 65 , 77 , 78 ]. However, only one study reported statistically significant results for direct medical costs [ 77 ].

The average cost (Euros [€)/month/patient) of well-controlled asthma versus “not well-controlled” asthma was reported as €28 versus €140 in France and €77 versus €252 in Spain [ 50 ]. In Spain, indirect costs were significantly higher in older patients (41–65 years, €405.08), patients with more severe disease (€698.95), and patients with more poorly controlled asthma (€466.86) [ 65 ]. Mean per-patient annual costs of asthma management for patients with derived ACT scores of < 15, 15–19 and ≥ 20 were reported as, in the Asia-Pacific, US$861, US$319 and US$193 [ 70 ]; and in Europe, €1604, €512, and €232 [ 76 ]. Patients with asthma control spent S$48 (US $36) more per doctor visit on asthma drugs ( p  < 0.01) but incurred S$65 (US$48) less per doctor visit in total costs ( p  < 0.01) than those with suboptimal asthma control [ 77 ].

The data suggest that asthma that was not well controlled (ACT score < 20) led to higher direct medical costs [ 65 , 77 ], higher unscheduled care costs [ 70 , 76 ], and higher total societal costs of asthma [ 50 ], while data on indirect costs suggest that “not well-controlled” asthma (ACT score < 20) leads to higher indirect medical costs [ 77 , 78 ], and higher cost of workdays lost [ 65 ].

This review aimed to qualitatively assess the link between ACT score and key asthma outcomes through a targeted review of the available literature. Substantial evidence was identified for relationships between ACT score and ACQ score, lung function, and asthma-related QoL; moderate evidence was obtained for relationships between ACT score and rescue medication use, exacerbations, sleep quality, and work and productivity; limited evidence was identified for relationships between ACT score and general health-related QoL, HRU, and healthcare costs. While links to reductions in the use of rescue medication and the number of asthma exacerbations were also reported, there was limited or no evidence to suggest that there is a relationship between ACT score and general HRQoL, HRU, and healthcare costs.

Overall, these findings support the use of the ACT in a clinical setting, as a valid measure of disease control and associated patient outcomes, including ongoing symptomology and future risk. They also support the clinical use of the ACT to guide the appropriate management of patients with asthma, including when and how to select between alternative treatments. Additionally, the available evidence provides a foundation for the use of the ACT as a primary or secondary endpoint in clinical trials, allowing investigators to gauge accurately the effectiveness of a treatment.

The overall strength of this review is that it collates the published relationships between ACT score and a broad range of clinical outcomes into a coherent whole. By aiding our understanding of how ACT score is reflective of the different aspects of patients’ asthma experience, this review provides support for its use as a viable measure for other outcomes.

Limitations include the targeted nature of the literature search, which may not have encompassed the full body of literature on the correlation being investigated, and the presence of large differences in scientific rigor and reporting standards between the included articles. Additionally, the statistical power may have been inadequate in some of the evaluated studies, either by being insufficiently powered to evaluate the relationships between ACT score and the outcomes of interest, or overpowered to the extent such as a weak relationship became highly statistically significant.

With respect to future work, the exploratory setup of this research provides a characterization of the topics on which scientific data regarding the ACT are present or absent. As such, the current report provides a starting point to explore and corroborate these findings in future research initiatives on the value of ACT scores in real-world clinical settings. More studies evaluating relationships between ACT score and general HRQoL, healthcare costs, and resource use are also needed, as well as additional research into relationships in populations with differing levels of asthma severity.

Despite some limitations inherent to the nature of a targeted literature review, this report provides an informative qualitative assessment of the available literature on the relationships between ACT score and a broad range of outcomes of interest, supporting the use of the ACT in clinical practice and trial settings.

Availability of data and materials

All data used in this review were taken from publicly available articles, and can be found at the relevant journal websites.

Abbreviations

Asthma Control Questionnaire

  • Asthma Control Test

Analysis of variance

Asthma Quality of Life Questionnaire

American Thoracic Society

Annual meeting of the American College of Chest Physicians

EuroQol five dimensions questionnaire

European Respiratory Society

Forced expiratory volume in 1 s

Forced vital capacity

Health-related quality of life

Healthcare resource use

Impact on Work Productivity Index

Medical Outcomes Study

Pittsburgh Sleep Quality Index

  • Quality of life

Short-acting beta agonist

Short Form (12-item) Health Survey

Work Productivity and Activity Impairment questionnaire

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Acknowledgements

Pharmerit International would like to thank Anne Marie Trip and Susan Tempelaar for their assistance with this study. Trademarks are the property of their respective owners. Medical writing support in the form of development of the draft outline and manuscript drafts in consultation with the authors, editorial suggestions to draft versions of this paper, assembling tables and figures, collating author comments, copyediting, referencing and graphic services was provided by David Mayes, MChem and Samantha McKenna, BSc (Hons) of Gardiner-Caldwell Communications (Macclesfield, UK), and was funded by GlaxoSmithKline plc.

This study was designed and funded by GlaxoSmithKline plc. (GlaxoSmithKline plc. Study number HO-17-18170). Employees of GlaxoSmithKline plc. were involved in the study concept and design, data analysis, and preparation of the manuscript.

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CA and BvD (guarantor) conceived and designed the literature review design. BvD and JB collected, analyzed and interpreted the data. CA supervised the project. HS, AH, LN, and JB were involved in the conception/design and data analysis/interpretation of the manuscript. All authors critically reviewed and approved the final version to be published.

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van Dijk, B.C.P., Svedsater, H., Heddini, A. et al. Relationship between the Asthma Control Test (ACT) and other outcomes: a targeted literature review. BMC Pulm Med 20 , 79 (2020). https://doi.org/10.1186/s12890-020-1090-5

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Acid-Base Disturbances in Patients with Asthma: A Literature Review and Comments on Their Pathophysiology

Affiliations.

  • 1 Intensive Care Unit, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, 115 27 Athens, Greece. [email protected].
  • 2 4th Department of Respiratory Medicine, Sotiria Hospital, 115 27 Athens, Greece. [email protected].
  • 3 5th Department of Respiratory Medicine, Sotiria Hospital, 115 27 Athens, Greece. [email protected].
  • 4 Intensive Care Unit, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, 115 27 Athens, Greece. [email protected].
  • 5 Intensive Care Unit, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, 115 27 Athens, Greece. [email protected].
  • 6 Intensive Care Unit, 1st Department of Respiratory Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, 115 27 Athens, Greece. [email protected].
  • PMID: 31027265
  • PMCID: PMC6518237
  • DOI: 10.3390/jcm8040563

Asthma is a common illness throughout the world that affects the respiratory system function, i.e., a system whose operational adequacy determines the respiratory gases exchange. It is therefore expected that acute severe asthma will be associated with respiratory acid-base disorders. In addition, the resulting hypoxemia along with the circulatory compromise due to heart-lung interactions can reduce tissue oxygenation, with a particular impact on respiratory muscles that have increased energy needs due to the increased workload. Thus, anaerobic metabolism may ensue, leading to lactic acidosis. Additionally, chronic hypocapnia in asthma can cause a compensatory drop in plasma bicarbonate concentration, resulting in non-anion gap acidosis. Indeed, studies have shown that in acute severe asthma, metabolic acid-base disorders may occur, i.e., high anion gap or non-anion gap metabolic acidosis. This review briefly presents studies that have investigated acid-base disorders in asthma, with comments on their underlying pathophysiology.

Keywords: asthma; hypercapnia; hyperchloremic acidosis; hypocapnia; lactic acidosis.

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  • Published: 14 June 2017

Association between HMGB1 and asthma: a literature review

  • Egidio Imbalzano 1 ,
  • Sebastiano Quartuccio 1 ,
  • Eleonora Di Salvo 2 ,
  • Teresa Crea 1 ,
  • Marco Casciaro 3 &
  • Sebastiano Gangemi 3  

Clinical and Molecular Allergy volume  15 , Article number:  12 ( 2017 ) Cite this article

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Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation.

This literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma.

We reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma.

A total of 19 studies assessing the association between HMGB1 and asthma were identified.

Conclusions

What emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. Findings reported suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy; finally, inhibiting HMGB1 in humans in order to contrast inflammation should be the aim for future further studies.

The proinflammatory factor high‑mobility group box protein (HMGB) is a non-histone and ubiquitous chromosomal protein found enriched in active chromatin forming part of the high mobility group family of proteins and is encoded by the HMGB1 gene (13q12) in human [ 1 , 2 ]. In particular HMGBs have specific motifs that are DNA-binding domains [ 3 , 4 ]. The HMGBs are composed of four categories (HMGB1-4). HMGB1 (also known as HMG1, HMG-1, HMG 1, amphoterin, p30) is the most frequently expressed of the entire HMG family proteins [ 5 ]. Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders [ 6 , 7 , 8 , 9 , 10 ].

Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated with airway hyper-responsiveness (AHR) and airway inflammation. The dominance of Th2 response is characteristic of allergic eosinophilic asthma, T2 response characteristic of non allergic eosinophilic asthma, and T17 of neutrophilic asthma. Asthma currently affects ~300 million people worldwide, with a large socioeconomic burden. Until recently, the aetiology and pathogenesis of asthma remained elusive. It is clear, however, that airway inflammation induced by the release of inflammatory cytokines is responsible of the chronicity and progression of the disease [ 11 , 12 ]. In order to improve knowledge of the disease have been discovered new biomarkers of airway inflammation and respiratory diseases such as asthma, including HMGB1.

This review aim is to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma. We reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma.

This literature review has been conducted employing two databases: PubMed and ScienceDirect. On these websites we looked for articles from inception through December 2016 using a key term related to asthma: “asthma” and one key term related to HMGB1: “HMGB1”.

We determined that the abstracts of those articles whose titles suggested they might have examined the association between asthma and HMGB1 were to be considered. The whole article was read if the abstract indicated the article potentially met the inclusion criteria. Finally we reviewed and searched references of the selected articles and the ones whose titles suggested that could have considered the association between asthma and HMGB1 in order to identify further studies that met the inclusion criteria. Articles were included in our review according to the following inclusion criteria: English language, publication in peer reviewed journals. Articles were excluded by title, abstract or full text for irrelevance to the topic in question. Further exclusion criteria were: non-research articles.

Three authors (MC, SQ, TC) conducted the initial search and separately reviewed and selected the references based on the inclusion and exclusion criteria.

Data obtained from our research of articles includes: study author names, publication dates, study designs (i.e., case–control, cross-sectional, longitudinal), groups studied, clinical and biological variables, outcome of interest of the study.

Principal outcome of interest included studies about advanced molecular targets on animals and humans as either disease marker or pathogenic mechanisms.

Given considerable diversity in the study designs and subjects of the selected studies (in terms of biological and clinical variables), characteristics of the observed populations and protocols are summarised and the study outcome is delineated using descriptive statistics without conducting any meta-analyses. The heterogeneity of the studies included in our paper is a limitation of our review since both animals and humans, in vivo and in vitro studies are included; moreover pathogenetic and clinical research are described.

As resumed in Table  1 a total of 19 studies assessing the association between HMGB1 and asthma were identified.

HMGB-1 human clinical studies

Watanabe et al. were the first to test the level of HMGB1 and of the endogenous secretory receptor for advanced glycation end products (esRAGE) in sputum of asthmatic patient. In 2011 they dosed HMGB-1 and esRAGE levels in induced sputum of 44 asthmatic patients (before any asthma treatment) and 15 normal controls (Japanese, non-smokers subjects, with no history of respiratory infection for minimum of 4 weeks before the study). HMGB-1 sputum levels were significantly augmented in asthmatic patients than in controls, and there was an accordance between HMGB-1 level and the severity of disease. esRAGE levels in induced sputum from asthmatic subjects were considerably higher than those in healthy ones, with no significant differences in esRAGE levels between the mild persistent and the severe asthmatic patients [ 13 ].

In 2011 Hou et al. enrolled 61 asthmatic and 47 COPD untreated patients and compared them with controls. HMGB1 levels in induced sputum were higher in patients with all severities of asthma and in those with COPD than healthy subjects. Plasma and sputum HMGB1 levels were higher in patients with severe asthma than in patients with mild one. There were no significant variation in sputum HMGB1 levels between subjects with mild asthma and controls and between mild asthma and moderate asthma. Plasma HMGB1 levels were noticeably higher in patients with moderate asthma than in those with mild asthma. Serum and sputum HMGB1 levels of COPD patients were significantly augmented than levels in asthmatic ones. The differences of plasma and sputum HMGB1 levels were not significant between patients with non eosinophilic asthma and eosinophilic asthma patients. In every patient, HMGB1 levels in plasma and induced sputum pointed out a significant negative correlation with lung function parameters (FEV1, FEV1) and FEV1/FVC ratio [ 14 ].

Sukkar et al. in 2012, enrolled asthmatic subjects (n = 516), COPD ones (n = 537) and healthy controls (n = 518). They rated total sRAGE, neutrophils, endogenous secretory RAGE (esRAGE), HMGB1 and serum amyloid A (SAA) on bronchial lavage fluid. They enrolled subjects using inhaled corticosteroids (ICS) reporting increased HMGB1 in the airways in stable COPD and in asthmatic sputum. Moreover, they dosed systemic levels of soluble RAGE (sRAGE) in a separate group of asthmatic (n = 5101) and COPD (n = 534) patients. Subjects with neutrophilic asthma or COPD had no levels of lung sRAGE, while levels of sRAGE in non-neutrophilic asthma/COPD were almost the same to those in controls. Systemic sRAGE was significantly decreased in patients affected by neutrophilic asthma or COPD compared to those which haven’t airway neutrophilia. sRAGE and esRAGE in the lung and systemically had a significant positive correlation. HMGB1 levels were similar in all subject groups, while SAA was undetectable. Thus, they aimed to report whether reduced sRAGE was associated with augmented levels of HMGB1 and SAA, both mediators of neutrophil inflammatory reaction. They observed similar BL levels of HMGB1 in every group speculating that HMGB-1 levels differences were abrogated by the use of ICS [ 15 ].

Shim et al. in 2012 joined up 50 asthmatics and 15 normal controls. This study confirmed that sputum HMGB1 expression was higher in asthmatics than in healthy controls; sputum HMGB1 expression was significantly higher in subjects with sputum eosinophilia than in subjects without sputum eosinophilia. There was a positive correlations between sputum HMGB1 expressions in sputum eosinophilia and sputum TNF-a, IL-5 and IL-13 levels [ 16 ].

Zhou et al. in 2012 recruited 72 asthmatic patients in treatment and 30 healthy individuals. In induced sputum samples of asthma group was detected an augmented presence of neutrophils, HMGB1 and RAGE levels. In severe asthmatics, the percentage of neutrophils and HMGB1 levels were noticeably higher than in mild and moderate asthmatic patients. The percentage of neutrophils, HMGB1 and RAGE levels were diminished after treatment administration than before treatment administration. It was reported a negative correlations between HMGB1 or RAGE levels and FEV1%, and positive one between HMGB1 or RAGE levels and the percentage of neutrophils [ 17 ].

Liang et al. isolated normal Human bronchial epithelial cells from human lung tissue obtained from four patients undergoing lobectomy. They focused on specific receptor of p38 MAPK, ERK1/2, or PI3-K and showed that HMGB1 increased the expression and secretion of TNF-a, TSLP, MMP-9, and VEGF; this event was dose and time dependent. Elevated expression of RAGE protein was induced by HMGB1. RAGE blockade and p38 MAPK pathway inhibition decreased secretion of TNF-a, VEGF, MMP-9, and TSLP, ERK1/2 inhibition determined a smaller decrease. This study suggested that HMGB1 promotes activities of p38 MAPK and ERK1/2 pathways in bronchial epithelial cells by enhancement of TNF-a, VEGF, MMP-9, and TSLP level [ 18 ].

Cuppari et al. enrolled 50 children or adolescents with mild, moderate and severe asthma and 44 healthy children. They showed that sputum HMGB1 levels were significantly augmented in patients with asthma compared to healthy ones. Particularly, patients with severe asthma presented higher sputum HMGB1 levels than patients with mild asthma and than moderate asthmatic ones. In addition, total serum IgE levels in the asthmatic group were noticeably elevated than those in the control group and positively correlated to sputum HMGB1. Sputum HMGB1 values were positively related to total IgE levels in children with asthma. It emerged an inverse correlation between sputum HMGB1 levels and lung function indices [ 7 ].

Ojo et al. in 2015 treated human bronchial epithelial cell line with various concentrations of HMGB1 and demonstrated the reduction of E-cadherin and an enhanced scratch wound closure. Then they assessed the impact of glycyrrhizin, an inhibitor of extracellular HMGB1, and demonstrated that it is sufficient to block this effect. Also the addiction of TLR4 or RAGE inhibitors block this effect, so this study demonstrated that TLR4 and RAGE may be required to response to HMGB1. For the first time, this study demonstrated HMGB1 promotes bronchial epithelial cell wound repair by enhanced production of integrins and ECM proteins. HMGB1 interacted with TLR4 and/or RAGE, actived downstream signaling MAPKs (ERK1/2 and JNK; 2), induced fibronectin, laminin-5(2 chain), 3-integrin. Also the addiction of TLR4 or RAGE inhibitors blocked the production of laminin-5(2chain) and 3integrin. By ERK1/2 and JNK signaling, (possible through SMAD2) the HMGB1-induced wound repair through TGF-receptor1 [ 19 ].

HMGB-1 experimental animal studies

Shim et al. created an animal model of asthma (mice) to analyse lung tissue and bronchoalveolar lavage (BAL) fluid after an intraperitoneal injection of neutralizing antibodies. They observed that RAGE and TLR2 expression on the CD11b−CD11c+ cells (dendritic cells) augmented importantly in asthmatic animals compared with control ones and these changes were incredibly attenuated by the injection of HMGB1 neutralizing antibodies [ 16 ].

Lee et al. in 2013 created a animal model (mice) of chronic asthma in order to demonstrate that the inhibition of HMGB1 expression decreased airway inflammation, mucus generation, and collagen production in lung tissues. The count of CD4+ T helper (Th) cells in the mediastinal lymph nodes and lungs demonstrated that Th17 had a greater increase than Th2 cells and Th1 cells in OVA-immunized mice; moreover Th1, Th2, and Th17 cells got lower in anti-HMGB1 antibody (Ab)-treated animals. In OVA-immunized mice, TLR-2 and TLR-4 expression, but not RAGE expression, was expressed ex novo in the lungs and diminished after anti-HMGB1 Ab administration [ 20 ].

Ullah et al. in 2014 investigated TLR4 and RAGE interaction in a house dust mite asthma mice model. They demonstrated that the shortage of RAGE reduced the allergic airway inflammation but in absence of both RAGE and TLR4 there was not further reduction in inflammatory response. The release of HMGB1 from the airway epithelium obtained in a biphasic way, lead to the sequential activation of TLR4 then RAGE and was followed by the downstream of IL-1a, and the upstream of IL-25 and IL-33 production. They, also, demonstrated that Immunoneutralization of HMGB1 reduced allergic airway inflammation [ 21 ].

Qiao et al. investigated the consequence of different doses of 1,25-(OH)2D3 on airway remodelling and on the expression of HMGB1 and TLR4 in a mice model. They used groups of 10 mice: a control, an asthmatic and 1,25-(OH)2D3 low, middle, high dose group. There was a higher expression of HMGB1 and TLR4 mRNAs in the lungs of asthmatic group than in control one. The expression of HMGB1 and TLR4 mRNAs in 1,25-(OH)2D3 low and middle dose groups was considerably lower than the asthma group and higher than the control one; the high dose group had an augmented expression of HMGB1 and TLR4 mRNAs compared to the asthmatic group [ 22 ].

Tang et al. in 2014, made a toluene-2,4-diisocyanate (TDI)-induced murine asthma model, dominated by granulocytic inflammation and explored the role of ethyl pyruvate (EP) on this model. Their paper demonstrated the capability of EP in suppressing inflammation in the peribronchial and perivascular lung structure and in reducing the amount of neutrophils in BAL. Levels of HMGB1 were significantly higher in TDI induced murine asthma model and EP treatment down-regulated HMGB1 in a dose-dependent manner [ 23 ].

Zhang et al. thanks to their previous observation in a murine model of neutrophilic asthma of positive correlation between the increase in HMGB1 expression and Th17-mediated airway inflammation, speculated that HMGB1 promoted the production of Th17 polarization-related factors, and that HMGB1 blocking inhibited the Th17 response. They assessed that rHMGB1-stimulated DCs secreted IL-23, in vitro, that act as a Th17 polarization factor. IL-23 antibody, added in the culture, reduced the IL-17A expression level and the percentage of IL-17+ CD4+ T cells, suggesting that the IL-17 expression level was dependent upon rHMGB1 and potentially regulated by the endogenous production of IL-23 by BMDCs. They showed that anti-HMGB1 IgG decreased HMGB1 expression, levels of neutrophilic inflammation in lung tissue, in BALF by decreased levels of Th17-related cytokines (IL-23 and IL-17A) [ 24 , 25 ].

Shim et al. considered eosinophils, dendritic, and CD4+ T cells obtained from a mice model of asthma. They demonstrated that HMGB1 levels were higher in the supernatant of the eosinophil culture stimulated with IL-5. On the contrary, anti-HMGB1 antibodies significantly decreased IL-4 and IL-5 levels in the supernatant of CD4+ T cells co-cultured with DCs [ 26 ].

Yao et al. in 2015 investigated the role of HMGB1 in TDI-induced asthma with the IgY anti-HMGB1 antibody. They used a TDI-induced asthmatic murine model, measured levels of IFNg, IL-4, IL-5, IL-13, IL-17A and TNF-a in supernatants of cultured lymphocytes and accomplished pulmonary histopathological examination. They found that IgY could augment cytokine release in asthma [ 27 ].

Liang et al. in 2015, using a TDI-induced murine asthma model, demonstrated that caspase-1 activation and HMGB1 production was mediated by Phosphatidylinositol 3-kinases (PI3Ks); this study also assessed the role of LY294002 a specific inhibitor of PI3K. They considered lymphocytes by cervical lymphonodes, total serum IgE, Bronchoalveolar lavage (BAL), lung histopathology. First, they proved administration of LY294002 abolished the TDI induced elevated p-Akt expression, involved in downstream of PI3K signal pathway. Level serum IgE was significantly increased in TDI-induced murine asthma model, as well as IL-4 in supernatant of cultured lymphocytes, the number of inflammatory cells and the protein level of HMGB1 in BAL fluid and lung tissue. These changes in both BALF and lung tissue were reversed after LY294002 treatment. HMGB1 trans-located from the nuclei to the cytoplasm after TDI challenge; both the higher protein expression and nucleocytoplasmic translocation of HMGB1 were diminished after LY294002 adminstration. In TDI-induced murine asthma model, caspase-1 was activated after TDI exposure; after LY294002 adminstration was found abnormal distribution of cleaved caspase-1 but not procaspase-1, so the role of this specific inhibitor was established in the cleavage process of caspase-1 rather than increasing its protein expression. Also they detected higher level of IL-1b after TDI exposure, and showed that LY294002 administration reduced this TDI induced IL-1b expression in the cytoplasm [ 28 ].

Ma et al. reported that levels of HMGB1 in BALF and lung tissue of asthmatic mice were significantly augmented than controls. HMGB1 injection was correlated to increased mucus production and presence of eosinophils and neutrophils in the airways together with a decreased pulmonary function, to increased levels of IL-4, IL-5, IL-6, IL-8 and IL-17 and reduction of IFN-γ in the BALF and lung tissue, enhanced GATA3 expression of Th2 cells and attenuated T-bet expression of Th1 cells. These effects could be reversed after inhibiting HMGB1 [ 29 ].

Finally in 2015 Hou et al. elaborated a mice model of chronic asthma (which have a considerably high HMGB1 expression) in order to consider the effects of HMGB1 on airway responsiveness and re-modeling. They administered to the mice anti-HMGB1 antibody therapy. The anti-HMGB1 antibody animals exhibited diminished levels of IgE, inflammatory cytokines and inflammatory cell accumulation, airway hyperresponsiveness (AHR), mucus generation, smooth muscle thickness and lung collagen levels [ 30 ].

Many studies demonstrated that HMGB1 is actively released extracellularly from cells belonging to the immune system or passively released from damaged cells [ 6 ]. In addition to its nuclear functions, HMGB1 has extracellular activity; i.e. HMGB1 can have a role in a danger associated molecular pattern (DAMPs) [ 31 , 32 ]. DAMPs, are part of the alarmins group; they are warning signals which are secreted from permanently damaged cells. Their function is to “alert” the immune system by activating the “inflammasome” through the interaction with the pattern recognition receptors (PRRs) situated on the plasma membrane, inside endosomes after endocytosis and in the cytosol (i.e. toll-like receptors), advanced glycosylation end product-specific receptor RAGE (receptor for advanced glycation end products), RIG-I-like receptors, NOD1-like receptors, and AIM2-like receptors [ 9 , 10 ]. HMGB-1 in the nucleus play different roles such as DNA replication, repair, recombination, transcription, apoptosis and it have also genomic stability. It also have important functions outside the cell in inflammation, immunity, as a signal for cell growth, proliferation and death [ 33 , 34 ].

The variety of results obtained suggests that HMGB1 is an important protein which regulates many receptors involved in the phosphorylation and in the synthesis of glycation end products by interacting with RAGE and toll-like receptors (TRL). These receptors lead to an increase of some cytokines, i.e. TNF-alpha, IL-4 and IL-6, that characterise an innate inflammatory response. Thus, an increase of HMGB1 has been linked to many inflammatory diseases such as allergic asthma, diabetes, atherosclerosis and heart failure [ 35 ].

In fact, as illustrated in Fig.  1 , recent studies have shown the interaction of HMGB1 with RAGE, TLR2, and TLR4 that transduces intracellular signals that activate protein kinases (MAPKs) and nuclear factor kappaB (NF-kB), which lead to the activation and the release of pro-inflammatory cytokines (e.g., TNF and Interleukins) [ 36 , 37 ].

Intracellular and extracellular HMGB-1 main interactions

Furthermore, recent researches have clarified the role of the immune system thanks to the analysis of two characteristic cytokines, IL-4 and IL-13, secreted by T helper type 2 cells (Th2), basophils and mastocytes typical of allergic immunity, leading to pathological conditions such as asthma and allergy. In particular IL-4Rα, a subunit in cognate receptors with IL-4, activate signal transducer and transcription of factor-6 (STAT-6), important for IL-4 release from antigen-stimulated, which play a predominant role in the immune system [ 36 , 37 ].

Recently, it has been observed that IL-4, IL-13 and STAT6 are fundamental in the progression of airway hyper-responsiveness, inflammation, as well as mucus production in Th2 asthma. Additionally, more studies demonstrated that IL-4Rα subunit and others receptors, are activators of STAT-6. Consequently, it was reported that IL-4/STAT-6 pathway is involved in asthma pathogenesis because STAT-6 activation lead to the differentiation of naïve T-cells into Th2 effector cells, and it regulates the production of Th2 chemokine induced by IL-4 and IL-13 [ 38 , 39 ].

What emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. In a previous literature review we demonstrated how HMGB-1 levels were augmented in different tissues of smokers and COPD patients [ 8 ]. Severe asthma subjects had higher sputum levels of HMGB-1 than moderate and mild patients. These findings suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy. Sputum analysis is a non-invasive cheap methodology which could be useful in clinical practice as a disease screening procedure. Furthermore asthmatic population have augmented levels of the protein in serum too compared to normal subjects. On the other hand animals studies also demonstrated that treating asthma with drugs known to lower HMGB-1 levels or with anti-HMGB-1 antibodies ameliorate animals condition and decrease in situ inflammatory markers. This model should be applied on humans in order to confirm these results in vivo. Bronchostenosis mechanism, fundamental in the asthmatic disease, could be sustained and modulated by this alarmin. Data obtained and collected in this review indicate that HMGB1 is a potential therapeutic target of allergic asthma, nevertheless it is difficult to detect its levels, because it is a nuclear protein. Therefore future studies could be focused on the detection and the consequent blockage of HMGB-1 receptors, such as STAT-6 and in order to decrease HMGB1 expression.

In conclusion detecting levels of HMGB-1 in order to use it as disease marker and inhibiting HMGB1 in humans to contrast inflammation should be the aims for future further studies.

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Authors’ contributions

SG and EI designed the study, made data analysis and interpretation, and revised the manuscript. MC, SQ and TC carried out the bibliographic search, contributed to the draft of the manuscript. EDS made data interpretation and contributed to figure and tables. MC wrote and coordinated the draft of the manuscript. All authors read and approved the final manuscript.

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Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

Egidio Imbalzano, Sebastiano Quartuccio & Teresa Crea

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Eleonora Di Salvo

School and Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

Marco Casciaro & Sebastiano Gangemi

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Imbalzano, E., Quartuccio, S., Di Salvo, E. et al. Association between HMGB1 and asthma: a literature review. Clin Mol Allergy 15 , 12 (2017). https://doi.org/10.1186/s12948-017-0068-1

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