Uncontrolled asthma: A review of the prevalence, disease burden and options for treatment

Open ArchivePublished:May 24, 2006DOI:https://doi.org/10.1016/j.rmed.2006.03.031

      Summary

      An estimated 300 million people are affected by asthma worldwide and the burden is likely to rise substantially in the next few decades. Estimates of the prevalence of asthma range from 7% in France and Germany to 11% in the USA and 15–18% in the United Kingdom. Approximately 20% of these patients have severe asthma, of which 20% is inadequately controlled. Patients with inadequately controlled severe persistent asthma are at a particularly high risk of exacerbations, hospitalization and death, and often have severely impaired quality of life. Current management of asthma focuses on a stepwise approach tailored to disease severity. In addition to needing high-dose inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs), patients with severe persistent asthma often require additional controller medications, such as anti-leukotrienes, oral LABAs, oral corticosteroids and/or anti-IgE therapy. There is currently little evidence on which to base treatment decisions in patients with inadequately controlled severe persistent asthma already treated with ICS and LABAs. The anti-IgE monoclonal antibody omalizumab is the most recent addition to the list of treatment options for these patients and has been shown to reduce exacerbations and emergency visits and improve lung function, symptom scores and quality of life in patients with difficult-to-treat asthma whose symptoms remain inadequately controlled despite receiving ICS and LABAs. Comparative trials are needed to determine the merits of different treatments and strategies for patients with inadequately controlled severe persistent asthma and to identify patients likely to benefit from new treatment options.

      Keywords

      Introduction

      Asthma affects 300 million people worldwide and is predicted to affect an additional 100 million people by 2025.
      • Masoli M.
      • Fabian D.
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      The global burden of asthma: executive summary of the GINA Dissemination Committee report.
      It causes approximately 239,000 deaths per year (0.4% of all deaths due to disease)

      World Health Organization. The world health report 2003.

      and results in a large burden of disability, accounting for a similar number of disability adjusted life years (DALYs) as osteoarthritis, cirrhosis, diabetes and schizophrenia.
      • Masoli M.
      • Fabian D.
      • Holt S.
      • Beasley R.
      The global burden of asthma: executive summary of the GINA Dissemination Committee report.

      World Health Organization. The world health report 2003.

      Inadequate control of asthma continues to present a serious problem, despite advances in our understanding of the inflammatory basis of asthma and a growing acceptance of disease management guidelines. Patients with inadequately controlled asthma often have limited therapeutic options and remain at a high risk of serious morbidity and mortality.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659. 2002. National Institutes of Health/National Heart, Lung, and Blood Institute.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659 (updated 2004). 2004. National Institutes of Health/National Heart, Lung, and Blood Institute.

      • Chung K.F.
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      • et al.
      Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.
      In this review, we will discuss current strategies for controlling asthma, describe the causes and consequences of inadequate control, and evaluate new options for improving asthma control.

      Asthma control: guidelines and definitions

      Global Initiative for Asthma (GINA) guidelines classify asthma severity into four steps according to clinical features before treatment, as well as by the daily medication regimen and the response to treatment (Fig. 1).

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659. 2002. National Institutes of Health/National Heart, Lung, and Blood Institute.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659 (updated 2004). 2004. National Institutes of Health/National Heart, Lung, and Blood Institute.

      Thus, asthma is classified as intermittent, mild persistent, moderate persistent or severe persistent according to clinical features (Fig. 1). Treatment should be tailored to asthma severity. For example, patients with intermittent asthma should receive a rapid-acting inhaled β2-agonist while those with mild persistent asthma should also receive a low-dose inhaled corticosteroid (ICS). Patients with moderate or severe asthma should receive inhaled long-acting β2-agonists (LABAs) coadministered with an ICS (LABAs should never be used as monotherapy for the treatment of asthma).
      Figure thumbnail gr1
      Figure 1GINA guidelines for the classification of asthma severity.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659. 2002. National Institutes of Health/National Heart, Lung, and Blood Institute.

      The GINA guidelines define control of asthma as minimal chronic symptoms, minimal (infrequent) exacerbations, no emergency visits, minimal use of as-needed (rapid-acting) β2-agonists, no limitations on activities, daily peak expiratory flow (PEF) variation of less than 20%, near normal PEF and minimal adverse effects from medications.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659. 2002. National Institutes of Health/National Heart, Lung, and Blood Institute.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659 (updated 2004). 2004. National Institutes of Health/National Heart, Lung, and Blood Institute.

      In the stepwise approach to therapy recommended in the GINA guidelines, treatment should progress to the next step if control is not achieved or is lost with the current treatment and the patient is using medication correctly. Thus, a patient with mild persistent asthma despite step 2 treatment should be treated using step 3, proceeding to step 4 if control is still not achieved.
      The response to treatment is also incorporated in various other terms used to categorize asthma at the severe end of the spectrum. For example, the European Respiratory Society (ERS) adopted a concept of ‘difficult/therapy-resistant asthma’ for patients whose asthma is not controlled despite high-dose ICS.
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      Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.
      Adult patients are defined as having difficult/therapy-resistant asthma if their symptoms remain uncontrolled despite daily ICS doses in excess of 2000μg beclometasone dipropionate (BDP), 1600μg budesonide, 1000μg fluticasone or equivalent. In children, the dose thresholds above which asthma is considered difficult to treat are 800μg of BDP, 800μg of budesonide or 400μg of fluticasone.
      The American Thoracic Society (ATS) describes ‘refractory’ asthma as encompassing several subgroups of patients with asthma that is severe, corticosteroid dependent/resistant, difficult to control, brittle or irreversible.
      American Thoracic Society
      Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions.
      Patients with refractory asthma are those who require high doses of controller and reliever medications to maintain symptom control, or who have persistent symptoms, exacerbations or airflow obstruction despite near continuous high-dose medication use. They also have at least two of the following features: need for additional daily controller medication; need to use a short-acting inhaled β2-agonist daily or near-daily; persistent airway obstruction (forced expiratory volume in 1s (FEV1)<80% predicted and PEF variability>20%); one or more urgent care visits per year; three or more oral steroid ‘bursts’ per year; prompt deterioration with reduction in steroid dose; or a near-fatal asthma event in the past.
      Pathologic (airway and bronchoalveolar lavage) studies of severe asthma suggest that one-half to two-thirds of patients with severe asthma have persistent airway tissue eosinophilia, despite receiving high-dose oral and ICSs.
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      Severe asthma in adults.
      The presence of eosinophils (as measured by sputum, lavage, biopsy or exhaled nitric oxide) may represent another subtype of severe asthma, characterized by a higher level of active symptoms, reduced FEV1 and a greater likelihood of exacerbations and near-fatal events occurring than in a subtype without eosinophils.
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      Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.
      Differentiation by presence or absence of eosinophils has been applied to early and late-onset severe asthma, with indication for both similarities and differences in the eosinophilic process dependent on age onset.
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      Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.
      In some, but not all, cases where eosinophils are absent there may be an increase in neutrophils. The increase in neutrophils does not always accompany the absence of eosinophils, and the two cell types may be concomitantly present in tissue.
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      Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics.
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      Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticosteroids.
      The mechanisms or clinical implications for this neutrophilic inflammation are unclear.

       Co-morbid risk factors for severe asthma

      Certain co-morbidities are associated with severe or difficult-to-manage asthma.
      Asthma co-exists with rhinitis in a large proportion of patients and epidemiological studies have estimated that the majority of patients with asthma (60–80%) also have rhinitis, with 20–40% of patients with rhinitis also having asthma.
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      Airway hyperresponsiveness in allergic rhinitis. A risk factor for asthma.
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      Epidemiology and natural history of asthma, allergic rhinitis, and atopic dermatitis (eczema).
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      • Neukirch C.
      • et al.
      Perennial rhinitis: an independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey.
      A recent study conducted in the United Kingdom found that adults with asthma and documented concomitant allergic rhinitis experienced significantly more asthma-related hospitalizations and GP visits as well as incurring higher asthma-related drug costs compared with adults with asthma alone.
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      • et al.
      Effect of concomitant diagnosis of allergic rhinitis on asthma-related health care use in adults.
      The high frequency of co-morbidity of rhinitis and asthma and the similarity of their epidemiological, pathological and physiological features have resulted in recommendations for a common approach to management.
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      • Khaltaev N.
      Allergic rhinitis and its impact on asthma.
      Indeed, effective rhinitis management has been shown to improve asthma control
      • Durham S.R.
      Effect of intranasal corticosteroid treatment on asthma in children and adults.
      and two recent studies have shown that treating allergic rhinitis, particularly with intranasal steroids, confers significant protection against asthma exacerbations that result in emergency department visits for asthma.
      • Crystal-Peters J.
      • Neslusan C.
      • Crown W.H.
      • Torres A.
      Treating allergic rhinitis in patients with co-morbid asthma: the risk of asthma-related hospitalizations and emergency department visits.
      • Adams R.J.
      • Fuhlbrigge A.L.
      • Finkelstein J.A.
      • Weiss S.T.
      Intranasal steroids and the risk of emergency department visits for asthma.
      Gastroesophageal reflux disease (GERD) affects approximately 20% of adults in the United States on a weekly basis and 40% on a monthly basis.
      • Harding S.M.
      The potential role of gastroesophageal reflux in asthma.
      GERD is also a trigger for asthma and the prevalence of GERD is higher in patients with asthma when compared with control groups, with 77% of asthma patients having reflux symptoms and 82% of asthmatics having abnormal esophageal acid contact times on 24-h esophageal pH testing.
      • Harding S.M.
      The potential role of gastroesophageal reflux in asthma.
      Esophageal acid elicits respiratory responses including decreases in airflow, oxygen saturation, and increases in respiratory resistance, minute ventilation and respiratory rate. Additionally, therapy of GERD improves asthma outcomes: in combined studies examining 326 asthma patients receiving drug therapy for GERD, asthma symptoms improved in 69% of these patients while surgical therapy trials to alleviate symptoms of GERD in 417 asthma patients showed that asthma symptoms improved in 79% of patients.
      • Harding S.M.
      The potential role of gastroesophageal reflux in asthma.
      A number of environmental factors have been shown to be associated with the onset of asthma. These include exposure to tobacco smoke, allergen sensitization, viral infection, occupational agents and air pollutants.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659 (updated 2004). 2004. National Institutes of Health/National Heart, Lung, and Blood Institute.

      While these factors can precipitate exacerbations and prolong symptoms, their role in the development of severe asthma is not known. Aspirin and related drugs are more likely to act as specific triggers for asthma symptoms in susceptible individuals rather than being responsible for the development of asthma. However, the symptoms provoked by aspirin are often severe and patients with aspirin-sensitive asthma account for a substantial proportion of life-threatening exacerbations.
      • Marquette C.H.
      • Saulnier F.
      • Leroy O.
      • et al.
      Long-term prognosis of near-fatal asthma. A 6-year follow-up study of 145 asthmatic patients who underwent mechanical ventilation for a near-fatal attack of asthma.
      Obesity has also been shown to be associated with asthma,
      • Weiss S.T.
      • Shore S.
      Obesity and asthma: directions for research.
      but it seems that asthma may predispose to later weight gain rather than vice versa, and a common other factor such as depression during critical periods of early life may be involved.

      Hasler G, Gergen PJ, Ajdacic V, et al. Asthma and body weight change: a 20-year prospective community study of young adults. Int J Obes (London) 21 February 2006 [Epub ahead of print].

      A link with severe disease has not been clearly established.
      Increased stress is not only known to trigger worsening symptoms and exacerbations
      • Fagan J.
      • Galea S.
      • Ahern J.
      • et al.
      Relationship of self-reported asthma severity and urgent health care utilization to psychological sequelae of the September 11, 2001 terrorist attacks on the World Trade Center among New York City area residents.
      but may also be associated with the development of asthma and atopy, possibly as early as in utero.
      • Wright R.J.
      Stress and atopic disorders.
      Possible pathways by which stress may exert an effect include neuroimmunoregulation and oxidative stress pathways.
      • Wright R.J.
      Stress and atopic disorders.
      Although asthma is not itself a psychosomatic condition, people with severe asthma are prone to anxiety and depression that can result in non-adherence to medication regimens and thus loss of asthma control.
      • Barton C.
      • Clarke D.
      • Sulaiman N.
      • Abramson M.
      Coping as a mediator of psychosocial impediments to optimal management and control of asthma.

      Prevalence and control of asthma

      It is important to distinguish between the severity of asthma and the degree of control.
      • Vollmer W.M.
      Assessment of asthma control and severity.
      Severity can be used to describe the underlying nature or intensity of asthma in the absence of treatment. In patients receiving treatment, asthma severity can be estimated from the minimum level of treatment required to achieve good control and the intensity of exacerbations while on appropriate controller therapy. Asthma severity and control are distinct terms and it is important to note that patients with severe asthma can have good control, while patients with mild asthma can have poor control. The level of asthma control is particularly important to patients as it impacts directly on quality of life, while physicians need to determine the degree of control in order to decide whether treatment adjustments are required.
      The recent European Community Respiratory Health Survey (ECRHS) estimated that 4.5% of people aged 20–44 years had asthma.
      • Janson C.
      • Anto J.
      • Burney P.
      • et al.
      The European Community Respiratory Health Survey: what are the main results so far? European Community Respiratory Health Survey II.
      The overall prevalence of asthma in adults and children varies between countries, with estimates of 7% in France and Germany, 11% in the USA and 15–18% in the United Kingdom.
      • Masoli M.
      • Fabian D.
      • Holt S.
      • Beasley R.
      The global burden of asthma: executive summary of the GINA Dissemination Committee report.
      A survey of 2803 European patients showed that asthma is frequently poorly controlled and that levels of control do not meet the goals of the GINA guidelines.
      • Rabe K.F.
      • Vermeire P.A.
      • Soriano J.B.
      • Maier W.C.
      Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study.
      Forty-six percent of patients reported daytime symptoms and 30% had asthma-related sleep disturbances at least once a week. In the past year, 25% of patients with asthma had an unscheduled urgent care visit, 10% had an emergency room visit and 7% had an overnight hospitalization. Similarly, a survey of 7786 adults and 3153 children with asthma in Europe, North America and Asia showed that many patients failed to meet one or more of the GINA goals.
      • Rabe K.F.
      • Adachi M.
      • Lai C.K.
      • et al.
      Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.
      The GINA goal of minimal chronic symptoms was not met in a large percentage of patients, with 45–84% of patients having daytime symptoms and 33–70% having night-time awakenings during the previous 4 weeks. In addition, many patients did not meet the goal of minimal exacerbations and no emergency visits, with 9–31% having hospital admission due to asthma. The other GINA goals of minimal need for short-acting inhaled β2-agonists and normal or near-normal lung function were also not met by a large proportion of patients. Similar findings were reported from a telephone survey of European asthma patients, which showed that only 35% had good asthma control (failed to meet ⩽1 GINA goal), 40% had moderate control (failed to meet 2–3 GINA goals) and 25% had poor control (failed to meet 4–5 GINA goals).
      • Soriano J.B.
      • Rabe K.F.
      • Vermeire P.A.
      Predictors of poor asthma control in European adults.
      In many cases, the inadequate control of asthma reported in these surveys was associated with inadequate use of anti-inflammatory controller medication and differences between patient perceptions of control and actual symptoms.
      • Rabe K.F.
      • Vermeire P.A.
      • Soriano J.B.
      • Maier W.C.
      Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study.
      • Rabe K.F.
      • Adachi M.
      • Lai C.K.
      • et al.
      Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.
      However, studies have also shown that many patients have inadequate asthma control despite GINA step 4 therapy. For example, the Gaining Optimal Asthma Control (GOAL) study investigated whether treatment with fluticasone propionate or salmeterol/fluticasone combination therapy could achieve guideline-based asthma control in patients with uncontrolled asthma.
      • Bateman E.D.
      • Boushey H.A.
      • Bousquet J.
      • et al.
      Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study.
      The GOAL study looked at three categories of patients according to their corticosteroid usage: stratum 1, corticosteroid naive; stratum 2, ⩽500μg/day BDP or equivalent; and stratum 3,>500–1000μg/day BDP. Patients were treated in two phases. During phase I, treatment was stepped up every 12 weeks until total control of asthma was achieved. Patients entered phase II if they achieved total control or if they had not achieved total control after 12 weeks at the maximum dose. In phase II, treatment was continued at the dose at which control was achieved (or at the maximum dose). At the end of phase II, 22% of salmeterol/fluticasone-treated patients in stratum 1, 25% in stratum 2 and 38% in stratum 3 did not achieve well controlled asthma, with higher percentages in the fluticasone arm. These results show that, although treatment goals can be met in many patients by guideline-based use of ICS and inhaled LABAs, many patients still fail to achieve adequate control of their asthma. Importantly, in patients with the most severe asthma, adding an oral corticosteroid at the end of the study, combined with the highest recommended dose of fluticasone and salmeterol, resulted in only another 7% of patients achieving well-controlled asthma.
      The prevalence of severe asthma as a percentage of all asthma varies from country to country, with estimates of 18% in Western Europe, 19% in the USA and 32% in Central Europe.
      • Rabe K.F.
      • Vermeire P.A.
      • Soriano J.B.
      • Maier W.C.
      Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study.
      • Rabe K.F.
      • Adachi M.
      • Lai C.K.
      • et al.
      Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.
      An estimated 20% of these patients with severe asthma have uncontrolled disease.
      • Rabe K.F.
      • Adachi M.
      • Lai C.K.
      • et al.
      Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.
      It has also been estimated that approximately 50% of patients with severe asthma have a positive skin-prick test for common aeroallergens,
      ENFUMOSA
      The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.
      which would suggest that approximately 2% of all asthma patients have uncontrolled severe persistent allergic asthma. New treatments targeting this relatively small group of asthma patients might be expected to have a disproportionately large effect on the overall disease burden.

      Personal, social and economic burdens of asthma

      Patients with inadequately controlled severe persistent asthma despite GINA step 4 therapy are a particularly challenging patient population with significant unmet medical needs. These patients are at high risk of severe exacerbations and death
      • Tough S.C.
      • Hessel P.A.
      • Ruff M.
      • et al.
      Features that distinguish those who die from asthma from community controls with asthma.
      • Turner M.O.
      • Noertjojo K.
      • Vedal S.
      • et al.
      Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma.
      and have few therapeutic options available. In addition, patients with asthma often have co-morbid conditions, including psychiatric illness (depression, anxiety, panic, phobia or other psychiatric diagnoses).
      • Heaney L.G.
      • Conway E.
      • Kelly C.
      • et al.
      Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol.
      The high prevalence of psychiatric illness was also apparent in a systematic assessment of patients with difficult-to-treat asthma.
      • Robinson D.S.
      • Campbell D.A.
      • Durham S.R.
      • et al.
      Systematic assessment of difficult-to-treat asthma.
      Retrospective analyses of patients who have died of asthma suggest that psychosocial factors (including social isolation, marital problems, alcoholism, anxiety and depression) contributed to poor asthma control, although the relationship between the pathophysiology of asthma and psychosocial factors is difficult to determine.
      • Chung K.F.
      • Godard P.
      • Adelroth E.
      • et al.
      Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/Therapy-Resistant Asthma. European Respiratory Society.
      The high prevalence of psychiatric illness is likely to add to the difficulty in maintaining patient compliance, which is a frequent underlying factor in poor asthma control.
      Asthma adversely affects numerous aspects of daily life, including sleep, work, study, exercise and daily activities,
      • Juniper E.F.
      Effect of asthma on quality of life.
      and causes a similar level of disability to diabetes.
      • Masoli M.
      • Fabian D.
      • Holt S.
      • Beasley R.
      The global burden of asthma: executive summary of the GINA Dissemination Committee report.
      An English survey in 2001 found that 16% of men and 20% of women with asthma symptoms said that their sleep was disturbed at least once a week and ∼50% (46% of men, 54% of women) said that they were unable to carry out their everyday activities.
      • Primatesta P.
      • Stamatakis M.
      Respiratory symptoms, atopic conditions and lung function. Health Survey for England 2001.
      The degree of asthma-related impairment of quality of life increases with disease severity, with the most profound effects seen in patients with chronically uncontrolled severe disease.
      • Juniper E.F.
      • Wisniewski M.E.
      • Cox F.M.
      • et al.
      Relationship between quality of life and clinical status in asthma: a factor analysis.
      These patients are frequently admitted to hospital and have regular absences from work or school. In surveys conducted during 1999–2001, 7% of Western Europeans with asthma were admitted to hospital due to asthma during the previous 12 months and 10% required an emergency room visit.
      • Rabe K.F.
      • Adachi M.
      • Lai C.K.
      • et al.
      Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys.
      Between 80% and 85% of asthma deaths occur in patients with poorly controlled severe disease,
      • Papiris S.
      • Kotanidou A.
      • Malagari K.
      • Roussos C.
      Clinical review: severe asthma.
      and there is a strong association between increased recurrences of hospitalization and asthma severity.
      • Hartert T.V.
      • Speroff T.
      • Togias A.
      • et al.
      Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma.
      The European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) investigated the characteristics of patients with poorly controlled severe asthma.
      ENFUMOSA
      The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.
      The 163 patients with severe asthma enrolled in the ENFUMOSA study had all had at least one exacerbation despite treatment with ⩾1200μg/day of BDP or equivalent and almost 40% had been hospitalized in the previous year. As well as ICS, 96% of patients were treated with inhaled LABAs, 46% required oral theophylline and a small proportion (<20%) were treated with anticholinergics, chromones or frequent nebulized short-acting β2-agonists. In addition, 33% of the group also required oral corticosteroids (median prednisone dose 19mg). Patients with uncontrolled severe asthma were more likely to be female and had a higher body mass index than patients with mild-to-moderate asthma (Table 1). In addition, aspirin sensitivity was more common in the severe group, reflected in higher urinary levels of the leukotriene LTE4.
      Table 1Differences in clinical phenotype of patients with severe asthma and controlled asthma.
      ENFUMOSA
      The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.
      Controlled asthma (n=158)Severe asthma (n=163)P value
      Sex ratio, female:male1.6:14.4:1<0.001
      Weight (kg) (females)66.570.9<0.05
      BMI, females25.627.2<0.05
      Systolic BP (mmHg)
       Males127.0131.4<0.01
       Females123.1130.2<0.01
      Diastolic BP (mmHg)
       Males79.683.1<0.001
       Females76.882.0<0.001
      Heart rate (beats/min)
       Males67.782.3<0.001
       Females73.982.7<0.001
      Dose of ICS (μg/day)6661676<0.001
      Mean total serum IgE (IU/ml)109148<0.05
      ⩾1 positive allergen skin-prick test (%)5978<0.05
      FEV1 (% predicted)88.571.8<0.001
      FEV1 post-salbutamol (% predicted)97.680.9<0.001
      FVC (% predicted)103.194.1<0.001
      FEV1/FVC89.779.9<0.001
      RV/TLC104.2113.4<0.01
      KCO95.090.6<0.05
      PaO2 (kPa)12.011.2<0.001
      PaCO2 (kPa)5.14.9<0.01
      Pulmonary function and blood gases were measured in 130 subjects with controlled asthma and 133–153 subjects with severe asthma. BMI, body mass index; BP, blood pressure; ICS, inhaled corticosteroid; FEV1, forced expiratory volume in 1s; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; KCO, carbon monoxide transfer coefficient; PaO2, arterial oxygen tension; PaCO2, arterial carbon dioxide tension.
      The ongoing US multicentre TENOR study is currently investigating a cohort of patients with severe or difficult-to-treat asthma.
      • Dolan C.M.
      • Fraher K.E.
      • Bleecker E.R.
      • et al.
      Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.
      The ongoing study recruited 4756 patients aged ⩾6 years with difficult-to-treat asthma, defined as having high healthcare utilization in the past year (⩾2 unscheduled visits or ⩾2 oral steroid bursts), or high medication use (⩾3 medications or long-term daily high-dose ICS or ⩾5mg/day prednisone). Consistent with ENFUMOSA, the majority of adult patients with severe or difficult-to-control asthma were female (71%), although the children and adolescents were more likely to be male (67% and 57%, respectively). Immunoglobulin E (IgE) levels were elevated in all age groups and increased with severity of asthma in children and adolescents but not adults. Patients with IgE levels ⩾100IU/ml had a lower FEV1 than those with IgE<100IU/ml, the difference in lung function being greatest in children.
      • Borish L.C.
      • Miller M.K.
      • Zheng B.
      • et al.
      Serum IgE and lung function in the TENOR asthma cohort.
      In general, lower FEV1 values were associated with greater healthcare utilization (Fig. 2).
      • Hayden M.L.
      • Johnson C.A.
      • Dolan C.M.
      • et al.
      High level healthcare utilization in severe and difficult-to-treat asthma.
      Figure thumbnail gr2
      Figure 2Healthcare utilization and missed days from work/school according to asthma severity in a cohort of 4756 patients with severe or difficult-to-treat asthma. *P<0.05 for difference in lung function (FEV1).
      • Hayden M.L.
      • Johnson C.A.
      • Dolan C.M.
      • et al.
      High level healthcare utilization in severe and difficult-to-treat asthma.
      In addition to the impact on affected patients, asthma places a large economic burden on healthcare systems and society. In Europe, the total cost of asthma has been approximated at €17.7 billion per annum, of which an estimated €9.8 billion is accounted for by the indirect costs of lost productivity due to absence from work.

      European Federation of Allergy and Airways Diseases Patients’ Association. Fighting for breath: a European patient perspective on severe asthma. 2005.

      Severe asthma accounts for a large proportion of the overall costs,
      • Wenzel S.
      Severe asthma in adults.
      with uncontrolled disease responsible for much of the economic burden.
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      • et al.
      Asthma severity and medical resource utilisation.
      • Hoskins G.
      • McCowan C.
      • Neville R.G.
      • et al.
      Risk factors and costs associated with an asthma attack.
      In a Spanish study, patients with severe asthma accounted for 51% of total costs for the whole group.
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      • et al.
      Costs of asthma according to the degree of severity.
      Similar findings have been reported in France
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      • et al.
      Costs of asthma are correlated with severity: a 1-yr prospective study.
      and Italy
      • Antonicelli L.
      • Bucca C.
      • Neri M.
      • et al.
      Asthma severity and medical resource utilisation.
      (Fig. 3). Patients with poorly controlled asthma utilize significantly greater amounts of healthcare resources than ‘controlled’ patients.

      Hoskins G, McCowan C, Everhard, et al. Identifying the characteristics and cost of treating ‘poorly controlled’ asthma patients. C42. 2001. American Thoracic Society.

      McCowan C, Hoskins, G, Thomas, GE, et al. The effect of asthma severity and frequency of attack on health service costs. A27. 2002. American Thoracic Society.

      For example, a study of 13,241 UK asthma patients with varying degrees of severity showed that patients with ‘poorly controlled’ asthma had recurrent asthma exacerbations requiring emergency treatment and were around 3–4 times more costly to manage than well-controlled patients.

      Hoskins G, McCowan C, Everhard, et al. Identifying the characteristics and cost of treating ‘poorly controlled’ asthma patients. C42. 2001. American Thoracic Society.

      Figure thumbnail gr3
      Figure 3Direct and indirect costs increase with asthma severity.
      • Antonicelli L.
      • Bucca C.
      • Neri M.
      • et al.
      Asthma severity and medical resource utilisation.

      Management approaches for patients with poorly controlled severe asthma

      Physicians face substantial challenges when treating patients with uncontrolled or severe asthma. The complexity of a multiple daily medication regimen is often a factor in patient non-adherence, which in turn affects asthma control. Patients with severe asthma may require particularly intensive patient education and referral to appropriate sources of support to assist in treatment compliance.
      Patients with severe persistent asthma frequently require regular use of multiple controller medications, including high-dose ICS (>1000μg/day of BDP or equivalent) plus a LABA twice daily. If needed, one or more of the following are often added: sustained-release theophylline, anti-leukotriene, oral LABA, oral corticosteroids or anti-IgE therapy (GINA step 4 therapy).

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659. 2002. National Institutes of Health/National Heart, Lung, and Blood Institute.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659 (updated 2004). 2004. National Institutes of Health/National Heart, Lung, and Blood Institute.

      There is currently little evidence on which to base management decisions in patients with uncontrolled asthma despite GINA step 3 or step 4 treatment. It is now recognized that addition of a LABA is associated with better outcomes than increasing corticosteroid doses.
      • Bateman E.D.
      • Boushey H.A.
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      • et al.
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      • Greening A.P.
      • Ind P.W.
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      Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group.
      • Woolcock A.
      • Lundback B.
      • Ringdal N.
      • Jacques L.A.
      Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids.
      However, there is a lack of comparative data to determine the relative merits of other agents when added to high-dose corticosteroid therapy. Anti-leukotrienes have been shown to provide clinical benefit in patients with chronic persistent asthma who were symptomatic despite ICS
      • Robinson D.S.
      • Campbell D.
      • Barnes P.J.
      Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial.
      and improve asthma control in patients receiving high-dose ICS,
      • Virchow Jr, J.C.
      • Prasse A.
      • Naya I.
      • et al.
      Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids.
      perhaps reflecting the relatively high level of aspirin sensitivity among patients with severe asthma. In practice, as seen in the ENFUMOSA study, oral corticosteroids are used by approximately one-third of patients with severe asthma.
      ENFUMOSA
      The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.
      However, regular use of oral corticosteroids is associated with significant side effects.
      American Thoracic Society
      Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions.
      • Vollmer W.M.
      Assessment of asthma control and severity.
      The anti-leukotrienes are a relatively new class of anti-asthma drugs that either block leukotriene synthesis by inhibiting 5-lipoxygenase (an example being zileuton), or are antagonists of the cysteinyl leukotriene 1 receptor (CysLT1), such as montelukast, zafirlukast and pranlukast. Hence, the major effect of the anti-leukotrienes is a selective anti-inflammatory one. Zafirlukast has been shown to improve asthma control in patients receiving high-dose ICSs,
      • Virchow Jr, J.C.
      • Prasse A.
      • Naya I.
      • et al.
      Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids.
      and the benefit of anti-leukotrienes may be particularly apparent in the large percentage (20–25%) of patients with severe asthma who may be aspirin sensitive.
      ENFUMOSA
      The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma.
      • Gibbs R.
      • Miranda C.
      • Wenzel S.
      Initial demographic information from an extensive data base of severe, steroid dependent asthmatics studied at National Jewish [abstract].
      Theophylline is a bronchodilator that may have extrapulmonary effects, including an anti-inflammatory action.
      • Barnes P.J.
      • Pauwels R.A.
      Theophylline in the management of asthma: time for reappraisal?.
      When given as a sustained-release preparation, it has a long duration of action and is useful in the control of nocturnal symptoms that persist despite regular treatment with anti-inflammatory therapy.
      • Weinberger M.
      • Hendeles L.
      Theophylline in asthma.
      Theophylline is also a possible additional bronchodilator for use in patients with severe asthma, although as add-on therapy, it is less effective than LABAs.
      • Davies B.
      • Brooks G.
      • Devoy M.
      The efficacy and safety of salmeterol compared to theophylline: meta-analysis of nine controlled studies.
      • Wilson A.J.
      • Gibson P.G.
      • Coughlan J.
      Long acting beta-agonists versus theophylline for maintenance treatment of asthma.
      It is, however, a less expensive option. In practice, the routine use of theophylline in patients hospitalized for asthma is no longer advocated in some countries due to the potential for serious adverse effects and the lack of benefit.
      • Self T.H.
      • Redmond A.M.
      • Nguyen W.T.
      Reassessment of theophylline use for severe asthma exacerbation: is it justified in critically ill hospitalized patients?.
      Further clinical research is needed to verify the value of theophylline in adults and children with severe asthma exacerbations and impending respiratory failure.
      Omalizumab, a recently developed anti-IgE monoclonal antibody for the treatment of asthma has proven to be effective and well tolerated as add-on therapy in patients with severe persistent asthma. In a pooled analysis of 2511 omalizumab-treated patients and 1797 control patients in seven clinical trials, 93% of patients met the criteria for severe persistent asthma set out in the GINA 2002 guidelines.
      • Bousquet J.
      • Cabrera P.
      • Berkman N.
      • et al.
      The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma.
      Analysis of pooled data showed that addition of omalizumab to current asthma therapy significantly reduced the rate of asthma exacerbations by 38% (0.910 vs. 1.474, P<0.0001 vs. control) and total emergency visits by 47% (P<0.0001 vs. control; Table 2). Analysis of demographic subgroups showed that the efficacy of omalizumab on asthma exacerbations was unaffected by patient age, gender, baseline serum IgE (split by median) or by 2- or 4-weekly dosing schedule, although the greatest absolute benefit was observed in patients with poor baseline FEV1 values.
      • Bousquet J.
      • Cabrera P.
      • Berkman N.
      • et al.
      The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma.
      Add-on omalizumab treatment in patients with co-morbid asthma and rhinitis has also been shown to lead to significantly fewer asthma exacerbations and significant improvements in both asthma and rhinitis-related quality of life, compared with placebo.
      • Vignola A.M.
      • Humbert M.
      • Bousquet J.
      • et al.
      Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR.
      The anti-inflammatory effect of omalizumab produces a profound reduction in airway eosinophilia (observed in patients with mild-to-moderate asthma). Omalizumab also significantly reduces the number of T-lymphocytes (CD3+, CD4+, CD8+), B-cells, mast cells expressing the high-affinity IgE receptor, and cells showing surface IL-4.
      • Djukanovic R.
      • Wilson S.J.
      • Kraft M.
      • et al.
      Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma.
      Table 2Hospitalizations and other unscheduled visits in patients receiving omalizumab.
      • Bousquet J.
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      • Berkman N.
      • et al.
      The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma.
      Type of visitRate per yearRatio (95% CI)P value
      OmalizumabControlTreatment difference
      Total emergency visits0.3320.6230.2910.533 (0.401, 0.709)<0.0001
      Hospital admission0.0300.0620.0320.489 (0.246, 0.972)0.041
      Emergency room visits0.0260.0660.0400.397 (0.192, 0.820)0.013
      Unscheduled doctor visits0.2520.4430.1910.568 (0.417, 0.774)0.0003
      Omalizumab has been shown to be particularly effective in patients with severe asthma. Regression analysis of data from more than 1000 patients shows that baseline characteristics reflecting more severe asthma (high doses of ICS, history of frequent emergency asthma treatment, poor lung function) were predictive of the greatest response to omalizumab treatment (Fig. 4).
      • Bousquet J.
      • Wenzel S.
      • Holgate S.
      • et al.
      Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma.
      In addition, subgroup analyses have shown that omalizumab was particularly effective in reducing exacerbations in patients at high risk of death, as indicated by prior intubation or recent hospitalization/emergency treatment.
      • Holgate S.
      • Bousquet J.
      • Wenzel S.
      • et al.
      Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality.
      Figure thumbnail gr4
      Figure 4Venn diagram of odds ratios for response with omalizumab relative to placebo, according to three baseline high-severity covariates. Response was defined as at least one of the following: reduced symptoms with no increase in rescue use of β2-agonist, reduced rescue use of β2-agonist with no increase in symptoms, improved lung function, improved quality of life; plus no exacerbations during 16 weeks of treatment). The likelihood of response increases with the presence of more than one high-severity covariate.
      • Bousquet J.
      • Wenzel S.
      • Holgate S.
      • et al.
      Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma.
      The recently updated GINA guidelines recommend anti-IgE therapy (of which omalizumab is the only currently available option) for patients with severe allergic asthma.

      Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH publication no. 02-3659 (updated 2004). 2004. National Institutes of Health/National Heart, Lung, and Blood Institute.

      Anti-IgE therapy is listed as an option in GINA step 4 therapy if additional control is needed beyond that achieved on high-dose ICS and LABAs. A recent 28-week study of omalizumab as add-on therapy (INNOVATE) exclusively enrolled patients with inadequately controlled severe persistent asthma despite GINA step 4 therapy.
      • Humbert M.
      • Beasley R.
      • Ayres J.
      • et al.
      Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE.
      All patients were receiving ICS plus LABAs and two thirds were receiving additional controller medication (including oral corticosteroids in 22% of patients). Statistically significant reductions were observed in the rate of clinically significant asthma exacerbations after adjustment for baseline exacerbation history (0.68 vs. 0.91, P=0.042; Fig. 5a), severe exacerbation rate (0.24 vs. 0.48, P=0.002; Fig. 5b), and emergency visit rates (0.24 vs. 0.43, P=0.038). Omalizumab also provided significant improvements over placebo in morning PEF, FEV1, asthma symptom scores and quality of life scores (Juniper AQLQ) and patients’ and investigators’ global evaluations of treatment effectiveness (both P<0.001).
      Figure thumbnail gr5
      Figure 5(a) Effect of omalizumab treatment on the rate of clinically significant asthma exacerbations (adjusted for baseline exacerbation history) during the 28-week treatment period (PITT population); mean (95% confidence interval).
      • Humbert M.
      • Beasley R.
      • Ayres J.
      • et al.
      Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE.
      (b) Effect of omalizumab treatment on severe exacerbations (PEF or FEV1<60% of personal best) during the 28-week treatment period (PITT population).
      In addition to the clinical benefits that omalizumab provides in patients with severe persistent asthma, it is also relevant that the anti-IgE monoclonal antibody is administered by subcutaneous injection every 4 weeks (or every 2 weeks for patients requiring higher doses).
      • Hochhaus G.
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      • Fox H.
      • et al.
      Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma.
      The relative simplicity of treatment may aid adherence for patients already on a complicated regimen of multiple inhaled and oral medications. The potential to improve adherence could be particularly important in poorly controlled and difficult-to-treat asthma given the strong association between compliance and treatment outcomes.
      • Barnes P.J.
      • Woolcock A.J.
      Difficult asthma.
      Potential future therapies for severe asthma include anti-IL-5 monoclonal antibodies and agents that block interleukin synthesis or its effects. The anti-IL-5 monoclonal antibody SCH55700 was evaluated in a small study of different single doses in patients with severe persistent asthma and was shown to be biologically active (decrease in circulating eosinophils), with signs of an improvement in FEV1.
      • Kips J.C.
      • O’Connor B.J.
      • Langley S.J.
      • et al.
      Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study.
      Another anti-IL-5 antibody (SB240563, mepolizumab) was shown to deplete circulating eosinophils and partially reduce airway eosinophils without having an observable clinical effect.
      • Flood-Page P.T.
      • Menzies-Gow A.N.
      • Kay A.B.
      • Robinson D.S.
      Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.
      Although mepolizumab had a marked effect on blood eosinophils (median 100% decrease, interquartile range 67–100%), the decrease in lung eosinophils was considerably smaller (median 55%, interquartile range 29–89%),
      • Flood-Page P.T.
      • Menzies-Gow A.N.
      • Kay A.B.
      • Robinson D.S.
      Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.
      which might explain the lack of clinical effect. In addition, mepolizumab had no effect on T-cell subsets or cytokine production.
      • Buttner C.
      • Lun A.
      • Splettstoesser T.
      • et al.
      Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions.
      It remains to be seen whether mepolizumab can achieve the degree of reduction in airway eosinophils required to produce a clinical response or even whether eosinophil depletion is capable of achieving clinical benefits.
      In a study of 85 patients with moderate-to-severe asthma receiving high-dose ICS (⩾1500μg/day BDP), suplatast (an orally administered agent that blocks the synthesis of cytokines, including IL-4 and IL-5, from Th2 cells) proved superior to placebo for symptoms and lung function when ICS doses were halved, although the level of exacerbations was not recorded.
      • Tamaoki J.
      • Kondo M.
      • Sakai N.
      • et al.
      Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Tokyo Joshi-Idai Asthma Research Group.
      Further investigation in a clearly defined group of patients with severe asthma is required to evaluate its usefulness in this population.
      Other experimental drugs, including methotrexate,
      • Davies H.
      • Olson L.
      • Gibson P.
      Methotrexate as a steroid sparing agent for asthma in adults.
      cyclosporine,
      • Nizankowska E.
      • Soja J.
      • Pinis G.
      • et al.
      Treatment of steroid-dependent bronchial asthma with cyclosporin.
      gold salts,
      • Evans D.J.
      • Cullinan P.
      • Geddes D.M.
      Gold as an oral corticosteroid sparing agent in stable asthma.
      troleandomycin,
      • Evans D.J.
      • Cullinan P.
      • Geddes D.M.
      Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma.
      azathioprine
      • Dean T.
      • Dewey A.
      • Bara A.
      • et al.
      Azathioprine as an oral corticosteroid sparing agent for asthma.
      and chloroquine
      • Dean T.
      • Dewey A.
      • Bara A.
      • et al.
      Chloroquine as a steroid sparing agent for asthma.
      have failed to demonstrate an acceptable risk/benefit ratio.

      Discussion

      Despite improved understanding and adherence to recommended management strategies, many patients who have inadequately controlled asthma, particularly those with severe disease, are at high risk of exacerbations and asthma-related death. Patients who are not well controlled on high-dose ICS in combination with other available controller medications, or who require additional systemic corticosteroid treatment, have an identifiable need for a new therapy that can improve clinical outcomes, in particular life-threatening exacerbations, without adding to the complexity or burden of adverse effects of medication.
      The addition of omalizumab therapy is a promising new therapeutic option for patients with severe persistent asthma that is inadequately controlled despite best available therapy. Comparative trials are needed to determine the relative merits of different treatments and strategies as add-on therapy for patients with inadequately controlled asthma despite GINA step 4 therapy (i.e. high-dose ICS plus LABAs) and additional studies are needed to identify patients who may benefit from these new treatment options.

      Acknowledgements

      We thank medical writers Dr. Dominic Hague and Dr. Paul Hutchin for their assistance in drafting this article and Helen Venables for editorial support.

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