(Chest. 2006;130:29S-40S.)
© 2006
American College of Chest Physicians
The Right Tools at the Right Time
Marc Humbert, MD, PhD
* From Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, Clamart, France.
Correspondence to: Marc Humbert, MD, PhD, Service de Pneumologie, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France; email: marc.humbert{at}abc.aphp.frr
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Abstract
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Asthma is underdiagnosed and undertreated or inappropriately treated, even though approximately 300 million people worldwide currently have the disease. While asthma in most patients can be controlled using currently available medications, in practice this rarely happens. Despite the wide availability of treatment guidelines, there are clear discrepancies between recommendations and the reality of treatment. There is excessive use of relief medications, particularly among patients with moderate-to-severe persistent asthma, coupled with a marked underuse of inhaled corticosteroids (ICS). This underuse by patients is likely to be related to anxiety about side effects and a misunderstanding about asthma. Many patients overestimate their degree of control and have a perceived lack of need for medication. Early therapeutic intervention, with optimal antiinflammatory therapy and a stepwise approach, has a positive impact on long-term outcomes, achieving suppression of airway inflammation, prompt symptom control, and restoration of pulmonary function. Even at low doses, ICS rapidly improve clinical symptoms and measures of lung function, while their long-term use markedly reduces the frequency and severity of exacerbations and asthma mortality. Although ICS monotherapy achieves successful control of persistent asthma in a significant proportion of patients, add-on therapy with a long-acting ß2-agonist provides control for most patients with moderate-to-severe persistent asthma. Fixed combination inhalers (ICS plus a long-acting ß2-agonist) have become popular, but these have drawbacks and there is the potential for overuse. In conclusion, ICS are the cornerstone of therapy for persistent asthma of all degrees of severity in adults and children, and early therapeutic intervention is recommended for optimal long-term outcome.
Key Words: add-on therapy • asthma • early intervention • inhaled corticosteroids • management guidelines
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Introduction
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Asthma is a chronic inflammatory respiratory disorder that currently affects > 300 million people worldwide.1 Because airway inflammation is such a critical etiologic feature of asthma, it has become the target of therapy. The inflammatory pattern in asthma is multicellular in nature with mast cells, neutrophils, eosinophils, T-lymphocytes, epithelial cells, and their mediators participating in the response.
The prevalence of asthma is rising globally, particularly among children, with subsequent increases in morbidity, mortality, and health-care expenditure.1 The high and rising global burden of disease represents a significant public health concern. There are multiple barriers to reducing the global burden of asthma, and these are discussed in detail elsewhere in this Supplement (see the article by Braman). In the developing world, poverty and a lack of education, health-care resources, and infrastructure represent significant barriers to asthma management.1 However, even in the developed world, and despite therapeutic advances, underdiagnosis and inappropriate treatment remain key contributors to asthma morbidity and mortality.2
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Underdiagnosis of Asthma
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While asthma can be diagnosed on the basis of symptoms, an effective diagnosis should also include measurements of lung function (particularly the reversibility of lung function abnormalities), the most helpful being FEV1, FVC, peak expiratory flow (PEF), and airway hyperresponsiveness.3 Asthma is underdiagnosed or misdiagnosed in adults,4 particularly the elderly,5 and in children.67 This is a serious concern, as early detection and treatment can improve the long-term prognosis of patients and possibly prevent irreversible loss of lung function.89 While it is beyond the scope of this article to describe the various objective measures required to support a diagnosis of asthma, the reader is directed to the Global Initiative for Asthma (GINA) workshop report3 that reviews this topic more extensively. The subject of underdiagnosis of asthma is also discussed in the article by Graham in this Supplement.
It is not entirely clear why asthma is being underdiagnosed, although a major factor is the unwillingness by patients with respiratory symptoms to present to their primary care physician.4 This unwillingness is believed to be related to a reluctance to take asthma medication, associated with a distorted perception regarding drug therapy, and highlights the need for patient education.10 Some patients have symptoms for many months or years before a correct diagnosis is made.11
Underdiagnosis of patients with respiratory symptoms who do present to their physician is less frequent but is more likely to occur in children < 5 years old who may be labeled as having other illnesses, such as recurrent croup, wheezy bronchitis, or recurrent upper respiratory tract infection. There are also inherent difficulties in obtaining measurements of lung function in children.2 A diagnosis of asthma in the elderly is also complicated by the presence of other illnesses with symptoms overlapping those of asthma, such as COPD and heart failure.5 A study12 conducted in Sweden indicated that, while physicians were highly accurate in identifying patients who did not have asthma, they were less able to identify patients who did have the disease.
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Asthma Management Guidelines
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Although there is no cure for asthma, symptoms can be controlled in most patients using currently available medications; however, in practice this rarely happens. Asthma guidelines are now available in most countries and can lead to significant benefits in improving the management of disease.13 The most recent set of guidelines is that of GINA.3 GINA was implemented to develop a network of individuals, organizations, and public health officials to disseminate information about the care of patients with asthma, while at the same time ensuring a mechanism to incorporate the results of scientific investigations into asthma care. In 2002, the GINA committee published a workshop report that aimed to provide a comprehensive summary of the scientific findings on which asthma management decisions are made. Specifically, the asthma management goals of GINA are as follows: - Achieve and maintain control of symptoms (including nocturnal symptoms)
- Minimize the use of rescue medication (ß2-agonists)
- Prevent exacerbations
- Maintain pulmonary function as close to normal levels as possible
- Achieve a circadian variation in PEF of < 20%
- Maintain normal activity levels (including exercise)
- Avoid adverse effects due to medication
- Prevent development of irreversible airflow limitation
- Prevent asthma mortality
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The Gap Between Clinical Guidelines and Reality
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Despite the wide availability of management guidelines, there are clear discrepancies between guideline recommendations and the reality of treatment. It has been suggested that primary care physicians, with their heavy workloads, find guidelines too lengthy and complex. As such, they may not be conducive to rapid understanding or effective implementation into treatment schedules.13
To some extent, the guidelines themselves have inherent limitations. For example, the randomized controlled studies on which guidelines are based have strict patient inclusion and exclusion criteria. Therefore, data obtained during these studies do not necessarily reflect a real-world situation. Clinical trials frequently exclude particular patient populations, such as the elderly, smokers, pregnant women, or those with concomitant disease. In addition, patients taking part in asthma studies are frequently required to show a predefined bronchodilator response, have stable asthma, and be compliant with treatment.13
The recent Asthma Insights and Reality in Europe (AIRE)14 and Asthma in America (AIA)15 surveys described the current knowledge, attitudes, and behavior of professionals and patients toward asthma. The AIRE survey14 comprised 2803 asthmatics from Spain, the United Kingdom, France, Germany, the Netherlands, Sweden, and Italy, while the AIA survey15 involved 2,059 patients in the United States.
The results of these two surveys indicated that the current long-term management of asthma falls far short of the goals established by GINA (Fig 1
).141516 There are a number of possible reasons for this, including the following: (1) a lack of patient awareness about asthma and its treatment, leading to noncompliance and delays in initiating therapy; (2) overuse of acute relief medications; (3) underuse of controllers; and (4) a lack of ongoing monitoring of lung function by physicians.
Patients Show Poor Levels of Control
Many patients who took part in the AIRE and AIA surveys underestimated their disease severity and overestimated their degree of control. In the AIRE survey,14 when asked to describe their asthma over the past 4 weeks, 6% of patients described their symptoms as severe, 22% as moderate, 40% as mild, and 32% had no symptoms. However, over this period 56% reported that they had a cough, wheezing, shortness of breath, or chest tightness, and 36% were woken at night by these symptoms. In all, 48% of patients had asthma symptoms brought on by exercise or exertion over the past 12 months.1416 Using the international guidelines for the combined symptom severity index, based on symptom frequency over the last 4 weeks, 18% of all asthma patients in the AIRE survey would be classified as having severe persistent asthma, 19% would have moderate persistent asthma, 19% would have mild persistent asthma, and 44% would have mild intermittent asthma.16
Similarly, in the AIA survey,15 only 7% of patients self-classified their symptoms as severe, 23% as moderate, 45% as mild, and 25% as none over the previous 4 weeks. However, based on reports of symptoms frequency, the guideline severity classification would be severe persistent asthma in 19%, moderate persistent in 19%, mild persistent in 22%, and mild intermittent in 40% of patients.15
These levels of poorly controlled asthma had a significant impact on patients’ lives and health-care use (Fig 1),16 resulting in hospitalizations, emergency department and urgent care visits, sick days, and limitations in patient activity. Many patients taking part in the surveys appeared to have settled for a quality of life and frequency of asthma symptoms that were far short of current guideline expectations.
A large proportion of the morbidity identified in these surveys could be avoided with the regular use of inhaled corticosteroids (ICS) by patients with persistent asthma.16 The surveys indicated that patients were relying on short-acting ß2-agonist rescue medication, and that ICS were underused (Fig 1).16 Approximately 15% and 23% of patients in the United States and Western Europe, respectively, received ICS. In comparison, > 60% of patients in both regions were receiving short-acting ß-agonists. For patients with severe asthma, only 20% in the United States and 26% in Western Europe received ICS therapy (Fig 2
).1516 In fact, the proportion of patients receiving ICS was not strongly related to disease severity (Fig 2).1516 Underuse of ICS by patients is likely to be a result of two main factors: anxiety about the drugs themselves (eg, potential side effects or difficulties in using the inhaler device), and misunderstanding about their disease (eg, overestimating asthma control and perceiving a lack of need for medication). Fewer than 10% of patients in both surveys were able to say, unprompted, that inflammation was the underlying cause of their symptoms, and approximately 50% did not understand that ICS would act on this inflammation.1415
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The Right Time
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Early Therapeutic Intervention
Examination of bronchial biopsy specimens indicates that significant inflammation is present early in the course of asthma, even in those patients having symptoms for a short time and in those with mild disease.17 There is a progressive decline in pulmonary function that correlates with the duration of asthma and its severity.1819 In a study19 of 1,006 randomly selected asthmatic outpatients aged 12 to 95 years, the unadjusted annual decline in FEV1 was 80.1 mL/yr and the decline in FVC was 20.5 mL/yr. One of the major developments in asthma therapy during the 1990s was the recognition that slowing or arresting this progressive decline in lung function should be a key objective of asthma management. It was also suggested that this objective could be achieved by early therapeutic intervention with ICS using a stepwise approach. This approach to therapy has particularly significant implications for patients with mild asthma, who are frequently undertreated, and in whom initiation of therapy is often delayed.
Early use of ICS achieves suppression of airway inflammation, prompts symptom control, and restores pulmonary function.89171819 A prospective, controlled study8 measured pulmonary function in 216 children during long-term treatment with budesonide, and compared the findings with those from 62 children not treated with ICS. Children who started budesonide therapy > 5 years after asthma diagnosis had significantly lower FEV1 values than those starting corticosteroid therapy within 2 years of asthma onset. Additionally, children treated with budesonide had significantly fewer hospital admissions due to severe exacerbations and a lower accumulated dose of steroid in the long term. Over a 3.5-year treatment period, the mean daily dose of budesonide decreased from 710 to 430 µg (p < 0.01). The effect of early vs delayed ICS therapy has been studied in patients with asthma symptoms for < 1 year and no previous exposure to antiinflammatory therapy.20 Over a 2-year period, 50 patients received budesonide at 1,200 µg/d and 50 patients received terbutaline at 500 µg per dose, taken as needed. After this period, the 37 patients remaining in the terbutaline group were switched to budesonide, and results were compared after a further year of therapy. Patients who switched to budesonide did improve but to a lesser degree than those receiving early budesonide therapy. There was a trend for greater improvement in all lung function measures in the patients who received early budesonide treatment, with a significant difference between the two groups for morning and evening PEF (Fig 3
). This difference was significant as early as 1 week after the start of budesonide therapy. Bronchial responsiveness, as tested by histamine challenge, was also reduced to a significantly greater extent in patients who received early vs late ICS therapy (p = 0.027).
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The Right Tools: a Stepwise Approach
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The GINA guidelines,3 as well as many national guidelines, recommend a stepwise approach to asthma therapy. Guidelines are directed toward achieving suppression of airway inflammation, predominantly through the use of ICS therapy. The GINA guidelines3 use an asthma severity assessment to determine where a patient will "step" in regard to the amount and frequency of medication. This classification groups patients into one of four categories: mild intermittent, mild persistent, moderate persistent, and severe persistent (this classification and its limitations are discussed in more detail in the article by Graham). The severity classification is applied as a means of balancing the potential risks of adverse events from asthma medication with benefits in terms of reduced symptoms, control of exacerbations, and better long-term outcomes. Thus, ICS therapy is not currently recommended for patients with mild intermittent asthma, as these patients can often be managed with infrequent, short-acting ß2-agonist therapy. For persistent asthma, guidelines recommend the aggressive use of therapy to obtain prompt control, which is then stepped down cautiously once control is achieved and maintained. Thus, the aim is to achieve continuing asthma control with the minimum amount of medication.
As asthma is a dynamic process, ongoing patient monitoring and assessment is required to ensure that therapeutic goals are being met. Treatment plans should include regular patient reviews (every 1 to 6 months), which should cover feedback on home PEF and symptom records, techniques in the use of medication, risk factors and their control, and ongoing measurement of lung function. Once again, there is a gap between guideline recommendations and reality. Very few patients in the AIRE and AIA surveys1415 (< 30%) had received or were using a treatment plan.
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Inhaled Corticosteroids: the Cornerstone of Asthma Therapy
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All international guidelines categorically state that ICS are the cornerstone of therapy for persistent asthma of all degrees of severity in adults and children. No other currently available therapy is as effective at controlling the underlying inflammatory processes of asthma.
ICS monotherapy achieves successful control of persistent asthma in a significant proportion of patients. Generally, the dose-response curve of ICS is relatively flat for a number of outcome measures (Fig 4
),21 and for many patients the therapeutic benefits of high-dose ICS vs low-dose or medium-dose ICS may be marginal.2122 Individual patients with severe persistent asthma may gain some benefit from high-dose ICS therapy.21 Such therapy may also be useful in patients who have had an exacerbation, or as a means of reducing the dose of oral corticosteroids,23 as the safety profile of high-dose ICS is clearly better than that of oral corticosteroids. However, for the majority of patients, even at low doses, ICS rapidly improve clinical symptoms and measures of lung function (Fig 5
).17 The antiinflammatory action of ICS markedly decreases airway hyperresponsiveness,2425 and the long-term use of ICS reduces the frequency and severity of exacerbations.1726
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Figure 5.. Steroid dose-response relationships for asthma symptoms, FEV1, exercise, nitric oxidem, and forced expiratory flow from 25 to 75% of FVC (FEF25–75). The shape of the dose-response curve varies for different outcomes, but the use of ICS in asthma leads to rapid improvement in clinical symptoms and lung function, even at low doses. Reproduced with permission from Barnes et al.17
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The use of ICS on a regular basis also leads to reduced mortality from asthma. Suissa et al27 used the Saskatchewan Health data to review a population-based cohort of 30,569 patients who were receiving antiasthma drugs between 1975 and 1991. Subjects who had died from asthma and for whom records were complete (n = 68) were matched with 2,681 control subjects within the cohort. Rate ratios for death from asthma were calculated after adjusting for a number of variables, including age, sex, number of theophylline prescriptions, ß-agonist use, oral corticosteroid use, number of canisters of inhaled ß-agonists, and number of hospitalizations. The mean number of ICS canisters used was found to be 1.18 for patients who died, compared with 1.57 for control subjects. The authors27 calculated that the rate death from asthma decreased by 21% with each additional canister of ICS used in the previous year (Fig 6
).
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Add-On Therapies in Persistent Asthma
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Although the majority of patients can achieve good asthma control with ICS monotherapy, some patients may require add-on therapy, particularly those with moderate-to-severe persistent disease. The as-needed use of short-acting ß2-agonists is an effective and inexpensive add-on therapy for patients whose asthma is generally controlled with ICS but who may still have occasional symptoms. For patients with persistent asthma not controlled by ICS monotherapy, several classes of agent (eg, long-acting ß2-agonists, leukotriene modifiers, and theophylline) may be effective as add-on therapy.
Long-Acting ß2-Agonists
In line with international guidelines, the preferred add-on option for patients with persistent asthma not well controlled on ICS monotherapy is a long-acting ß2-agonist. Inflammation is the underlying disease process in asthma, leading to bronchial hyperresponsiveness causing reversible airway obstruction. Long-acting ß2 agonists do not exhibit any meaningful in vivo antiinflammatory activity but work downstream of the inflammatory process, causing sustained bronchodilation and airway smooth-muscle stabilization.28 Long-acting ß2-agonists can, therefore, reduce the symptoms of asthma, such as coughing, wheezing, and dyspnea, but the inflammatory process will continue, requiring the maintenance of ICS therapy.
Although there is evidence that long-acting ß2-agonists permit the use of a lower dose of ICS,2930 there are several reasons why ICS monotherapy should be used as first-line therapy, with long-acting ß2-agonists reserved as add-on therapy for patients who continue to have significant symptoms.
The potential side effects of ICS therapy are often cited as a reason for using long-acting ß2-agonists with low-dose ICS rather than trying a higher dose of ICS monotherapy. However, ß2-agonists, as for all drugs, are not free from side effects. In particular, a potential problem with the use of ß2-agonists in patients with asthma is an increased risk of cardiovascular events.31 Salpeter et al31 performed a metaanalysis of randomized, placebo-controlled trials of ß2-agonist treatment in patients with COPD or asthma to evaluate the cardiovascular effects of these agents. A total of 13 single-dose trials and 20 longer-term studies were included in the analysis. A single dose of ß2-agonist increased heart rate by 9.12 beats/min (95% confidence interval [CI], 5.32 to 12.92) and reduced potassium concentration by 0.36 mmol/L (95% CI, 0.18 to 0.54) compared with placebo. The long-term effect on adverse cardiovascular events was also investigated (sinus and ventricular tachycardia, syncope, atrial fibrillation, congestive heart failure, myocardial infarction, cardiac arrest, or sudden death). For trials lasting from 3 days to 1 year, ß2-agonist treatment significantly increased the relative risk (RR) for a cardiovascular event (RR, 2.54; 95% CI, 1.59 to 4.05) vs placebo. For sinus tachycardia alone, the RR was 3.06 (95% CI, 1.70 to 5.50); for all other events, the RR was 1.66 (95% CI, 0.76 to 3.6). The authors31 concluded that ß2-agonists increase the risk of cardiovascular events in patients with COPD and asthma, and this is of particular concern in patients with underlying cardiac conditions.
Although long-acting ß2-agonists improve FEV1 and symptoms as well as reducing the need for rescue medication, these benefits may occur at the expense of optimal antiinflammatory control. The regular use of long-acting ß2-agonists has been shown to delay recognition of increasing airway inflammation as determined by sputum eosinophil concentrations.32 Despite stable symptoms, FEV1, and PEF, sputum eosinophil counts were found to increase in the week before an exacerbation and were significantly higher in the salmeterol (SAL) treatment arm (19.9%) vs placebo (9.3%, p = 0.006). Thus, the efficacy of long-acting ß2-agonists in improving FEV1 and reducing symptoms through their bronchodilatory effects may cause patients’ symptoms to become decoupled from the underlying inflammation. Although patients will benefit from fewer symptoms, they may in fact be undertreated with ICS, with a potential progression of the underlying inflammatory process. This is particularly likely to be the case with fixed-dose combination inhalers, in which it is not always possible to titrate antiinflammatory therapy with ICS upwards without also overtreating the patient with high doses of long-acting ß2-agonists.28
Several clinical studies303334 have demonstrated the complementary actions of ICS and long-acting ß2-agonists when used in fixed-dose combination inhalers. Patients receiving a fixed combination of SAL at 50 µg plus fluticasone propionate (FP) at 100 µg or 250 µg had significantly better morning PEF, FEV1, asthma symptom scores, reduced albuterol use, and a greater percentage of nights with no waking compared with patients receiving placebo, SAL at 50 µg, or FP at 100 µg or 250 µg alone.3334 In the recently published Gaining Optimal Asthma Control (GOAL) study,30 a fixed combination of SAL/FP was compared with FP monotherapy in 3,421 randomized patients with uncontrolled asthma. The study30 lasted 1 year and had a double-blind, parallel-group design. The primary outcome was the proportion of patients who were well controlled: a composite, guideline-based outcome incorporating lung function measurements, symptoms frequency, rescue medication use, and exacerbations (Table 1
).30 Patients were described as uncontrolled if they did not meet the criteria for either well controlled or totally controlled. Patients were allocated to one of three groups according to their prior use of ICS therapy: stratum 1: corticosteroid naïve or corticosteroid free; stratum 2: 
500 µg of beclomethasone or equivalent (low users); or stratum 3: > 500 to 1,000 µg of beclomethasone or equivalent (moderate users).
It is important to recognize that these three groups do not correspond to asthma severities of mild, moderate, and severe persistent. Although no stratification of asthma severity was presented, applying the GINA severity classification to the baseline data indicated that patients in stratum 1 had moderate persistent asthma and those in strata 2 and 3 had severe persistent asthma. Treatment was initiated at FP at 100 µg bid (strata 1 and 2) or FP at 250 µg bid (stratum 3) with or without the fixed dose of SAL at 50 µg bid, and stepped up until total control was achieved or a maximum FP dose of 500 µg bid was administered. Therapy could not be stepped down at any point during the study. After 1 year, significantly more patients were well controlled with SAL/FP vs FP (Fig 7
).30 This finding was not unexpected as, according to GINA guidelines, patients in strata 2 and 3 corresponded to a population who should be treated with ICS plus a long-acting ß2-agonist. The difference between SAL/FP and FP alone for stratum 1 (moderate persistent asthma) was only 8%. SAL/FP may not be the preferred treatment for all patients with uncontrolled asthma, as the majority will be well controlled on ICS monotherapy.35 The small proportion of patients in stratum 1 who benefited from the addition of SAL may not justify starting subjects with moderate persistent asthma on combination therapy that is more costly and exposes the patient to possible ß-agonist side effects. Even with combination therapy, only 62% of patients in stratum 3 were well controlled. These findings indicate that new strategies are required for these patients as, at present, it is unclear what the next treatment option should be.3035
The fixed combination products have a number of advantages and disadvantages (Table 2
). The main advantage is the potential for increased compliance among patients who have difficulty in adhering to a regimen that requires multiple inhaled medications and devices. The most significant drawback of combination inhalers is the lack of flexibility when asthma is not well controlled, although this has been overcome to some degree with the availability of inhalers containing different ICS doses.36 There is also a belief that, to some extent, the use of fixed combinations is counterintuitive to the stepwise approach to therapy recommended in guidelines. Furthermore, there is the potential for overuse of these agents if step-down therapy to ICS monotherapy is not attempted once symptoms are controlled. The asthma in many patients can be controlled successfully with low-dose or medium-dose ICS monotherapy, and combination inhalers should not be considered until efforts have been made to achieve this.
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Table 2.. Advantages and Disadvantages of Fixed Combination Inhalers (Corticosteroid Plus a Long-Acting ß2-Agonist)
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Leukotriene Modifiers
Cysteinyl leukotrienes act as potent bronchoconstrictors and are part of the inflammatory cascade initiated during an asthma attack. They are produced along with other inflammatory agents by inflammatory cells, including mast cells and eosinophils. Leukotriene modifiers act by either inhibiting leukotriene formation (zileuton) or as leukotriene receptor antagonists (montelukast and zafirlukast), and downgrade that component of the inflammatory response. However, they have no effect on other pathways in the inflammatory cascade. Currently, the GINA guidelines3 recommend the use of leukotriene modifiers in mild persistent asthma when the asthma is not controlled with ICS monotherapy, or as an alternative to a long-acting ß2-agonist as add-on therapy for moderate or severe persistent disease.
Clinical evidence suggests that these agents can provide additional clinical benefits to ICS. In one large study37 (n = 642), the addition of oral montelukast at 10 mg/d to inhaled beclomethasone dipropionate at 200 µg bid provided significantly greater control (in terms of FEV1, daytime asthma symptom scores, morning PEF, and nocturnal awakenings) over a 16-week treatment period in adults and adolescents compared with beclomethasone dipropionate alone. Similarly, the addition of zafirlukast at 80 mg bid to symptomatic patients receiving high-dose ICS has been shown to produce significant improvements in pulmonary function, asthma symptoms, and number of acute exacerbations compared with placebo.38
Leukotriene modifiers may also permit a reduction in the dose of ICS. In a trial39 of 226 adults with asthma receiving the minimum dose of ICS required to maintain clinical stability, montelukast at 10 mg/d demonstrated a 17% greater efficacy than placebo in enabling a reduction in ICS dose. A review40 has concluded that add-on therapy with leukotriene modifiers appeared to be comparable to increasing the ICS dose, and was associated with superior asthma control after ICS dose tapering, but that the corticosteroid-sparing effect was probably modest.
Nevertheless, leukotriene modifiers have been shown to be less effective than long-acting ß2-agonists as add-on therapy. In a 4-week trial,41 patients with persistent asthma treated with ICS were administered add-on therapy with inhaled SAL at 42 µg bid or oral zafirlukast at 20 mg bid. Treatment with SAL resulted in significantly greater improvements from baseline compared with zafirlukast for most efficacy measures, including morning PEF, percentage of symptom-free days, and percentage of days and nights with no supplemental albuterol use.41
Leukotriene modifiers are generally safe and well tolerated.42 Churg-Strauss syndrome has been reported with these agents, although this may be due to the unmasking of an already present syndrome that is manifested when the leukotriene modifiers permit systemic corticosteroid doses to be reduced.42 Although the exact role of leukotriene modifiers in the treatment of asthma is still unclear, they offer a useful alternative to long-acting ß2-agonists and, as oral agents, they do have the advantage of ease of use in children, the elderly, and patients who may have difficulties with inhalers.
Theophylline
Low-dose theophylline has been used for some years and with some degree of success in patients receiving low-to-medium-dose ICS. Theophylline is administered orally, which may have some compliance benefits; but despite the use of lower doses, it has undesirable side effects and a narrow therapeutic index.3
Anti-IgE Therapy
IgE blockers, such as omalizumab, attenuate the cascade of events leading to airway inflammation and subsequent symptoms in moderate-to-severe allergic asthma. IgE blockers do have some add-on benefit to ICS use in moderate-to-severe asthma, for example, by reducing exacerbation frequency.4344 Readers are directed to the literature454647 for more data on IgE blockers.
Allergen Immunotherapy
Although allergen-specific immunotherapy (injecting allergens in increasing doses under the skin) can reduce asthma symptoms, the risk of severe asthma attacks, and medication use, there have been concerns about the risk of severe, anaphylactic reactions. A Cochrane review48 of 75 randomized controlled trials confirmed the beneficial effects of allergen-specific immunotherapy in asthma and found that severe reactions were actually very rare.
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Participant Feedback and Discussion
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During the breakout sessions, participants reviewed this presentation and focused their discussions around the following questions: - What is your biggest challenge in asthma management?
- How do you assess asthma control?
- Define your current treatment algorithm for asthma management to include ICS, leukotriene receptor antagonists, and combination therapy.
- How important is the delivery device in selecting therapy?
- What factors determine your intervention point?
- When is the right time to intervene?
The need for clear, open channels of communication between patients and their health-care providers was highlighted as a key challenge, as has been described in the AIRE and AIA surveys.1415 The AIA survey15 specifically demonstrated the widespread misunderstanding among patients about the underlying condition causing their asthma symptoms, as well as confusion about appropriate treatment and other aspects of asthma management. It is also of concern that a significant proportion of patients receive information about asthma from friends and family.49 The pulmonologists included in the meeting agreed that many patients needed convincing about the benefits of ICS therapy, and that patients were often concerned about side effects (eg, long-term effects on bone and weight). Participants commented that, even among patients who were knowledgeable about asthma management and the benefits of treatment, the degree of compliance that could be expected was of concern (this issue is reviewed more extensively in the article by Horne). The need for continuity of care was also emphasized, with the relative roles of the physician and asthma nurse highlighted. Good team working and continuity of care have a crucial role to play in asthma—particularly in children—as lower continuity of primary care has been associated with a higher risk of emergency department utilization and hospitalization.50 Participants believed that simplicity was key to the assessment of asthma control, and recommended the use of a standard questionnaire/clinical checklist containing the following indicators to help evaluate the degree of asthma management: daytime and nocturnal symptoms; symptoms during exercise; number of exacerbations; work absenteeism; lung function; and number of short-acting ß2-agonist refills.
Both the AIRE and AIA surveys1415 highlighted that patients tend to overestimate their level of control, and the pulmonologists stressed that it was more realistic to aim for "good" control rather than "total" control. The need for ongoing patient review was emphasized, particularly with regard to factors that could adversely affect the degree of control, such as comorbid conditions (eg, sinusitis).
Participants commented that many primary care physicians find asthma guidelines too complex and lengthy, and this was also the opinion of the panel, who urged the simplification of current guidelines (see also the article by Graham in this supplement). A simpler approach that would provide a good starting point for treatment could be as follows: for mild-to-moderate asthma, low-dose ICS monotherapy; and for moderate-to-severe asthma, ICS plus add-on therapy.
Although the GINA guidelines3 recommend a step-down approach, in practice this is not always implemented. There was widespread agreement with the view that there is no "one size fits all," with support for step-up and step-down therapy as required. Approximately 44% of the asthma experts participating in the meeting started 80 to 100% of their patients with mild or moderate persistent asthma on ICS monotherapy, whereas only 13% started patients with severe persistent asthma on ICS monotherapy. The choice of delivery device was emphasized as being critical for good compliance, with patient preference being the most important consideration. Simplicity and ease of use were the two characteristics highlighted. Interestingly, the delivery device selected by patients may differ for relievers and controllers.
Currently, the role of leukotriene modifiers in asthma management is unclear. Participants tended to use these agents as add-on therapy with ICS, more often in children than in adults, and for patients who have a steroid phobia. They may also be of value in patients with aspirin-induced or exercise-induced asthma.42 There were concerns about the percentage of nonresponders and whether the use of these drugs is cost-effective.
Overall, participants agreed that early intervention in asthma was a key objective and that ICS are the cornerstone of therapy. The use of a written action plan—as outlined in the guidelines—was considered to be imperative.
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Conclusion
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Despite the availability of international asthma management guidelines, there is a distinct gap between guideline recommendations and actual clinical practice. ICS remain the cornerstone of therapy for persistent asthma, but patients are underusing these agents while overusing relief medication. Consequently, many patients have asthma that is not well controlled, resulting in a significant degree of morbidity and greater expenditure. Early intervention with ICS promotes a better long-term outcome, with ICS monotherapy providing successful control of asthma in a significant proportion of patients.
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Acknowledgements
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The author thanks Carole Manners, PhD, for writing and editorial support in the development of this article.
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Footnotes
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Abbreviations: AIA = Asthma in America; AIRE = Asthma Insights and Reality in Europe; CI = confidence interval; FP = fluticasone propionate; GINA = Global Initiative for Asthma; GOAL = Gaining Optimal Asthma Control; ICS = inhaled corticosteroids/corticosteroid; PEF = peak expiratory flow; RR = relative risk; SAL = salmeterol
Dr. Humbert was supported by grants from Université-Paris Sud 11.
Dr. Humbert has relationships with drug companies, including Novartis, Altana, AstraZeneca, GlaxoSmithKline, Pfizer, and Schering Plough. In addition to being an investigator in trials involving these companies, Dr. Humbert’s relationships include consultancy services and membership on scientific advisory boards.
Received for publication July 2, 2005.
Accepted for publication March 20, 2006.
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Abstract
Introduction
p < 0.001.