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Asthma is a chronic inflammatory disorder of the airways that is characterized clinically by recurrent episodes of wheezing, dyspnea, chest tightness, and coughing. The major pathophysiologic abnormality in patients with asthma is a combination of significant airway inflammation and airway hyperresponsiveness that leads to the aforementioned symptoms. Airway inflammation is modulated by various cellular elements and chemical mediators and results in 4 distinct types of airflow limitation: acute bronchoconstriction; airway wall swelling; mucous plug formation; and, rarely, airway wall remodeling.1 Collectively, these processes result in a disease process that is clinically variable and that may lead to progressively worsening airflow limitation. The response to recommended therapies is also variable and patients may be unresponsive to controller medications including inhaled corticosteroids. Airway hyperresponsiveness in people with asthma is characterized by an exaggerated bronchoconstrictor response in those who are allergic to a wide variety of stimuli, including infections, exercise, cold air, and allergens. Clinically, this may result in a large daily variation in airway caliber, leading to a fluctuating level of symptoms throughout the day and night.
The etiology of asthma is completely understood. Both the genetic and environmental inputs appear to play major roles. Atopic allergy, defined as an immune mediated hypersensitivity reaction involving the presence of immunoglobulin E (IgE), has been shown to be a key factor in both children and adults.2 Several studies have shown that there is a clear link between IgE, atopy, and asthma.3-5 Similarly, in the Collaborative Study of the Genetics of Asthma, more than 75% of individuals had both asthma and skin test reactivity, indicating the presence of atopy.6
The diagnosis of asthma is primarily based upon the presence of a pattern of clinical symptoms and the presence of airway hyperresponsiveness based either on response to bronchodilators or airway challenge. Abnormal findings on pulmonary function testing may or may not be present. The classic triad of asthma symptomsâ€”persistent wheezing, cough, and dyspneaâ€”is only present in a small proportion of patients.7 Recurrent or persistent patterns of cough, chest tightness, and shortness of breath are characteristics of asthma. While the presence of more than 1 of these increases the likelihood that asthma is present, it is important to use other tools, in addition to the clinical history, to make an accurate diagnosis of asthma. A physical examination often shows wheezing when patients are symptomatic, and in some patients atopic or allergic findings may be present.8 Spirometry is a key element in the diagnosis of asthma. All patients for whom the diagnosis of asthma is considered should undergo spirometry before and after the inhalation of a short-acting bronchodilator. The presence of asthma is highly likely if there is an increase of more than 12% and 200 mL in forced expiratory volume in 1 second (FEV1) after the inhalation of a short-acting bronchodilator. Alternatively, reversibility may be demonstrated by treating the subject with inhaled or oral corticosteroids for days or weeks and comparing spirometry before and after treatment. However, some people with asthma may exhibit lesser degrees of reversibility on spirometry. These patients may require airway challenge testing (eg, methacholine) to confirm the diagnosis. In any case, a thorough assessment is essential, and it is important to consider the patient's entire clinical picture when making the diagnosis.
Management of asthma involves 4 components: (1) monitoring of disease activity and disease control including symptoms and lung function; (2) controlling asthma triggers; (3) patient and caretaker education; and (4) pharmacologic therapy. Pharmacotherapy includes the use of short-acting reliever medications for acute symptoms, such as albuterol and pirbuterol. It also includes the use of controller medications for long-term control of symptoms, such as inhaled corticosteroids, long-acting bronchodilators, leukotriene modifiers, as well as other therapies guided by specific clinical circumstances, such as anti-IgE monoclonal antibody therapy. As with other diseases, management strategies are tailored to individual patient needs.
The Burden of Asthma
Asthma is a very common chronic disease which places substantial economic, social and public health burdens on society. It is highly prevalent in children, with estimates commonly ranging from 14% to as high as 30% in some populations.8 In the International Study of Asthma and Allergies in Childhood, the prevalence of asthma symptoms was highly variable among different geographic regions, with a particularly high prevalence in English speaking countries and Latin America.9 This finding was a confirmation of data obtained in the European Community Respiratory Health Survey, in which the highest prevalence of asthma was seen in the British Isles, New Zealand, Australia, and the United States.10
The prevalence of asthma has increased over the past 2 decades. According to the Centers for Disease Control and Prevention, the overall annual age-adjusted prevalence rate of self-reported asthma increased by 209% from 1980 to 1996, but it seems to have stabilized since that time.11,12 There has been an increase of 17% in the overall hospitalization rate and an increase of 53% in the hospitalization rate among children from 1980 to 1999. It is speculated that this increased rate of hospitalization represents an increase in the severity of asthma, rather than a change in practice patterns.13 Mortality from asthma has also increased during this time period by approximately 61%.12 The cause for this is uncertain, but is speculated to involve increasing severity of asthma, variable and deceptive disease activity, and failure of asthma management, including inadequate assessment of severity by providers and noncompliance with medical therapy by patients. The mortality rate remains high but has remained steady likely because of the increased adherence to guidelines and greater availability of medications. Studies from Australia, Canada, and the United States have supported this observation.14
The cost of asthma is substantial. As with prevalence, estimates of the costs of asthma care are variable, with one study estimating a cost of $300 to $1300 per patient per year.15 Patients with more severe asthma incur disproportionately more costs than those who have mild asthma. Specifically, 10% of the population with severe asthma are responsible for 50% of the costs of asthma, while 70% classified with mild asthma are only responsible for 20% of total asthma costs. In the United States alone, direct and indirect financial costs for all forms of asthma total $14 billion, including $9.4 billion in direct costs and $4.6 billion in indirect costs (missed school and workdays).16
Challenges of Asthma Management
Despite the sobering statistics noted above, and despite the presence of well-studied and generally effective treatments for asthma, the management of patients with asthma is often fraught with problems. Challenges abound with difficulties in early and accurate diagnosis, effective and appropriate treatment, compliance with prescribed therapeutic regimens, and increasing barriers to effective asthma care. Currently, the business structure in healthcare motivates many providers to conduct a high volume of short patient visits. This structure is not well suited for patients with asthma and may result in chronically ill patients not receiving the adequate education and reinforcement required for long-term maintenance and control of their condition. It is therefore not surprising that numerous studies have shown that a large portion of patients fall short of acceptable asthma treatment goals.17-19
Managed care organizations (MCOs) have become increasingly aware of the impact of asthma on healthcare expenditures. With increases in the cost of asthma, there has been a proliferation of programs to assist in the management of asthma patients, including disease management programs, case management programs, population health initiatives, and educational initiatives of providers and patients. While some of these strategies have been successful in reducing healthcare costs,20 the overall quality of care of the asthma population has not improved consistently, as noted above. There is a great need to improve the care of patients with asthma. Managed care companies have a particular interest in optimally managing chronic illnesses. Its prevalence makes asthma a logical choice upon which to focus quality improvement (QI) efforts. One effective QI strategy in managed care is the identification and incorporation of clinical guidelines.
Using Guidelines to Manage Asthma
As with other chronic conditions, there is no shortage of guidelines for the management of patients with asthma. Foremost are the guidelines put forth by the National Asthma Education and Prevention Program (NAEPP) and National Heart, Lung, and Blood Institute (NHLBI), which were initially published in 1997 and updated in 2002.8,21 These guidelines divide the process of asthma management into 4 individual components (Table 1), which are then reviewed in detail. The first component emphasizes the importance of proper diagnosis, noting that considerable clinical judgment is required in diagnosing asthma because signs and symptoms vary from patient to patient, as well as within each patient over time. Once proper diagnosis is made, the guidelines emphasize the importance of ongoing monitoring and periodic assessment to determine if the goals of asthma therapy are being achieved. The second component emphasizes the importance of controlling environmental and other factors in patients with asthma, in an effort to reduce the severity of asthma. The third component discusses the appropriate utilization of pharmacologic therapies. The fourth, and final, component discusses the importance of education, including self-management and action plans, and emphasizing compliance and open communication between patient and provider. The 2002 update of these guidelines added information on long-term management of asthma in children, with specific reference to the use of inhaled corticosteroids, the use of combination bronchodilator/corticosteroid therapy, the use of antibiotics to treat asthma exacerbations, the use of written asthma action plans and peak flows, and the effects of early treatment on the progression of asthma.
The NAEPP/NHLBI guidelines also describe a widely used classification of asthma severity, which divides patients into 1 of 4 symptom categories (Table 2). Severity assessment and classification is best performed during the initial evaluation and before the initiation of treatment. Patients with mild intermittent asthma have symptoms less than twice weekly and are generally asymptomatic between exacerbations. Patients with mild persistent asthma have symptoms more than twice weekly but less than once daily, and/or nocturnal symptoms greater than twice per month, and exacerbations may be significant enough to affect their level of activity. Patients with moderate persistent asthma have daily symptoms and/or nocturnal symptoms more than once weekly, and they may require daily use of short-acting bronchodilators. Patients with severe persistent asthma have symptoms greater than once daily, limited physical activity, and frequent exacerbations. Currently, treatment recommendations are based upon a patient's given level of severity.
Another well-known set of guidelines is the Global Initiative for Asthma (GINA), which was originally published as a result of collaboration between the NHLBI and the World Health Organization in 1995.1 These guidelines have been subsequently updated several times, the last update occurring in October 2004. The GINA guidelines provide a thorough review of 7 key topics in asthma management (Table 3). They are similar to the NAEPP/NHLBI guidelines in many ways and cover much of the same information. Within each topic area, there are several key points enunciated to assist the provider with asthma care. One section recommends a 6-part asthma management program, offering a very important framework to apply to asthma care. It recommends education, assessment and monitoring of symptoms and lung function, avoidance of exposure to risk factors, establishment of long-term medication plans for stable asthma and for exacerbations, and provision of adequate follow-up care. A unique feature of the GINA guidelines is the specification of 8 goals for the long-term management of asthma (Table 4).
Despite the availability of the NAEPP/NHLBI and GINA guidelines, as well as other published guidelines, many patients have suboptimally controlled asthma. There are numerous reasons for this, including poor compliance with the guidelines. One study analyzed survey data from 5580 health maintenance organization members with asthma and found that providers often did not follow guideline recommendations. In this study, only 54% of patients with severe asthma reported using an inhaled steroid regularly, and only 26% of patients reported having a peak flow meter.22 Another study in Europe demonstrated similar results, with only 31% to 53% of eligible patients receiving inhaled corticosteroids.23 Possible reasons for the lack of adherence to guidelines include the complex and time-intensive nature of thorough asthma care, lack of knowledge on the part of the provider, poor compliance on the part of the patient, a relationship between the patient and provider that is inadequate to promote patient confidence, and the lack of direct unencumbered access to an asthma specialist.
The utility of existing asthma guidelines in daily practice is limited in many respects. While the guidelines contain essential information about asthma and its management, their use is often confined to assisting physicians and other providers in the general care of patients with asthma rather than being viewed or used as a set of specific rules to be followed. The use of guidelines in managed care should be individualized, and all aspects of the guidelines need not necessarily be used when the MCO formulates an asthma management program.
Reaching Total Asthma Control
Because adherence to asthma guidelines is generally poor, there is concern that attaining treatment goals may not be feasible for the majority of patients. In addition, the level of asthma control in a given patient and the severity of that patient's asthma are often felt to mean the same thing, which is an inappropriate interpretation of the definitions of asthma control and severity.24 It may be assumed incorrectly that patients with well-controlled asthma have mild asthma, and that patients with poorly controlled asthma have severe asthma. On the contrary, patients with mild asthma may be poorly controlled if they are not meeting asthma treatment goals. Conversely, a patient with severe asthma may be well controlled if they are meeting asthma treatment goals. The level of asthma severity for a given patient should be assessed before treatment and, once established, it should not be changed, even if control of symptoms is achieved. Assignment of asthma severity should always be independent of control.
Because of the inherent confusion regarding the concepts of asthma severity and control, as well as the belief that this confusion may be limiting the proper assessment of the effects of asthma treatment, the concept of "total asthma control" has been put forth in the GINA/National Institutes of Health guidelines.1 Total control is a composite measure that includes 7 asthma outcomes: daytime symptoms, rescue inhaler usage, morning peak expiratory flow (PEF), nighttime awakening, asthma exacerbations, emergency visits, and treatment-related adverse events. The goal of the currently available guidelines is that patients should have either negative or minimally positive responses to all of the items mentioned. For example, patients should have minimal to no daytime symptoms, rescue inhaler usage, nighttime awakenings, or exacerbations, and should not require any emergency visits. In addition, the morning PEF for patients should be near normal if they are to be considered to have "total control" of their asthma. In promulgating this concept, it has been hoped that when a patient achieves total asthma control, their quality of life (QOL) will improve, and potentially their morbidity as well.
Several studies have examined the concept of total control in asthma. A hypothesis-generating study by Bateman et al attempted to determine if guideline-based control was achievable and generalizable to people with asthma at large.25 The reason for this study was that treatment goals, which are part of guideline-based asthma control, are based on expert opinion rather than being evidence based, so the authors wanted to determine if patients could actually achieve the asthma control that is recommended in the guidelines. A review of 8 studies of a salmeterol/fluticasone combination, using 3 levels (Levels 1, 2, and 3) of guideline-based asthma control as the outcome measure, was performed. The levels of control were based on the GINA definition of asthma control but at different levels of stringency, with Level 1 being the most stringent and Level 3 the most liberal. The analysis found that control of asthma was achievable in a proportion of patients and for a proportion of days in all studies reviewed. The percentage of patients achieving Level 1 control for 95% of the days of the studies ranged from zero to 20%; for Level 2 control, 3% to 27%; and for Level 3 control, 12% to 49%. The authors recommended that these findings be prospectively validated with a randomized controlled trial.
Based on the parameters of guideline-based asthma control, it has been assumed that patients who achieve control of asthma symptoms will have improved QOL, but this notion requires validation. Accordingly, another study examined the relationship between the achievement of guideline-based asthma control and improvement in the patient's QOL, using the Asthma Quality-of-Life Questionnaire (AQLQ).26 Clinical data from 3 studies of salmeterol/fluticasone were retrospectively analyzed to determine if any association existed between level of asthma control and AQLQ score. The authors found that patients who had achieved guideline-based control had consistently higher overall AQLQ scores than patients who were not well controlled. Additionally, those patients who were well controlled at the end of the study achieved greater improvements in their AQLQ than those who were not well controlled. Finally, a significant number of patients who were well controlled achieved near-maximal AQLQ scores, which indicated that their asthma was having little or no impact on their QOL.26
In addition to the 2 studies cited above, which were retrospective by design, the Gaining Optimal Asthma Control study was a prospective, 1-year, randomized, double-blind trial comparing the use of salmeterol/fluticasone versus fluticasone propionate alone in the achievement of asthma control.27 Definitions of asthma control in this study were based on GINA guidelines, and stratified into 3 levelsâ€”totally controlled, well controlled, or uncontrolled. Patients were recruited by investigators from general practice and hospital clinics. They were between 12 and 80 years of age, had asthma for at least 6 months, and demonstrated at least a 15% increase in FEV1 after inhalation of a bronchodilator. Control was assessed at weeks 8, 12, 24, 36, and 52 by determining the proportion of patients who achieved well-controlled asthma in each group. Additional study end points included time required to reach the first controlled week, the dose of inhaled corticosteroid required to achieve asthma control, and AQLQ scores.
The results of the study showed that GINA-defined well-controlled asthma was achieved in 33% to 71% of patients, with more steroid-naive patients achieving control than those who had been on inhaled corticosteroids in the past 6 months preceding the study. In addition, totally controlled asthma was achieved in 8% to 42% of patients, with control seen in the steroid-naive group. A measurable proportion of patients in the study were unable to achieve control at all, and many others were only controlled for a portion of the 8-week study. Patients who achieved both well-controlled and totally controlled asthma experienced a lower rate of asthma exacerbations than those who did not. Likewise, both well-controlled and totally controlled patients reported higher AQLQ scores than those not achieving at least well-controlled asthma. Based on these results, the authors suggested that total control is an attainable goal in the majority of patients, and should be the aim of treatment for all asthma patients.
Despite the outcomes of these studies, the notion of total asthma control and its applicability to patient care can raise questions about the rigid nature of total control and the potential negative effect that using this as the primary goal of therapy could have on the asthma patient who, despite best efforts, is unable to achieve total control. Alternatively, stressing "optimal control" may provide a more realistic and acceptable goal for most patients and healthcare providers.
Measuring Asthma Symptom Control
As mentioned above, the GINA guideline-based definition of asthma control uses measures of patient symptoms, medication use, lung function, frequency of exacerbations, and adverse events. It is quite comprehensive, and thus its goals may not be fully achievable in many clinical practices. Additionally, studies have shown that there is a disparity between a patient's estimate of their asthma control and the level of guideline-based control achieved. In the New Zealand Patient Outcomes Management Survey (POMS), the majority of patients with asthma were not well controlled according to the guidelines used. Additionally, there was a mismatch between the patients' perception of asthma control and the actual level of guideline-based control achieved. Approximately 76% of patients felt that their asthma was well controlled and 80% were satisfied with their level of control, despite the fact that in more than 90% of patients control was suboptimal as assessed by objective criteria, 42% to 71% of patients had asthma that was not well controlled, and 4% to 19% of patients had asthma that was markedly out of control. This disparity indicates that utilization of guideline-based control parameters may not reflect actual patient experience. In some cases, this is likely due to patients accepting chronic symptoms as the norm.28
The findings of the POMS study have been noted in other reports. In the Asthma Insights and Reality in Europe (AIRE) study, more than 2800 patients were surveyed for their perceptions regarding their level of control compared with the level of control according to existing guidelines. Strikingly, only 5.3% of patients in this study achieved total guideline-based control of their asthma symptoms. In addition, there was a major discrepancy between patients' perceived control of asthma and their reported symptom severity. Patients tended to underreport the severity of their conditions, and overestimated their levels of control. Approximately 50% of patients with severe asthma perceived their disease to be well controlled, which led the authors to conclude that many patients often settle for a quality of life considerably less than that achievable if recommended management practices and asthma treatments are used."19
In the Asthma Insights and Reality in Asia-Pacific Study, more than 3200 patients were assessed for their level of asthma control, in a protocol similar to the AIRE study. The results showed that more than 50% of patients reported daytime symptoms within the past 4 weeks, 44% had been awakened by asthma symptoms within the past 4 weeks, and nearly 45% of patients reported activity limitation as a result of their asthma. Approximately 38% of patients believed their choice of job or career was affected by their asthma. As with the AIRE and POMS studies, there was an underestimation of asthma severity in this study. Approximately 34% of patients with severe asthma felt that their disease was either well or completely controlled.18
Unfortunately, the discrepancy between asthma severity and individual perception is not limited to patients. Several studies have shown that the perceptions of parents of children with asthma may not match the child's actual disease status. In one study, a survey of parents of children 3 to 7 years of age who had mild persistent to severe asthma was performed. This survey involved questions regarding asthma symptom frequency, medication usage, and parents' estimation of their child's asthma control, and the answers were compared to objective measures of the children's asthma status. The study showed that most parents underestimated the severity of their child's asthma, and frequently reported good control even when the child had daily asthma symptoms. The authors of the study recommended that pediatricians be more vigilant in asking about specific asthma symptoms during the clinical patient encounter, since global questions regarding asthma control are likely to underestimate the child's asthma severity.29
Another study assessed the difference in perception between parents of chronically ill children and the pediatricians caring for them. A subset of children with asthma were included in this study. Both parents and pediatricians completed a health status questionnaire, the Health Utilities Index, on each individual child in the study. This questionnaire included 8 attributes related to QOL (vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain), and then asked both the parent and the pediatrician to rank these attributes according to how each of them were affected by the particular disease process. The degree of agreement was then determined and reported as a percentage agreement. The study found that there was a substantial difference in perception of QOL between parents and pediatricians approximately 66% of the time, particularly with regard to the domains of emotion and pain. Because of this discrepancy, the authors recommended that physicians discuss QOL issues with parents and children more explicitly, to make certain that all parties are in agreement regarding the effects of chronic illness on the QOL of the patient. While this study dealt with a range of conditions, including asthma, the results were felt to be representative of the fact that an improvement in the communication between physicians, parents, and children is beneficial to adequately manage children with chronic conditions.30
It is also possible that the discrepancy between physicians' and patients' perceptions of asthma disease status is caused by gaps in physician knowledge and, accordingly, this has been investigated. A study addressing physicians' knowledge of asthma treatment guidelines was performed by surveying 108 physicians at the University of Iowa in 1998. Asthma specialists (n = 23) and fellows (n = 11), general internists (n = 11), internal medicine residents (n = 55), family physicians (n = 5), and family medicine residents (n = 5), all completed a 31-question multiple-choice test of asthma knowledge using the NAEPP/NHLBI guidelines as the source of information. The test assessed knowledge in 8 areas (Table 5). The average percentage correct was 60% across all specialties, with asthma specialists scoring the highest (78%) and internal medicine residents the lowest (51%). The lowest scores were achieved on those related to asthma severity. The authors concluded that physicians could benefit from more training regarding the guidelines, with specific emphasis on assessment of disease severity.31 Extrapolating the results of this study suggests that the asthma problem in this country and elsewhere could be positively affected by improved provider education and specifically by greater familiarity with published asthma guidelines.
The discrepancy between perception and reality of asthma control may require alteration of the current guidelines to address this issue. For example, investigators have attempted to develop tools that are simpler and more user friendly to assess asthma control. The Asthma Control Test (ACT) embodies one such approach. This brief 5-question survey is designed to assess the level of asthma control using a format that is easily applied to clinical practice in all settings. The components of the ACT are outlined in Table 6. In a study to assess the utility of the ACT, 407 patients completed the survey, and their responses regarding their level of asthma control were compared to the assessment of control as determined by an asthma specialist. The ACT was found to be reliable and valid, with an internal consistency reliability of 0.79 to 0.84. The ACT was felt to be a useful tool because of its multidimensional nature; it measures several different areas of asthma control, including symptoms, rescue inhaler usage, and the impact of asthma on everyday functioning. This led the authors to conclude that the ACT might be a more practical tool to use in a busy practice, or by any clinician who is interested in assessing asthma control in a given patient or group of patients.32
The ACT may serve as a good tool for MCOs; however, each MCO should individually determine if there are any other applicable measures available, based on the organization's own internal claims and administrative data. For example, the organization can monitor the number of canisters of rescue inhalers prescribed over a given period of time by examining claims data. Practitioners and MCOs need to assess all the available tools (such as the AQLQ and the ACT) to determine what fits best within their patient population.
Treatment Strategies in Patients With Asthma
The appropriate role of the various treatments for asthma is clearly elucidated in currently available guidelines, but there remains some controversy regarding certain treatments, including corticosteroids, combination therapy, leukotriene modifiers, and anti-IgE therapies. It is universally accepted that for those patients with intermittent or rare symptoms of asthma, an inhaled beta-2 agonist used on an as-needed basis is appropriate therapy. For patients with more severe asthma, a more intensive pharmacologic approach is necessary.
The Use of Corticosteroids in the Management of Asthma. Multiple studies have shown that inhaled corticosteroids improve control of asthma and reduce airway inflammation. One of the earliest studies of inhaled corticosteroids in asthma involved 103 patients in Finland and compared the use of inhaled budesonide, 600 Âµg twice daily, to inhaled terbutaline, 375 Âµg twice daily, on measures of asthma severity and control. When compared to the terbutaline group, those patients who received budesonide exhibited improved morning PEF, decreased symptoms of asthma, and decreased use of rescue inhalers. In addition, budesonide was well tolerated.33 In a follow-up study, 37 patients who were treated for 2 years with budesonide, 1200 Âµg twice daily, were assigned to treatment with a reduced dose of budesonide, 400 Âµg twice daily, or placebo. Additionally, patients who were treated for 2 years with terbutaline twice daily were crossed over to treatment with budesonide, 1200 Âµg twice daily. The outcome measure was level of asthma control. A total of 74% of the patients treated with the reduced dose of budesonide maintained asthma control versus 33% of patients treated with placebo, and those patients who were switched from terbutaline to budesonide experienced an improvement in their asthma control.34
Use of inhaled corticosteroids also may lower the death rate from asthma as well, although the data are not conclusive. A Canadian study reviewed the records of 30 569 patients with asthma between the ages of 5 and 44 who had been treated with an anti-asthma medication between 1975 and 1991. The results of the study showed that the use of inhaled corticosteroids decreased the death rate by 50%. Additionally, higher usage of inhaled corticosteroids (as demonstrated by the number of canister prescriptions filled) resulted in a decreased death rate, which became more significant as the number of canisters used increased. Finally, the study showed that the death rate from asthma was increased in patients who discontinued their inhaled corticosteroid compared with the group that continued on therapy.35 While these results are impressive, it is important to recognize that it was retrospective by design, and not randomized, so the results must be interpreted accordingly. The authors of this study note that it has been suggested that the decline in the death rate from asthma is temporally associated with increased sales of inhaled corticosteroids, but such a link has never been proved.
Inhaled corticosteroids may also reduce the hospitalization rate for asthma. A study conducted by the same Canadian group cited above reviewed the records of 2059 patients with asthma who had at least one hospitalization for asthma between 1977 and 1983. Of those patients, 482 were readmitted for asthma within the first year of the study, and it was determined that the regular use of inhaled corticosteroids reduced the rate of rehospitalization by 40%.36 Another study of 742 health maintenance organization members looked at the hospitalization rate of those patients who received inhaled corticosteroids and cromolyn. The relative risk for hospitalization in patients receiving regular inhaled corticosteroids was 0.5, and that for cromolyn was 0.8.37 These and other studies indicate that the benefit of inhaled corticosteroids is beyond pure symptom relief.
Inhaled corticosteroids have been shown to improve objective measures of lung function, reduce frequency of exacerbations, improve QOL, and prevent progressive loss of lung function in patients with asthma.38,39 They do not, however, produce lasting changes (ie, the benefits disappear once the drugs are discontinued), nor do they change the underlying nature of the disease process in patients with asthma. In fact, while inhaled corticosteroids have been shown to be important in the management of patients with asthma, a measurable number of patients do not respond (or have a less than adequate response) to these drugs. In a study by Szefler et al, which examined the relative beneficial and systemic effects of 2 different inhaled corticosteroids (fluticasone propionate and beclomethasone dipropionate), approximately one third of patients exhibited a suboptimal improvement in FEV1. Therefore, while the overall benefit of inhaled corticosteroids cannot be disputed, this study indicates that the response to these drugs is highly variable and some patients might not achieve benefits from inhaled corticosteroids.40
Because of the overall poor compliance with daily regular use of inhaled corticosteroids, studies have been conducted to determine if intermittent use may be beneficial. In a recent study, 225 adults with mild persistent asthma were randomized to receive intermittent therapy with inhaled or oral corticosteroids, daily inhaled budesonide, or daily oral zafirlukast (a leukotriene modifying agent). The primary objective was the identification of differences in outcomes between the intermittent versus daily treatment groups. Patients who received intermittent therapy experienced no difference in morning peak flows, had similar exacerbation rates, and had similar QOL scores as those receiving daily therapy. Patients in the inhaled budesonide group experienced increased scores for asthma control and increased numbers of symptom-free days when compared to the intermittent or zafirlukast groups. This led the authors to conclude that symptom-driven, intermittent treatment with inhaled or oral corticosteroids may be possible in some patients with mild persistent asthma.41
Inhaled corticosteroids are a central component of guideline-based asthma care, both in the NAEPP/NHLBI and the GINA guidelines. While the NAEPP/NHLBI guidelines do review other anti-inflammatory medications, such as leukotriene modifiers and cromolyn, they clearly state that inhaled corticosteroids are the most potent and effective medications currently available for the long-term control of asthma, and that the potential but small risk of adverse events from the use of inhaled corticosteroids is well balanced by their efficacy.8 The GINA guidelines echo the NAEPP/NHLBI, and add that inhaled corticosteroids are the preferred treatment for patients with persistent asthma at all levels of severity.1
Corticosteroids are generally considered the cornerstone of therapy in the treatment of persistent asthma. Improving patients' compliance with inhaled corticosteroids should be a goal of asthma management. Patients often need instruction regarding the use of the various corticosteroid inhalation devices. Regular and correct use of inhaled corticosteroids can result in dramatic improvements in asthma control, and this alone often encourages better compliance. MCOs can improve asthma outcomes by educating patients about the pivotal role of these drugs in asthma management.
The Use of Combination Therapy in the Management of Asthma. While the use of anti-inflammatory controller medication is the mainstay of asthma therapy, some patients do not respond fully to these agents, and the benefits of increasing the dose of an inhaled corticosteroid are limited by increasing incidence of side effects and a relatively flat dose-response curve. In other words, low-dose inhaled corticosteroid therapy is very effective, and increasing the dose does not necessarily provide improvement commensurate with the dose increase. Furthermore, side effects mount with an increased dose of inhaled corticosteroids. As a result, studies have been done to determine if the addition of a long-acting beta-2 agonist to a regimen of inhaled corticosteroids would be beneficial. In one study, 429 symptomatic asthma patients already on low-dose inhaled beclomethasone were randomized to either an increased dose of beclomethasone or the addition of salmeterol, a long-acting beta-2 agonist. The group that received the combination therapy experienced a greater decrease in symptoms, decreased rescue inhaler use, and an improvement in morning peak flow.42 In another study, 738 patients on high-dose inhaled beclomethasone who were still symptomatic were randomized to an increase in beclomethasone dosage or the addition of 2 dosages of salmeterol. Both groups that received the salmeterol experienced greater increases in morning and evening peak flows, as well as a greater increase in symptom-free days and a decreased use of rescue inhalers.43
A recent meta-analysis of 9 trials involving 3685 symptomatic patients looked at the addition of salmeterol to inhaled corticosteroids versus increasing the dose of corticosteroids. Patients who received salmeterol exhibited greater morning peak flows at 3 and 6 months; an increased FEV1 at 3 and 6 months; an increased percentage of days and nights without symptoms; and an increased percentage of days and nights without the need for rescue inhalers. In addition, fewer patients in the salmeterol-corticosteroid group experienced exacerbations and in those that did, the proportion of patients with moderate to severe exacerbations was lower as well.44
In consideration of the above information, the 2002 update on the NAEPP/NHLBI guidelines addressed the question of combination therapy. In mild persistent asthma, the guidelines currently recommend the use of regular inhaled corticosteroids, with leukotriene modifiers as an alternative, to control symptoms. The use of combination therapy is not recommended in mild persistent asthma, although there is not a specific recommendation against combination therapy if it is necessary to control the disease. In one study addressing this issue, 1272 patients with mild asthma on low-dose budesonide were randomized to receive increased dosages of budesonide or the addition of formoterol, a long-acting beta-2 agonist with a faster onset of action than salmeterol. The combination therapy group experienced a reduction in the risk of exacerbations and in the number of poorly controlled days, as well as improvements in lung function.39 This study suggests that the benefits of combination therapy may be expanded to the mild persistent asthmatic not well controlled on monotherapy. In patients with guideline-defined moderate persistent asthma who are not controlled on an inhaled corticosteroid, the addition of a long-acting beta-2 agonist is the preferred treatment, but increasing the dose of the inhaled corticosteroid concomitantly with the addition of the long-acting beta-2 agonist is an acceptable alternative as well.21
The Use of Leukotriene Modifiers in the Treatment of Asthma. Leukotrienes are a group of chemical mediators produced by the metabolism of arachidonic acid, and they are involved in the pathogenesis of asthma. Leukotrienes are produced by a number of cells involved in the asthmatic response, including eosinophils, mast cells, and neutrophils, and have been recovered in elevated amounts in the urine of patients undergoing acute asthma attacks.45 It has been shown that agents that affect the production or block the action of leukotrienes may have a beneficial effect in the treatment of patients with asthma. Currently, there are 3 leukotriene-modifier drugs approved by the US Food and Drug Administration (FDA) that are indicated for the treatment of asthma: zileuton, zafirlukast, and montelukast.
Clinical trials have addressed the effectiveness of leukotriene modifiers in the treatment of patients with asthma. All 3 available agents have been shown to produce improvements in FEV1, a decreased need for rescue inhalers, and improvements in asthma symptoms, in both adults and children.46 These agents have been compared to inhaled corticosteroids in the treatment of asthma, and results have suggested that inhaled corticosteroids are superior to leukotriene modifiers in most measures of asthma control, but, as in the case of inhaled corticosteroids, there is a variability of response seen in patients who take leukotriene modifiers.
In one 3-arm study of oral montelukast versus inhaled beclomethasone versus placebo, patients in both active treatment groups experienced improvements in various measures of asthma control, including lung function, symptom score, and QOL. Those patients who received inhaled beclomethasone, however, experienced significantly greater benefits than those who received oral montelukast. There was a great deal of variability in patient responses to both beclomethasone and montelukast, though, with approximately 25% to 33% of patients in both groups experiencing no increase or a decrease in FEV1.47 Additionally, while beclomethasone was superior in this trial, those patients who took montelukast experienced significant improvements in all study end points as well, suggesting it has value in certain patients with asthma. At least part of the reason that montelukast is effective relies on the fact that there may be better adherence with oral therapy than with inhaled corticosteroids.48
While leukotriene modifiers are inferior to inhaled corticosteroids and are therefore not recommended as preferred first-line treatment, they do have a potential role in the treatment of asthmatics of all severities. In patients with mild persistent asthma, they are listed as an alternative treatment after inhaled corticosteroids. In patients with moderate persistent asthma, they are recommended as an addition to inhaled corticosteroid treatment. In patients with severe persistent asthma, they are recommended as an addition to the treatment regimen in patients whose asthma symptoms are uncontrolled with high-dose inhaled corticosteroids and long-acting beta-2 agonists. This last recommendation stands although there have been no controlled studies, showing that the addition of leukotriene modifiers to combination therapy provides any benefit in terms of improved asthma control.
The Use of Anti-IgE Therapies in the Treatment of Asthma.
As mentioned previously, there is a significant association between asthma and atopy, and, since IgE plays a central role in the pathogenesis of atopy, it has been a target of therapeutic drug development over the past 20 years. Patients with moderate-to-severe persistent asthma are usually treated with multiple medications (as detailed), but a portion of these patients remain symptomatic and poorly controlled despite appropriate therapy. In this group, the search for additional, more effective treatments has led to research into the use of anti-IgE therapies.
Clinical studies have shown that IgE levels are elevated in most asthmatics compared to age-matched controls. In one study of 2657 patients, the odds ratio for the presence of asthma increased linearly as the serum IgE level increased, and those patients who had the lowest IgE levels (n = 177) had no asthma.3 More recent studies have shown that as the severity of a patient's asthma increases, the IgE level increases as well. In the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study, which was a 3-year, multicenter, observational study of patients with severe asthma, patients with mild asthma were shown to have a lower mean level of IgE (99.9 IU/mL) compared to those who had moderate asthma (102.1 IU/mL) and those who had severe asthma (112.0 IU/mL). While statistical significance was not reported in the TENOR study, the differences in IgE levels were larger in children and adolescents.49 A follow-up study looked at the association between IgE levels and lung function. Patients with IgE levels >100 IU/mL had lower prebronchodilator FEV1 than those who had IgE levels <100 IU/mL. Additionally, the group with higher IgE levels exhibited greater improvement in lung function after bronchodilator treatment. As in the original TENOR study, the findings were more pronounced in children.50
The first anti-IgE therapy developed, omalizumab, is a recombinant humanized murine antibody which binds IgE with high affinity. It is administered subcutaneously every 2 to 4 weeks in a dose that is determined according to the patient's baseline IgE level and weight. It was approved by the FDA in June 2003 for use in patients with moderate-to-severe asthma with an elevated IgE level, evidence of atopy, and incomplete symptom control with appropriate therapy that included inhaled corticosteroid treatment. The concept of anti-IgE therapies is discussed in the October 2004 update of the GINA guidelines, but no formal recommendation has been made thus far. The NAEPP/NHLBI guidelines have not been updated since the introduction of omalizumab.
Multiple studies have investigated the role of omalizumab in the treatment of moderate-to-severe allergic asthma. In one study, 546 patients with allergic asthma who were symptomatic despite the use of adequate doses of inhaled beclomethasone were randomized to receive omalizumab or placebo. Patients were initially maintained on their prestudy dose of beclomethasone, but, after 16 weeks, the dose was reduced to the lowest possible dose to control the patient's asthma symptoms. Those patients treated with omalizumab experienced 58% fewer exacerbations than the placebo group during the initial 16 weeks of the trial, and 52% fewer exacerbations than the placebo group as the dose of beclomethasone was reduced. 51 In another study, 525 patients with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive omalizumab or placebo.52 This study also uses a corticosteroid reduction design similar to the previously mentioned study. Patients treated with omalizumab experienced a significant reduction in the rate of asthma exacerbations, and the inhaled beclomethasone dosage was able to be lowered to a greater extent in the omalizumab group. There were also improvements in asthma symptoms, lung function, and a reduction in rescue inhaler use in the omalizumab group.
The use of omalizumab has also been shown to be beneficial in 2 other significant health outcomes: QOL and healthcare utilization. In one study, 525 adults with severe allergic asthma were randomized to omalizumab or placebo.53 The effect of asthma treatment on asthma QOL was assessed through the use of the AQLQ. Patients who were treated with omalizumab achieved significantly greater improvements in all AQLQ domains, as well as the total AQLQ score, indicating a measurable improvement in patient QOL. In another study, the effects of omalizumab on asthma exacerbations and emergency medical visits were ascertained. Data from 7 studies were pooled, and a total of 4308 patients were included in the final analysis. Those patients treated with omalizumab demonstrated a 38% reduction in exacerbations and a 47% reduction in emergency medical visits. The latter observation is particularly important in light of the enormous burden that asthma places on the healthcare system, but must be balanced with the considerations regarding the cost of omalizumab, which can add significant costs to the asthma treatment regimen.54
Many patients with poorly controlled asthma suffer from significant comorbidities, such as chronic sinusitis,55 gastroesophageal reflux disease,56 obesity,57 depression,58 and anxiety,59,60 which contribute to suboptimal control. Identifying and addressing these conditions is appropriate before initiating omalizumab therapy. Patients may also be referred for omalizumab therapy and not actually have asthma, which is the reason they have failed conventional therapies. Thus, it is essential to confirm the diagnosis of asthma before initiating omalizumab therapy or any other asthma therapy. Omalizumab should be monitored closely so as to maximize its proved benefits and minimize the costs associated with those benefits. As with all biologic therapies, cost-benefit analyses can be very useful to ascertain effectiveness.
Improving Outcomes in Patients With Asthma
A significant proportion of patients with asthma are not meeting asthma treatment goals. There are many reasons for this phenomenon, including patient nonadherence, provider perceptions and expertise, issues regarding the quality of asthma care, and the business environment that influences healthcare flow and patient access. As a result, improving outcomes in patients with asthma is a multidimensional process. Addressing patient factors, most notably nonadherence, is extremely important, as a compliant patient is more likely to be a controlled patient. Improving quality of care involves assisting the provider to effectively manage the asthma patient, making sure the provider is educated on how to achieve this goal. In addition, improving quality of care necessitates the removal of barriers that prevent patients from receiving the assistance they need, including medications and adequate follow-up. All of these issues have been extensively studied with the goal of improving care to patients with asthma.
Studies have shown that only about one half of prescribed asthma medications are taken. Of those that are taken, inhalation technique is frequently suboptimal.61 Poor adherence with prescribed medication is an important component of inadequate asthma management. Patient nonadherence with therapy contributes to excess urgent care and hospitalizations62 and has been estimated to cost $1.6 billion annually in Canada. One recent report reviewed the results of 29 different studies that addressed asthma medication adherence. The trials reviewed utilized questionnaires, focus groups, or interviews, and the results were distilled into several common points, which are listed in Table 7.53 Many of these points are the result of inadequate education regarding asthma medication, and may in part reflect the difficulty of delivering thorough asthma care in the face of limited resources. These complexities appear to have the greatest impact in lower socioeconomic environments. Interestingly, there were at least some people who either did not like their provider, or who distrusted the medical establishment entirely. Unfortunately, these are particularly difficult obstacles to remedy.
In a parallel study, strategies were discussed to overcome barriers to asthma control. Recognizing that asthma treatment involves a partnership between the provider and the patient, the study's author recommends several key methods to improve asthma outcomes. Simpler or streamlined asthma treatments, with a focus on decreased frequency of medication administration, may improve compliance. Patient education is extremely important, and providers must be certain that patients understand both the illness and the treatment. Concomitant psychological disorders, such as anxiety and depression, must be managed in order to maximize outcomes. Patients must be motivated to participate in their own healthcare and must be willing to work with their provider to effectively manage both exacerbations and stable chronic disease. Most important, patients must have faith in their provider and in the treatment they are prescribed. Without this, all other considerations become less relevant.63
Improving the quality of asthma care involves addressing several different issues. Proper (and ongoing) education of providers is important in an effort to make sure physicians (and other providers) treating patients have the most current clinical knowledge regarding the management of asthma patients. Appropriate and timely referral to an asthma specialist is also necessary, as it has been shown that the outcomes of patients who have specialist care are superior to those who have generalist care.64
Because of their ability and desire to manage chronic, high-cost conditions, managed care companies are uniquely poised to assist the provider in managing the asthma patient. MCOs have a number of options for asthma management programs, including case management, disease management, asthma education programs, asthma quality improvement programs, and asthma practice guidelines.65 The impact of these interventions is variable, but most often it is extremely valuable. With respect to disease management, there have been numerous studies assessing the effect of this intervention on asthma care and outcomes. One study of patients in a managed Medicaid program showed that the institution of a disease management program significantly increased the use of anti-inflammatory medications, reduced the number of nighttime symptoms, and resulted in a net savings of 18.4% in asthma care for the health plan.66 Another study showed that a pharmacist-provided comprehensive asthma education program in conjunction with the care of a pulmonologist improved economic, clinical, and humanistic outcomes in adults when compared to pulmonologist care alone.67
Other studies have shown that disease management programs have a beneficial impact upon asthma outcomes. In a study from Taiwan, 854 patients with already diagnosed asthma and 231 newly diagnosed asthmatics were enrolled in a government-sponsored disease management program, and their level of resource utilization and satisfaction was assessed before and after enrolling in the program. After 1 year in the program, the patients who had a preexisting diagnosis of asthma had nearly 40% fewer emergency department (ED) visits, 46% fewer inpatient visits, and a nearly 52% shorter length of stay. Those patients who were newly diagnosed with asthma showed a 197% increase in outpatient visits and approximately 61% fewer ED visits. Both patients and physicians were satisfied with the program, although the majority of physicians did feel that the program prolonged consultation time in outpatient visits. The program resulted in a majority of patients adhering to physicians' suggestions, and a greater number of patients had more accurate knowledge of their disease and better self-management skills.68
Another study looked at the institution of an asthma medication management information system (MMIS) as part of a pediatric disease management program. The MMIS collected patient asthma medication data, and evaluated prescribed pharmacotherapy relative to disease severity and symptom control, and then compared the prescribed medication regimen to guideline-based severity-appropriate medications. A feedback report was produced and provided to the physician as a tool to be used for improvement. Physicians were shown the percentage of the time they were prescribing severity-appropriate asthma medications, and when they prescribed more medication than was recommended, or less medication than was recommended. Overall, utilization of the MMIS in this study showed that physicians prescribed appropriate medications only 60% of the time, and when they did not prescribe appropriate medications, they usually prescribed "too much" rather than "too little." The authors commented that this program "shows promise as a tool for bringing guideline asthma care into primary practice as well as for advancing the study of primary care practitioners."69
Similar to disease management, case management services have also been studied in patients with asthma and have been found to be beneficial. In one study, 48 asthmatic patients were enrolled in a hospital-based asthma case management program, which involved 3 key components: patient education by a provider trained in national asthma guidelines, a home treatment plan completed by their primary care physician, and regular follow-up with a nurse case manager. Variables that were recorded before and after the institution of the project included hospital admissions, ED and clinic visits, number of chest radiographs, and use of both beta-agonists and anti-inflammatory medications. As a result of the intervention, there was a significant decrease in clinic visits, chest radiographs ordered, beta-agonist use, and oral anti-inflammatory use. Savings for the program were nearly $500 per patient, and those patients who had a home treatment plan included in their case management plan were noted to have even better outcomes than the group as a whole.70
In another study, the use of a nurse case management program in a group of patients in a regional managed care company was reviewed. Patients who had been dispensed a total of 3 or more beta-2 agonist prescriptions in a 12-month period were targeted for intervention. These patients received multiple contacts from a nurse case manager to provide education and information about asthma control and guidelines. At the end of the study, patients who received the intensive intervention were compared to matched controls who did not. These patients were found to be 4.3 times more likely to increase their usage of anti-inflammatory medications.71
Methods used by managed care companies to improve outcomes in patients with asthma involve a multidimensional process. Barriers to care on the part of the patient include difficulty getting access to prescription medications, including cost issues; inability to control environmental triggers of asthma; obtaining regular access to appropriate care, including asthma specialists; lack of recognition that good asthma control is achievable; and improper adherence with prescribed medications, including improper aerosol inhalation technique. Barriers to care on the part of the provider include maintaining up-to-date education; conducting thorough assessments to establish the diagnosis and carefully track the response to therapy; identifying and managing comorbidities; allotting sufficient compensated time or support staff for patient education; and improving communication with patients.
Asthma is a significant global health problem, yet patient outcomes can be improved. Utilization of guidelines and evolving concepts of asthma control is helpful in improving care for asthma patients. Appropriate understanding of traditional medications and of their combined use with novel biologic therapy, if necessary, is critical to successful management of the patient with asthma. Assisting both patient and provider in carrying out recommended treatment and monitoring is likewise essential, as many of the problems with inadequate asthma management stem from nonadherence to recommended therapies. While the task is daunting, making individual improvements in each of these areas can assist everyone in achieving the appropriate goals of asthma treatment and management.
Corresponding Author: Frank L. Urbano, MD, FACP, medical director, PRIME, 8201 West McNab Road, Tamarac, FL 33321; 954-718-6055, ext. 32; 954-718-6055 (fax); e-mail: firstname.lastname@example.org.