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Keywords:

  • asthma;
  • guidelines

Abstract

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

In the first National Heart Lung and Blood Institute and Global Initiative for Asthma (GINA) guidelines, the level of symptoms and airflow limitation and its variability allowed asthma to be subdivided by severity into four subcategories (intermittent, mild persistent, moderate persistent, and severe persistent). It is important to recognize, however, that asthma severity involves both the severity of the underlying disease and its responsiveness to treatment. Thus, the first update of the GINA guidelines defined asthma severity depending on the clinical features already proposed as well as the current treatment of the patient. In addition, severity is not a fixed feature of asthma, but may change over months or years, whereas the classification by severity suggests a static feature. Moreover, using severity as an outcome measure has limited value in predicting what treatment will be required and what the response to that treatment might be. Because of these considerations, the classification of asthma severity is no longer recommended as the basis for treatment decisions, a periodic assessment of asthma control being more relevant and useful.

The Global Initiative for Asthma (GINA) and National Heart Lung and Blood Institute (NHLBI) Education guidelines initially suggested that asthma should be classified by severity (1, 2) in order to determine a hierarchy of asthma therapy based on the patient's severity of disease. However, this severity classification has not been validated and has gained little acceptance in primary care where most asthmatics are seen. Moreover, such classification does not allow asthma control to be assessed after the initiation of treatment. It is therefore important to differentiate between asthma severity and control.

Asthma severity

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

Definition of asthma severity

In the first NHLBI and GINA guidelines (1, 2), the level of symptoms and airflow limitation and its variability allowed asthma to be subdivided by severity into four subcategories (intermittent, mild persistent, moderate persistent, and severe persistent). It is important to recognize, however, that asthma severity involves both the severity of the underlying disease and its responsiveness to treatment. Thus, the first update of the GINA guidelines defined asthma severity depending on the clinical features already proposed as well as the current treatment of the patient (3). In addition, severity is not a fixed feature of asthma, but may change over months or years, whereas the classification by severity suggests a static feature. Moreover, using severity as an outcome measure has limited value in predicting what treatment will be required and what the response to that treatment might be (4). Because of these considerations, the classification of asthma severity is no longer recommended as the basis for treatment decisions (5), a periodic assessment of asthma control being more relevant and useful.

Severe asthma

The majority of patients with asthma have mild to moderate disease that can be well controlled with standard treatment, including regular use of inhaled corticosteroids and long-acting β-2-agonists. There is, however, a subset of asthmatic patients in whom even high doses of these drugs fail to control the disease. Severe asthma remains poorly understood and frustrating to treat, partly because it is a heterogeneous disease (6, 7). Approximately 5–10% of asthmatics have severe disease. It is not one disease, but a multifaceted condition that can be subdivided into different phenotypes. Severe asthma phenotypes can be classified using a number of features of the disease including symptoms, health status, asthma control, airway obstruction (variable or partially fixed), airway hyperresponsiveness, atopy, inflammation, exacerbations and response to therapy (6, 7). This approach has led to the recognition of several important clinical phenotypes: brittle asthma, frequent exacerbators, those with irreversible airway obstruction, and those with oral corticosteroid dependency or resistance (6, 7). Other features such as date of onset of the symptoms or triggers such as aspirin sensitivity may represent interesting additional phenotypes. Assessment of airway inflammation has led to the identification of eosinophilic, neutrophilic, and paucigranulocytic asthma. Phenotyping severe asthma may help to guide current therapy and aid in understanding pathophysiology (7).

Asthma control: moving toward a composite approach

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

In management guidelines, the control of asthma is the goal of disease management (8, 9). Effective medical care depends on the ability to measure changes in the condition of patients as we try to improve disease control. Clinicians develop their own ways of doing this in the course of routine practice, usually by integrating patient and clinician and patient assessments and measures of lung function. However, the development of outcome measures capable of measuring the effectiveness of care for groups of patients raises problems (10) but appears to be essential in the management of asthma.

Definition of asthma control

Asthma control may be defined in a variety of ways. It may indicate disease prevention, or even cure; but in asthma, where neither of these are realistic options at present, it refers to control of the manifestations of disease. Control of asthma has been defined by guidelines. However, it has a different meaning for patients, physicians, or regulatory authorities. Because assessment of asthma control is independent of asthma medications, asthma control is dissociated from asthma severity classification (11).

Assessment of asthma control and questionnaires

There are short- and long-term measures of asthma control (12, 13). Short-term measures include the assessment of measures of airway inflammation and composite measures of asthma control such as the Asthma Control Questionnaire (ACQ).

Asthma control may be assessed by individual outcome measures such as daily or nocturnal symptoms, symptoms linked to nonspecific airways reactivity or exercise, exacerbation symptoms, β2-agonist use as rescue medications, lung function tests, peak expiratory flow (PEF) variability (14), or nonspecific bronchial reactivity (15). Although PEF variability was considered to be an important outcome measure for assessing asthma control, some studies have questioned its validity (14). Moreover, the majority of children and a large number of adults have PEF and FEV1 values that are within the normal range (16).

These measures used individually cannot accurately assess the control of asthma. A composite measure is a more comprehensive assessment of control (17). It is clinically more relevant, reflects all key endpoints and therefore more difficult to achieve. However, different composite measures from different trials (18, 19) should not be compared as the scores are highly variable. Several scores have been proposed for the control of asthma.

  • The three questions of the Royal College of Physicians (8).
  • The ACQ of Juniper based on six questions and FEV1 (20).
  • The Asthma Control Test (ACT) based on five questions (21).
  • The 30 s ACT.
  • The multiattribute Asthma Symptom Utility Index (22). This latter score is of importance as it can be used in cost-effectiveness studies.
  • The Asthma Therapy Assessment Questionnaire (23) mostly used for asthma healthcare utilization (24).
  • The Asthma Control Scoring System (ACSS) (25).

These questionnaires are based upon day/nighttime symptoms, rescue bronchodilators use and daily activities and have been validated. Only the ACQ-7 item version is based on pulmonary function tests (20). However, none of these questionnaires assess exacerbations appropriately which are of importance in the control of asthma and may deserve more attention.

Is asthma controlled in real life?

Surveys in the United States, Canada, Central and Western Europe (26), Asia (27) and Japan (28) have been carried out in around 12 000 subjects with a clinical diagnosis of asthma and who had symptoms or treatment for asthma during the past year. These studies have consistently shown that the disease is not well controlled as defined by National Asthma Education and Prevention Program (NAEPP) (29), Canadian (9) or GINA guidelines (3) because patients and their physicians often underestimate severity and overestimate control, patients are undertreated (inhaled corticosteroids) and have insufficient education and monitoring. It is important to assess the control of asthma.

A review of recent worldwide large population epidemiological surveys and clinical asthma studies of more than 20 000 children shows that only a small percentage of children with asthma reach the goals of good asthma control set out by GINA (30).

Using asthma control to manage asthma

Some new guidelines propose managing asthma on the basis of its control (5, 11). It seems easier to use control than severity as asthma is a variable disease and it better reflects the effects of the disease and medication needs. However, there has been no study comparing the two approaches, and it is possible that a mixture of control and severity may improve asthma management.

If control is used to manage asthma, as stated by the Joint Task Force on Practice Parameters for Allergy & Immunology (11), it encompasses the principles of chronic disease management including periodic assessment as asthma control is likely to change over time. Better control over time may reduce the severity (as mainly assessed by medication needs and other parameters).

Exacerbations

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

The definition of exacerbations in asthma varies widely (31). In the Formoterol and Corticosteroids Establishing Therapy study (32) mild exacerbations are defined by one of the following events: morning peak-flow under 20% from baseline values (which have been measured for 10 days) and/or the use of over three additional puffs of inhaled short acting β2-agonist for 24 h, and/or awakenings at night. In this definition, single isolated events are not counted. Usually, an exacerbation occurs for at least 2 or 3 days and sometimes for far longer. In the same publication, severe exacerbations are defined as one requiring treatment with oral glucocorticosteroids, as judged by the investigator, or a decrease in the morning peak-flow to over 30% below the baseline values on two consecutive days. It seems therefore very important to define a time course for the exacerbations in asthma.

However, other definitions have been used (‘unscheduled physician visit, visit to an emergency room, or hospitalization for the treatment of asthma symptoms during the day and night for over 48 h and not responding to usual medication, and the commencement or doubling of the dose of oral or inhaled corticosteroids for any of the foregoing reasons’), but the event was ascribed to an acute exacerbation (33).

It seems therefore that the definition of exacerbation in asthma should include symptoms, pulmonary function parameters, medication needs, and more severe events such as hospitalizations as well as the duration of the episode.

Assessment of asthma control using markers of inflammation

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

Asthma is currently defined as a chronic inflammatory disease of the airways (34). Thus, techniques to monitor inflammation may provide information useful for diagnosing asthma as well as assessing the biologic response to therapy. Although bronchoscopic sampling of airway tissue may be the most definitive measure of airway inflammation, only noninvasive techniques can be used in routine clinical practice. These include measurement of nonspecific airway hyperresponsiveness, cells and mediators from induced sputum, exhaled nitric oxide and components of exhaled breath air. There is at present no good peripheral blood analysis to measure airway inflammation.

A treatment strategy directed at normalization of the nonspecific bronchial responsiveness was found to reduce exacerbations and normalize airway inflammation (35). In another study, a strategy aimed at normalizing induced sputum eosinophil counts was found to reduce asthma exacerbations and admissions without the need for additional anti-inflammatory treatment (36). Another study showed similar results and suggested that assessment of asthma medication needs from evaluation of sputum eosinophilia was mostly useful in preventing exacerbations of the eosinophilic type (37) Among asthma control composite scoring systems, the ACSS (25) was the first to suggest including sputum eosinophils as a potential additional parameter to assess control. However, this test is not widely available. Nitric oxide is another interesting noninvasive marker and may be interesting to monitor in asthmatic children and adults with severe asthma (38, 39). Breath condensates are raising interest but they are not yet standardized and proteins are difficult to be measured (40). Although these studies suggest that the monitoring of inflammatory markers may improve asthma control, they are still very difficult to use in primary care.

The response of asthmatic patients to inhaled corticosteroids is an important question to be addressed. In addition, education and improvements in self-management skills may increase adherence to inhaled therapy, perceived control of asthma, and sputum eosinophilia in asthmatic patients treated with inhaled corticosteroids (41). Finally, the role of biomarkers in predicting the outcome of asthmatics after cessation of inhaled corticosteroids has been addressed in a recent study, showing that sputum eosinophils but not FENO and methacholine PC20 may be used to guide therapy (42).

Loss of control

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

Passive and active smoking

Around 24% of the US population are current smokers (43). The prevalence of smoking in asthmatics is similar to that in the general population (44). Moreover, many nonsmokers are exposed to environmental tobacco smoke (45). Smoking asthmatics have poorer asthma control and increased acute care needs (46). By comparison with nonsmokers, they have more respiratory symptoms, worse quality of life, and more emergency department visits and hospitalizations (47). Smoking is also associated with accelerated decline in baseline lung function over time (48). Exposure to environmental tobacco smoke also impacts asthma control in children and adults (49). Smoking also attenuates the therapeutic response to inhaled (50) and oral corticosteroids (51).

The reasons explaining the reduced activity of inhaled corticosteroids in asthmatic smokers are multiple (52). Cigarette smoke is associated with neutrophilic inflammation in the airways, and it is known that neutrophils are generally poorly sensitive to glucocorticosteroids (53). Cigarette smoke induces a decrease in histone deacetylase 2 activity (54) which plays a role in mediating the anti-inflammatory response of corticoids. Smoking also increases release of mediators and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-8 (55, 56).

Respiratory infections

Viral respiratory infections represent the most common cause of asthma exacerbations and, hence, contribute to a loss of asthma control. The importance of viruses eliciting asthma exacerbations was suspected by Minor et al. (57) and confirmed with polymerase chain reaction methods by Johnston et al. (58). Rhinovirus is the most frequently identified causal agent (59, 60). However, other viruses such as the human metapneumovirus have recently been identified (61). The role of glucocorticosteroids in the prevention and treatment of virus-induced exacerbations is still a matter of discussion. In asthmatic children, there is no current evidence to favor maintenance low dose-inhaled corticosteroids in the prevention and management of episodic mild viral-induced wheeze (62). The role of oral corticosteroids in the treatment of virus-induced exacerbations has also been discussed (63).

Acute and chronic allergen exposure

Allergens have been considered potential key contributors to the etiology and clinical course of asthma (64, 65), although in epidemiologic studies the relationship between asthma and allergy is not obvious (66).

The importance of environmental allergen exposure in the development of asthma exacerbations has not been fully defined except in some cases like thunderstorm-induced asthma (67) or the Barcelona asthma epidemic (68). Evidence that chronic allergen exposure caused by house dust mites (69) or pollens (70) can have the same effect is weaker possibly because chest symptoms in asthma may also be related to nasal symptoms (71). In experimental studies with asthmatic patients, a single, high-dose allergen challenge can easily reproduce most, if not all, features of an asthma exacerbation (72). Moreover, chronic low-dose allergen exposure also leads to increased airway inflammation and responsiveness, although the patients may remain asymptomatic (73).

The interaction between allergen exposure and respiratory virus infection is still a matter of discussion. A synergy has been observed between allergens and viruses and risk of hospital admission with asthma (74). However, this interaction has not always been demonstrated experimentally (75, 76).

Other causes

Other factors may contribute to poor asthma control including obesity, gastro-esophageal reflux, severe nasal and sinus disease, inappropriate medication use (e.g. β-blockers), air pollution episodes, hormonal changes, and psychological disturbances (7).

Treatment of patients with uncontrolled asthma

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References

Combination therapy

Whether control is an achievable goal of asthma treatment was prospectively studied in the 1-year Gaining Optimal Asthma ControL study (77). A significantly greater proportion of patients achieved control with the combination of fluticasone propionate/salmeterol than with fluticasone propionate alone. At the end of the year long trial, totally controlled asthma was achieved in 41% of patients treated with the combination fluticasone propionate/salmeterol compared with 28% of those treated with fluticasone propionate alone. Well-controlled asthma was achieved in 71% and 59%, respectively. Moreover, control was achieved more rapidly and at a lower fluticasone propionate dose with the combination of fluticasone propionate/salmeterol than with fluticasone propionate alone. Rates of severe exacerbation (exacerbations requiring oral corticosteroids or emergency department visits or hospitalizations) were very low in the patients with total and well-controlled asthma. This study demonstrates that guideline-derived asthma control is achievable in most patients, the step-up treatment aiming for total control is a valid approach to therapy, and that this approach reduces exacerbations rates and improves asthma quality of life. Another strategy has recently been proposed using budesonide/formoterol combination as a controller and reliever medication. Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline (78, 79). Leukotriene modifiers used as add-on therapy may reduce the dose of inhaled glucocorticosteroids required by patients with moderate to severe asthma, and may improve asthma control in patients whose asthma is not controlled with low or high doses of inhaled glucocorticosteroids (3). With the exception of one study that demonstrated equivalence in preventing exacerbations (80), several studies have demonstrated that leukotriene modifiers are less effective than long-acting inhaled beta-2 agonsits as add-on therapy (3).

New treatments

In the patients with most severe asthma, novel treatments have been tested to improve asthma control and/or as steroid-sparing agents (81). The most recent strategies based on the use of monoclonal antibodies or soluble receptors aimed at inhibiting mediators believed to play a key role in asthma. Omalizumab, an anti-immunoglobulin-E monoclonal antibody, is indicated as add-on therapy for patients with severe persistent allergic asthma whose symptoms persist despite receiving optimized treatment with high-dose inhaled or oral steroids and long-acting β-agonists, augmented with additional controller medications as necessary (GINA step 4 therapy) (82, 83). Whether novel agents such as anti-TNF will be of interest in this difficult to control population remains to be demonstrated (84, 85).

References

  1. Top of page
  2. Abstract
  3. Asthma severity
  4. Asthma control: moving toward a composite approach
  5. Exacerbations
  6. Assessment of asthma control using markers of inflammation
  7. Loss of control
  8. Treatment of patients with uncontrolled asthma
  9. References
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