Definition

Asthma is defined as a chronic inflammatory disorder of the airways causing recurrent episodes of cough, wheeze, shortness of breath, and/or chest tightness.¹ These episodes are associated with increased airway sensitivity to a variety of stimuli leading to variable airflow obstruction that is often either preventable or reversible with proper treatment. Clinical manifestations of asthma can be controlled with appropriate management. With asthma controlled, no more than seldom flare-ups should occur, with severe exacerbations presenting rarely, if ever.

This definition of asthma has evolved over the past three decades. Prior to the 1990s asthma was considered primarily a bronchospastic disease.² The role of inflammation was not appreciated, and treatment paradigms therefore focused on management of the bronchospasm without consideration of addressing the underlying progressive chronic inflammation. With a better appreciation of the pathophysiology of asthma, effective treatments have been developed that treat not only the acute symptoms of asthma but also the underlying inflammatory disease at its core.

Epidemiology

Asthma affects approximately 300 million individuals worldwide. The World Health Organization (WHO) has estimated 15 million disability-adjusted life years are lost each year due to asthma, representing a staggering 1% of the total global disease burden. Asthma mortality is at 250 000 lives lost yearly irrespective of disease severity.³ There is also significant international, national, and regional variability in asthma prevalence, a phenomenon which is not well understood. The economic impact of the disease is driven by level of control and extent of emergent care, highlighting the need for a systematic approach to management.

Factors that influence the risk of asthma can be divided into those which affect incidence, expression, or both. While the development of asthma is affected by genetic factors and asthma symptom exacerbation principally by environment, the mechanisms of effect are complex and interactive. We understand more, too, about the development of disease in the young than in adults. For example, the maturation of the immune response coupled with infectious disease exposure during infancy appears to play a crucial role in disease expression, intensity, and duration.

Pathophysiology

Airway inflammation is the hallmark of disease pathophysiology in asthma. As with other allergic conditions, activated mast cells, eosinophils, and T cells (Th2 and invariant natural killer T cells) are associated with disease expression. Inherent structural cells, such as airway epithelial and smooth muscle cells, also can play a role in the disease pathology.⁴

The clinical association with inflammation in asthma is highly variable. Inflammation is persistent even though symptoms may be episodic; the relationship between inflammatory intensity and disease severity is not clear. Inflammation typically affects all airways including the upper airway and nose even though the physiologic effects of asthma are most pronounced in the small to medium sized airways.

Over 100 different mediators are recognized in the complex asthma inflammatory response. Chemokines, cysteinyl leukotrienes, cytokines, histamine, nitric oxide, and prostaglandin D₂ all serve to orchestrate the asthmatic inflammatory milieu.

Structural changes can occur within the asthmatic airway but are not necessarily correlated with inflammatory intensity or disease severity. Increases in airway smooth muscle (as hypertrophy and hyperplasia) and goblet cell proliferation (with mucous hypersecretion) may occur. Increased airway thickness, which may contribute to irreversible narrowing and airflow limitation, can occur in the setting of subepithelial fibrosis (basement membrane collagen deposition) and proliferation of endothelial blood vessels.

Airway narrowing is the final common pathway that leads to the symptoms of asthma. In a variable and complex interplay, smooth muscle contraction, airway edema, airway thickening, and mucous hypersecretion may each play a role in airway narrowing.⁵

Airway hyperresponsiveness, often referred to as the “twitchy” or “irritable” state of the asthmatic airway, occurs in response to a stimulus or “trigger” which would cause no such variable airflow limitation in a nonasthmatic individual. Airway hyperresponsiveness is associated with inflammation and repair of the airways via mechanisms that are incompletely understood. The acute exacerbations, or symptomatic flare-ups, of asthma are also associated with exposure to triggers such as exercise, cold air, air pollutants, weather change, viral infection, or environmental tobacco smoke. Nighttime symptoms are more frequent, a pathophysiologic feature likely modulated by the circadian qualities of circulating hormones (e.g., epinephrine and cortisol) and neural mechanisms (e.g., cholinergic tone).

Diagnosis

The clinical diagnosis of asthma includes symptoms of breathlessness, wheezing, cough, and/or chest tightness.¹ These symptoms are usually episodic and recur with allergen or irritant exposure, seasonal variability, exercise, and/or concomitant respiratory infection. A family history of asthma and atopy is helpful, but not necessary, in making the diagnosis. Clinical and/or pulmonary function response to bronchodilation assists the diagnosis confirmation. Symptoms can occur at any time of day but are more frequently worse at night due to the circadian pathophysiology described above. A useful set of questions is important for all clinicians to consider in making the diagnosis.

Cough may present as the sole symptom of asthma and in most cases should not be treated differently than other symptoms. The differential diagnosis for cough, is of course, quite broad and therefore the clinician should carefully rule out other causes if the clinical diagnostic picture is unclear. In conditions where lung function and its variability are normal, diagnoses such as chronic sinusitis, allergic rhinitis, gastroesophageal reflux, chronic rhinitis with postnasal drainage, vocal cord dysfunction, eosinophilic bronchitis, and cough associated with angiotensin-converting enzyme (ACE) inhibitors should be considered.

Exercise is an important cause of asthma symptoms and may present as the only trigger. Exercise-induced bronchoconstriction typically occurs 5–10 minutes after, and not during, exercise. Again, therapeutic response either after or as pretreatment before symptoms assists in diagnosis confirmation. In the clinician’s office, a running protocol can be developed and, with the aid of pulmonary function measurement of airflow, the diagnosis is often confirmed.

▪ Pulmonary Function Testing

Given the variability of asthma clinical disease presentation, lung function assessment of airflow obstruction and/or bronchial hyperresponsiveness can provide useful complementary information for the clinician. Patients with chronic asthma symptoms frequently have poor perception of the severity of their disease. Furthermore, disease variability, response to treatment, and stability of airflow during medication withdrawal all merit careful clinical assessment via pulmonary function testing assisting achievement of maximal asthma control.

Spirometry provides the best assessment of airflow obstruction available to the clinician. Measurements of forced expiratory volume in one second (FEV₁) in relation to the forced vital capacity (FVC), as well as forced expiratory flow and peak flow, are compared to population normative values to provide clinical comparison. Published recommendations for standardized testing are available. Spirometric testing quality is maximized by well and properly trained technicians and, for younger patients, interactive software. Because of anthropomorphic differences, population normative values chosen should consider ethnic variation. A normal spirometric tracing is represented in Figure 5.1. An example of a flow–volume loop is displayed in Figure 5.2.

Figure 5.1 Normal spirometry. FEV₁ = forced volume within 1 second; FEV = forced vital capacity.

Figure 5.2 A normal flow loop with the top line in expiratory phase and the bottom line in inspiratory phase. Dot represents the start of the inspiration. PEFR = peak expiratory flow rate.

An improvement in FEV₁ by greater than or equal to 12% (or greater than or equal to 200 ml) after administration of bronchodilator indicates reversibility that is generally accepted as specific for asthma. Because this variability is itself variable (diurnal variation, seasonal variation, environmental exposure variation, etc.) and is affected by therapeutic choices, its absence does not mean the diagnosis of asthma does not exist (poor sensitivity).

FEV₁ is often considered as a fraction (or percentage) of FVC when assessing airflow obstruction. This relationship allows the clinician to assess the potential for asthma even if the FVC and FEV₁ are reduced due to other reasons (e.g., restrictive lung disease). The FEV₁/FVC ratio is normally greater than 0.75–0.80. Any values less than these suggest airflow limitation.

While no longer a mainstay of asthma management, peak expiratory flow (PEF) monitoring can serve as a valuable aid in the management of some patients with asthma. Measurements of PEF are not interchangeable with other measurements of lung function such as FEV₁ in either adults or children. PEF can underestimate the degree of airflow limitation, particularly as airflow limitation and gas trapping worsen. Because values for PEF obtained with different peak flow meters vary and the range of predicted values is too wide, PEF measurements should preferably be compared to the patient’s own previous best measurements using his/her own peak flow meter. Its value lies in the clinical scenario where one wishes to confirm the diagnosis of asthma by looking at diurnal variation, or in the patient where regular objective data confirmation may prove helpful in maintaining the treatment plan. Alternatively, in the difficult-to-diagnose patient, symptoms exacerbated by specific or repeated exposure (e.g., exercise regimens) may leave PEF measurement as the only objective data gathering option.

In patients who exhibit normal lung function without symptoms at the time of clinical evaluation, measurement of airway hyperresponsiveness is often helpful. Usually conducted within a specialist’s office or laboratory, the airway challenge is a sensitive tool which, if normal, helps to rule out the diagnosis of asthma. Various challenge agents are used such as methacholine, histamine, cold air, mannitol, or exercise to evaluate airway response. A 20% fall in FEV₁ in relation to the quantity needed to provoke that fall gives the clinician a quantifiable value for airway sensitivity. An example of the change in FEV₁ with methacholine challenge is displayed in Figure 5.3. Airway hyperresponsiveness has been described in illnesses other than asthma such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and bronchiectasis so this tool, while sensitive, is not specific and the clinician should consider other diagnostic possibilities when faced with a positive test result.

Figure 5.3 Diagram demonstrating bronchial challenge (PC20) with methacholine which causes a 20% drop in FEV₁.

Other Testing

Noninvasive markers of airway inflammation such as sputum eosinophilia or exhaled nitric oxide have not yet received full enough evaluation in population-based clinical settings to tell if they will become useful tools in the future. Should they prove robust, these tests would provide a closer correlation between disease pathology and clinical status in response to therapeutic intervention.

Because of the strong association between asthma and allergic rhinitis, the presence of allergies, allergic diseases, and allergic rhinitis, in particular, increases the probability of a diagnosis of asthma in patients with respiratory symptoms. Moreover, the presence of allergies in asthma patients (identified by skin testing or measurement of specific IgE in serum) can help to identify risk factors that cause asthma symptoms in individual patients. Deliberate provocation of the airways with a suspected allergen or sensitizing agent may be helpful in the occupational setting, but is not routinely recommended, because it is rarely useful in establishing a diagnosis, requires considerable expertise, and can result in life-threatening bronchospasm. Skin testing (see Chapter 2) remains the primary diagnostic method to determine allergic status.

Asthma Control

Control of asthma manifestations is the ultimate therapeutic goal. Prior classification schemes attempted to define disease based upon pretreatment severity. These strata were however limited by their inability to predict disease control or define a level of severity once therapy was initiated. While control of disease pathophysiology is important, we do not have a manner of gauging aspects of lung pathology in the clinical setting other than via symptoms and pulmonary function inference. The goal is to maintain complete control for long periods of time, utilizing the least medication possible at minimal cost and without medication adverse effect. Still, an emphasis on preemptive therapy in all but the mildest of patient is the hallmark of care.

Validated measures of assessing asthma clinical control (with and without the use of pulmonary function) are important clinical tools for every clinician. Examples of validated instruments are the Asthma Control Test (ACT; http://www.asthmacontrol.com), the Asthma Control Questionnaire (ACQ; http://www.qoltech.co.uk/Asthma1.htm), the Asthma Therapy Assessment Questionnaire (ATAQ; http://www.ataqinstrument.com), and the Asthma Control Scoring System.

Asthma Management

Current concepts in the management of the patient with asthma use therapeutic options based on the level of the patient’s asthma control, rather than directly on the severity of the disease as assessed by pulmonary function. Control is a more dynamic index of the patient’s current status, and can be more readily assessed and treated actively than through the use of a static concept of severity. The 2006 GINA guidelines therefore stress a control-based strategy for management of the asthmatic patient. In addition, the management of the patient with asthma requires an ongoing partnership between the physician, the patient, and the patient’s family that involves not only the manipulation of pharmacologic therapies, but also a dynamic strategy for bringing asthma under the best control that is practical. Components of this partnership are noted in Box 5.1.

Measures to prevent the development of asthma, acute and chronic asthma symptoms, and the progression of disease by avoiding and reducing exposure to risk factors should be a hallmark of asthma management and utilized whenever possible. The nonpharmacologic element of care is a critical component of disease control and must be discussed openly in patient–doctor communication.

Other than preventing tobacco exposure during pregnancy and postnatally, there are no widely accepted or proven interventions that prevent the development of asthma. Exacerbations of asthma are caused by a myriad of factors, or “triggers,” that include allergens, viral infections, pollutants or irritants, and medications. Reducing exposure to known triggers improves asthma control and reduces need for medication. Common indoor allergens include house dust mites, dander-laden pets, cockroaches, and fungi/mold. Evidence to reduce isolated allergen levels leading to clinical benefit is scanty (Table 5.2).⁷ Combined, targeted multiallergen reduction studies are yet to be conducted.

TABLE 5.2 Effectiveness of avoidance in certain indoor allergens (GINA 2006)⁶

Outdoor allergens are obviously difficult to avoid. A keen understanding of when certain tree, grass, weed, or plant allergens reach their seasonal zenith can assist the patient and family with self-management and control strategies. Outdoor air pollutants are known to aggravate asthma symptoms. Ozone, nitrogen oxides, acid aerosols, and particulate matter are all associated with symptoms and exacerbations of asthma. Community air quality policy and information can help asthma patients make critical decisions about outdoor activity and exercise that may affect asthma control.

Rhinitis, sinusitis (acute or chronic), and gastroesophageal reflux are all comorbid conditions that may increase asthma symptoms. In refractory or difficult-to-control patients, investigation into the potential for one of these conditions as “silent contributor” is warranted. Heart disease, too, can contribute to breathlessness in patients and compromise pulmonary function. Patients receiving medications that provide beta-agonist blockade may experience an increase in airway hyperresponsiveness, smooth muscle contraction with bronchoconstriction, and asthma symptoms. Increased body mass index or obesity is associated with heightened prevalence of asthma. While proinflammatory mechanisms are yet to be fully uncovered, weight reduction is associated with improvement in asthma symptom control. Lastly, while asthma is not a psychological or psychosomatic illness, stress is also associated with symptom exacerbation.

Asthma Medications

Medications used to treat asthma are classified as controllers or relievers. Controllers are taken daily on a long-term basis to keep asthma under clinical control mostly via their anti-inflammatory effects. They include inhaled glucocorticosteroids, leukotriene modifiers, cromones, long-acting β₂-agonists, sustained-release theophylline, and, as last resort, systemic glucocorticosteroids. Relievers are used on an as-needed basis to quickly reverse bronchoconstriction and its clinical effects. These medications include rapid-acting β₂-agonists, rapid-acting inhaled anticholinergics, and less commonly, short-acting theophylline or short-acting oral β₂-agonists.

Inhaled corticosteroids are the most effective asthma controller therapy. Their mechanism of action is via control or reduction of airway inflammation with demonstrated efficacy in reducing asthma symptoms, improving quality of life, improving lung function, decreasing airway hyperresponsiveness, reducing frequency and severity of exacerbations, and reducing asthma mortality. Despite their superiority, inhaled steroids are not a cure and up to 30% of asthma patients may have suboptimal response to therapy, and understanding controller treatment options is a critical component of the clinician’s asthma management. Inhaled steroids differ in potency and bioavailability, however lower doses are preferred given their relatively flat dose–response relationship and the desire to minimize potential medication side effect. Relative potencies of the inhaled corticosteroids are displayed in Table 5.3 for adults and in Table 5.4 for children.

TABLE 5.3 Estimated equipotent inhaled steroid dosing in adults^a (GINA 2006)⁶

TABLE 5.4 Estimated equipotent inhaled steroid dosing in children^a (GINA 2006)⁶

Local adverse effects from inhaled steroids include oropharyngeal candidiasis, dysphonia, and occasionally coughing from upper airway irritation. For pressurized MDIs the prevalence of these effects may be reduced by using certain spacer devices.

Mouth washing (rinsing with water, gargling, and spitting out) after inhalation may reduce oral candidiasis. The use of prodrugs that are activated in the lungs but not in the pharynx (e.g., ciclesonide), and new formulations and devices that reduce oropharyngeal deposition, may minimize such effects without the need for a spacer or mouth washing.

Inhaled glucocorticosteroids are absorbed from the lung, accounting for some degree of systemic bioavailability. The risk of systemic adverse effects from an inhaled steroid depends upon its dose and potency, the delivery system, systemic bioavailability, first-pass metabolism (conversion to inactive metabolites) in the liver, and half-life of the fraction of systemically absorbed drug (from the lung and possibly gut). Therefore, the systemic effects differ among the various inhaled steroids. Several comparative studies have demonstrated that ciclesonide, budesonide, and fluticasone propionate at equipotent doses have less systemic effect. Current evidence suggests that in adults, systemic effects of inhaled glucocorticosteroids are not a problem at doses of 400 μg or less budesonide or equivalent daily.

The systemic side effects of long-term treatment with high doses of inhaled corticosteroids include easy bruising, adrenal suppression, and decreased bone mineral density. Inhaled steroids are associated with cataracts and glaucoma in cross-sectional studies, but there is no evidence of posterior-subcapsular cataracts in prospective studies. One difficulty in establishing the clinical significance of such adverse effects lies in dissociating the effect of high dose inhaled glucocorticosteroids from the effect of courses of oral glucocorticosteroids taken by patients with severe asthma. There is no evidence that use of inhaled steroids increases the risk of pulmonary infections, including tuberculosis, and inhaled glucocorticosteroids are not contraindicated in patients with active tuberculosis.

Though differences exist between the various inhaled steroids and inhaler devices, treatment with inhaled steroid doses of less than 200 μg budesonide or equivalent daily is normally not associated with any significant suppression of the HPA axis in children. At higher doses, small changes in HPA axis function can be detected with sensitive methods. The clinical relevance of these findings is not known, since there have not been reports of adrenal crisis in clinical trials of inhaled steroids in children. However, adrenal crisis has been reported in children treated with excessively high doses of inhaled steroids.

Low doses of inhaled steroids given chronically during childhood do not affect final adult height while uncontrolled asthma does. At higher doses, children aged 4–10 years seem most susceptible to the systemic growth effects of inhaled steroids

Leukotriene modifiers include cysteinyl leukotriene (CysLT1) receptor antagonists (montelukast, pranlukast, and zafirlukast) and a 5-lipoxygenase inhibitor (zileuton). Clinical studies have demonstrated that leukotriene modifiers have a small and variable bronchodilator effect, reduce symptoms including cough, improve lung function, and reduce airway inflammation and asthma exacerbations. They may be used as an alternative treatment for adult or pediatric patients with mild persistent asthma, and some patients with aspirin-sensitive asthma respond well to leukotriene modifiers. However, when used alone as controller, the effect of leukotriene modifiers are generally less than that of low doses of inhaled glucocorticosteroids, and, in patients already on inhaled glucocorticosteroids, leukotriene modifiers cannot substitute for this treatment unless reduction of inflammatory control is desired. 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.

Long-acting β₂-agonists, including salmeterol and formoterol, do not influence inflammation control of asthma and therefore should not be used as monotherapy in asthma management. Addition of long-acting β₂-agonists to a daily regimen of inhaled steroids improves symptom scores, decreases nocturnal asthma, improves lung function, decreases the use of rapid-acting inhaled β₂-agonists, reduces the number of exacerbations, and achieves clinical control of asthma in more patients, more rapidly, and at a lower dose of inhaled steroids than inhaled glucocorticosteroids given alone.

The regular use of β₂-agonists in both short- and long-acting forms may lead to relative refractoriness to β₂-agonists. Data indicating a possible increased risk of asthma-related death associated with the use of salmeterol led to advisories from the US Food and Drug Administration (FDA) and Health Canada that long-acting β₂-agonists are not a substitute for first-line anti-inflammatory therapy, and should only be used in combination with an appropriate dose of inhaled steroid as determined by a physician. A study has identified that the asthma of subjects with an unusual genotype for the β-adrenergic receptor (with substitution of arginine for glycine at position B-16) may deteriorate with regular use of salmeterol whether or not administered with inhaled steroids.

Theophylline is a bronchodilator and, when given in a lower dose, has modest anti-inflammatory properties. It is available in sustained-release formulations that are suitable for once- or twice-daily dosing. Data on the relative efficacy of theophylline as a long-term controller is lacking. However, available evidence suggests that sustained-release theophylline has little effect as a first-line controller. It may provide benefit as add-on therapy in patients who do not achieve control on inhaled glucocorticosteroids alone. Additionally in such patients the withdrawal of sustained-release theophylline has been associated with deterioration of control. As add-on therapy, theophylline is less effective than long-acting inhaled β₂-agonists.

An algorithm for asthma management based on control, based on principles drawn from the 2006 GINA guidelines, is shown in Figure 5.4.⁶

Figure 5.4 Asthma management based on control (GINA 2006).⁶

When asthma control has been achieved, ongoing monitoring is essential to maintain control and to establish the lowest step and dose of treatment necessary, which minimizes the cost and maximizes the safety of treatment. On the other hand, asthma is a variable disease, and treatment has to be adjusted periodically in response to loss of control as indicated by worsening symptoms or the development of an exacerbation.

Asthma control should be monitored by the health care professional and also by the patient at regular intervals, using either a simplified scheme or a validated composite measure of control. The frequency of health care visits and assessments depends upon the patient’s initial clinical severity, and the patient’s training and confidence in playing a role in the ongoing control of his or her asthma. Typically, patients are seen 1–3 months after the initial visit, and every 3 months thereafter. After an exacerbation, follow-up should be offered within 2 weeks to 1 month.

Conclusion

Asthma is a common chronic disease that continues to have significant morbidity and mortality around the world, despite the presence of effective treatment modalities that can effect control in the majority of patients. An appreciation of the inflammatory nature of asthma is essential in guiding the clinician to apply appropriate therapeutic options to effectively treat the disease. Through the use of an assessment of the completeness of control of the patient’s asthma, dynamic interventions can be instituted in order to keep patient symptoms to a minimum and to maximize patient quality of life. The use of guidelines-based treatment is important in assisting physicians and their patients to achieve maximal levels of disease control.