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

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