Definition and Key Features of Asthma

Asthma is derived from the Greek word aazein, meaning “to labor in breathing” and was first used by Hippocrates, in 450 BCE, to describe a condition characterized by spasms of breathlessness. The present Global Initiative for Asthma (GINA) definition of the disease (Box 39-1) is a lengthy description of histopathologic, pathophysiologic, and clinical features that encompass the major disease characteristics. Fundamental features are airway hyperresponsiveness, chronic airway inflammation, disordered airway mucosal immunity, and structural changes to the airways (airway remodeling).

Box 39-1

Global Initiative for Asthma (GINA) Description of Asthma

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread airflow obstruction that is typically reversible either spontaneously or with treatment.

From Global Strategy for Asthma Management and Prevention (Update 2009). Available at www.ginaaasthma.org.

Airway Hyperresponsiveness

Airway hyperresponsiveness is considered to be the cardinal pathophysiologic abnormality in asthma. It represents an exaggerated bronchoconstrictor response to a variety of largely exogenous inhaled stimuli causing bronchoconstriction, either by a direct effect on airway smooth muscle or indirectly by interacting with neural pathways or mast cells. Airway hyperresponsiveness is likely to be the basis for the variable airflow obstruction that is responsible for many of the day-to-day symptoms of asthma, including those associated with exercise-induced asthma, nocturnal asthma, and asthma induced by fumes or cold air.

Airway hyperresponsiveness can be objectively demonstrated as a 20% fall in the forced expiratory volume in 1 second (FEV₁) after inhalation of histamine or methacholine) at a concentration below 8 mg/mL. This represents an abnormal effector response of airway smooth muscle, characterized by heightened pharmacologic sensitivity and reactivity to the bronchoconstrictor stimulus (Figure 39-1). Naturally occurring airway hyperresponsiveness reflects an abnormally amplified response of airway nerves and mast cells to exogenous stimuli, as well as an intrinsic abnormality of the airway smooth muscle response. The basis for this generalized hyperresponsiveness is not entirely clear, but sensitization of airway nerves, mast cells, and smooth muscle by inflammatory mediators, along with loss of epithelial barrier function, reduced production of bronchoprotective factors, an intrinsic abnormality of airway smooth muscle, and structural changes to the airway, all are likely to play a part (Figure 39-2). One key pathologic feature associated with airway hyperresponsiveness in asthma not seen in nonasthmatic eosinophilic bronchitis is infiltration of the bronchial smooth muscle layer by mast cells, implying that the interaction between these cells is fundamentally important in the pathogenesis of airway hyperresponsiveness.

Figure 39-1 Airway responsiveness measured as the fall in forced expiratory volume in 1 second (FEV₁) after increasing inhaled concentrations of methacholine. Severe (yellow), moderate (green), and mild (blue) airway hyperresponsiveness are shown. Note increased airway responsiveness is associated with a lower provocative concentration required to cause a 20% fall in FEV₁ (PC₂₀) (see green line), a steeper gradient, and a higher maximum % fall in FEV₁.

Figure 39-2 Schematic diagram of the inflammatory and remodeling processes in the airway that may potentially contribute to airway hyperresponsiveness and airflow obstruction.

(Courtesy Professor Mark Inman.)

Chronic Airway Inflammation

Histopathologic examination of postmortem specimens from patients with fatal asthma show an inflammatory response characterized in many cases by the presence of airway eosinophilia. Typically, eosinophilic infiltration can be found throughout the airway wall, within thick viscid plugs that occlude the airway lumen and often extend into the lung parenchyma and alveolar spaces and even into adjacent blood vessels (see Figure 39-2). In addition, extensive eosinophilic degranulation with deposition of major basic proteins occurs. Associated findings include widespread shedding of the airway surface epithelium, thickening of the reticular basement membrane, and enlargement of airway smooth muscle and submucosal glands. A minority of patients dying from asthma, particularly those with sudden-onset fatal asthma, exhibit evidence of eosinophilic inflammation. In these cases it is believed that widespread mast cell degranulation is the primary event with evidence for a relative excess of neutrophils in the distal airways and parenchyma.

Bronchoscopy and bronchial biopsy studies in patients with mild asthma show similar although less dramatic changes. Eosinophil numbers are increased in bronchial biopsy specimens and bronchoalveolar lavage (BAL) fluid, and the eosinophils are activated, with increased concentrations of major basic proteins and leukotrienes found in BAL fluid. Endobronchial biopsy specimens also show increased numbers of CD4⁺ T cells of T_H2 type, producing the interleukins IL-4, IL-5, and IL-13. These cytokines increase production of IgE and play an important role in the maintenance of eosinophilic airway inflammation.

The limited number of patients studied by bronchoscopy makes it difficult to investigate heterogeneity of the lower airway inflammatory response, but less invasive assessment of airway inflammation using induced sputum analysis has shown that a significant proportion of patients with asthma studied when stable and during an attack have normal eosinophil numbers in induced sputum samples. This sputum cell profile has been reported in patients with severe asthma and in patients who are not treated with inhaled corticosteroids, and the absence of eosinophilic airway inflammation has been confirmed by bronchoscopy studies. Thus, the presence of a distinct noneosinophilic corticosteroid-resistant asthma phenotype across the range of asthma severity seems secure. Noneosinophilic asthma is discussed in more detail later in the chapter.

Disordered Airway Mucosal Immunity

The airway mucosa in persons with asthma mounts an abnormally amplified immunologic response to a variety of exogenous stimuli, including inhaled allergens, cigarette smoke, infectious agents, and air pollutants. Some or all of these abnormal responses may be the consequence of failure of maturation of the immune response in early life as a result of reduced exposure to pathogens at a critical point in development.

Particular interest has focused in the response to allergen, because atopy is twice as common in patients with asthma as in control subjects without asthma, and inhalation of allergen in a patient with atopic asthma who is sensitized to the allergen results in a marked eosinophilic airway inflammatory response, developing 4 to 6 hours after inhalation associated with airflow obstruction (the late response) and increased airway responsiveness lasting for days and weeks. Common aeroallergens in many Westernized countries include house dust mite, cat fur, grass pollen, ragweed, and Aspergillus fumigatus spores. Most patients with childhood-onset asthma are sensitized to one of more of these allergens, and many have extrapulmonary manifestations of allergy, including eczema and allergic rhinitis. Opinions regarding the significance of the response to allergen vary, ranging from a fundamentally important role in the pathogenesis of airway inflammation and dysfunction in asthma to a position in which it is seen as a more peripheral mechanism. The occurrence of histopathologically similar forms of asthma in nonatopic patients and the disappointing therapeutic effect of allergen avoidance and anti-IgE treatment suggest that the latter position is correct, although uncertainty remains.

Growing evidence points to an abnormal airway response to infecting respiratory viruses, resulting in an amplified airway inflammatory response and more pronounced clinical consequences. The molecular mechanisms of this remain uncertain but constitute an active area of current study. There is little doubt that viral infection is an important trigger for acute severe asthma. Smoking and perhaps exposure to other environmental pollutants have been linked to worsening of symptoms, an increased risk of asthma attacks, and the development of fixed airflow obstruction. This association may reflect an abnormality of the innate immune response; patients with asthma who smoke or are exposed to environmental pollutants tend to have noneosinophilic, neutrophilic airway inflammation.

Structural Changes to the Airway

Structural changes in airway morphology (airway remodeling) probably occur as a result of chronic airway inflammation and dysfunction. These changes are likely to be the basis for the accelerated lung function decline and fixed airflow obstruction seen in some patients with asthma. Key features of airway remodeling include thickening of the subepithelial basement membrane caused by abnormal deposition of collagen, increased airway smooth muscle bulk, increased mucus-secreting cells, and increased airway vascularity (see Figure 39-2). In severe asthma, bronchiectasis, small airway fibrosis, and emphysema may be features. The bronchiectasis is associated with sensitization to Aspergillus.

Pathophysiologic Basis of Asthma

Asthma is a complex condition in which it is not always obvious which of the various pathophysiologic abnormalities is responsible for morbidity at any one time. In order to make some sense of this complexity, it can be helpful to consider five potentially important pathophysiologic factors, presented in alphabetical array for convenience:

• Airway hyperresponsiveness

• Bronchitis

• Cough reflex hypersensitivity

• Damage to the airways and surrounding lung

• Extrapulmonary factors.

These abnormalities are likely to be linked, but the mechanism is complex, and cross-sectional and longitudinal correspondence among them is not close. Accordingly, each is best considered as a relatively independent factor.

It is likely that these factors contribute to airflow obstruction and morbidity in different ways (Figure 39-3). Airway hyperresponsiveness is responsible for short-term, bronchodilator-responsive variable airflow obstruction which is the basis for many of the day-to-day symptoms experienced by patients and is suppressed by bronchodilator therapy, and to a lesser extent corticosteroids. Bronchitis, which may be eosinophilic and corticosteroid-responsive or neutrophilic and corticosteroid-unresponsive, manifests with cough and sputum and a relatively bronchodilator-resistant but potentially corticosteroid-responsive airflow obstruction of more gradual onset. Inflammation-mediated airflow obstruction is particularly important in the pathogenesis of asthma attacks. Cough and a small amount of sputum production is common in asthma. It probably reflects airway inflammation but also may be due to cough reflex hypersensitivity, a common but poorly understood and difficult-to-treat aspect of asthma and other airway diseases. Airway damage may manifest with disability caused by bronchodilator and corticosteroid-resistant airflow obstruction or mucus retention and infection as a result of airway and lung parenchymal damage. Extrapulmonary conditions linked to the inflammatory airway disease or independent of it also may contribute to symptoms (Box 39-2).