An expert panel of the National Institutes of Health, the National Asthma Education and Prevention Program (NAEPP), has provided the following working definition 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, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli.
Because asthma is a heterogeneous disease triggered by a variety of inciting agents, there is no universally accepted simple classification. Nevertheless, it is customary to classify asthma into two major categories based on the presence or absence of an underlying immune disorder:
1. Extrinsic asthma, in which the asthmatic episode is typically initiated by a type I hypersensitivity reaction induced by exposure to an extrinsic antigen. Three types of extrinsic asthma are recognized: atopic asthma, occupational asthma (many forms), and allergic bronchopulmonary aspergillosis (bronchial colonization with Aspergillus organisms followed by development of immunoglobulin E [IgE] antibodies). Atopic asthma is the most common type of asthma; its onset is usually in the first two decades of life, and it is commonly associated with other allergic manifestations in the patient as well as in other family members. Serum IgE levels are usually elevated, as is the blood eosinophil count. This form of asthma is believed to be driven by the TH2 subset of CD4+ T cells.
2. Intrinsic asthma, in which the triggering mechanisms are nonimmune. In this form, a number of stimuli that have little or no effect in normal subjects can trigger bronchospasm. Such factors include aspirin; pulmonary infections, especially those caused by viruses; cold; psychological stress; exercise; and inhaled irritants such as ozone and sulfur dioxide. There is usually no personal or family history of allergic manifestations, and serum IgE levels are normal. These patients are said to have an asthmatic diathesis.
Asthma is at least a partially heritable complex syndrome that requires a gene-by-environment interaction for phenotypic expression. Epidemiologic studies strongly support the concept of a genetic predisposition to the development of asthma.10 Genetic factors account for 35% to 70% of the susceptibility.
List of Agents and Events Triggering Asthma
Respiratory syncytial virus (RSV), rhinovirus, influenza,
parainfluenza, Mycoplasma pneumonia
Airbone pollens (grass, trees, weeds), house-dust mites, animal
danders, cockroaches, fungal spores
Cold air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke,
Anxiety, stress, laughter
Particularly in cold, dry climate
Aspirin, NSAIDs (cyclooxygenase inhibitors), sulfites, benzalkonium
Bakers (flour dust); farmers (hay mold); spice and enzyme workers; printers (arabic gum); chemical workers (azo dyes, anthraquinone, ethylenediamine, toluene diisocyanates, polyvinyl chloride); plastics, rubber, and wood workers (formaldehyde, western cedar, dimethylethanolamine, anhydrides)
Inhaled allergen challenge models contribute most to our understanding of acute inflammation in asthma.14 Inhaled allergen challenge in allergic patients leads to an early-phase allergic reaction that, in some cases, may be followed by a late-phase reaction. The activation of cells bearing allergen-specific IgE initiates the early-phase reaction. It is characterized primarily by the rapid activation of airway mast cells and macrophages. The activated cells rapidly release proinflammatory mediators such as histamine, eicosanoids, and reactive oxygen species that induce contraction of airway smooth muscle, mucus secretion, and vasodilatation.14 The bronchial microcirculation has an essential role in this inflammatory process. Inflammatory mediators induce microvascular leakage with exudation of plasma in the airways.14 Acute plasma protein leakage induces a thickened, engorged, and edematous airway wall and a consequent narrowing of the airway lumen. Plasma exudation may compromise epitheepithelial integrity, and the presence of plasma in the lumen may reduce mucus clearance.14 Plasma proteins also may promote the formation of exudative plugs mixed with mucus and inflammatory and epithelial cells. Together these effects contribute to airflow obstruction. The late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation and involves the recruitment and activation of eosinophils, CD4+ T cells, basophils, neutrophils, and macrophages. 14 There is selective retention of airway T cells, the expression of adhesion molecules, and the release of selected proinflammatory mediators and cytokines involved in the recruitment and activation of inflammatory cells.14 The activation of T cells after allergen challenge leads to the release of T-helper cell type 2 (Th2)–like cytokines that may be a key mechanism of the late-phase response.14 The release of preformed cytokines by mast cells is the likely initial trigger for the early recruitment of cells. This cell type may recruit and induce the more persistent involvement by T cells.14 The enhancement of nonspecific BHR usually can be demonstrated after the late-phase reaction but not after the early-phase reaction following allergen or occupational challenge.
In asthma, all cells of the airways are involved and become activated. Included are eosinophils, T cells, mast cells,
macrophages, epithelial cells, fibroblasts, and bronchial smooth muscle cells.
Bronchial epithelial cells traditionally have been considered as a barrier, participating in mucociliary clearance and removal of noxious agents. However, epithelial cells also participate in inflammation by the release of eicosanoids, peptidases, matrix proteins, cytokines, and nitric oxide (NO). Epithelial cells can be activated by IgE-dependent mechanisms, viruses, pollutants, or histamines. In asthma, especially fatal asthma, extensive epithelial shedding occurs. The functional consequences of epithelial shedding may include heightened airways responsiveness, altered permeability of the airway mucosa, depletion
of epithelial-derived relaxant factors, and loss of enzymes responsible for degrading proinflammatory neuropeptides.
Eosinophils play an effector role in asthma by release of proinflammatory mediators, cytotoxic mediators, and cytokines.15 Circulating eosinophils migrate to the airways by cell rolling, through interactions with selectins, and eventually adhere to the endothelium through the binding of integrins to adhesion proteins (vascular cell adhesion molecule 1 [VCAM–1] and intercellular adhesion molecule 1 [ICAM–1]). As eosinophils enter the matrix of the membrane, their survival is prolonged by interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). On activation, eosinophils release inflammatory mediators such as leukotrienes and granule proteins to injure airway tissue.
Mucosal biopsy specimens from patients with asthma contain lymphocytes, many of which express surface markers of inflammation. There are two types of T-helper CD4+ cells. Type 1 T-helper (Th1) cells produce IL-2 and interferon-γ (IFN-γ ), both essential for cellular defense mechanisms. Th2 cells produce cytokines (IL-4, -5, -6, -9, and -13) that mediate allergic inflammation. It is known that Th1 cytokines inhibit the production of Th2 cytokines, and vice versa.
Mast cell degranulation is important in the initiation of immediate responses following exposure to allergens.2 Mast cells are found throughout the walls of the respiratory tract, and increased numbers of these cells (three- to fivefold) have been described in the airways of asthmatics with an allergic component. Once binding of allergen to cell-bound IgE occurs, mediators such as histamine; eosinophil and neutrophil chemotactic factors; leukotrienes C4, D4, and E4; prostaglandins; platelet-activating factor; and others are released from mast cells.
The primary function of alveolar macrophages in the normal airway is to serve as “scavengers,” engulfing and digesting bacteria and other foreign materials. They are found in large and small airways, ideally located for affecting the asthmatic response.
FIBROBLASTS AND MYOFIBROBLASTS
Fibroblasts are found frequently in connective tissue. Human lung fibroblasts may behave as inflammatory cells on activation by IL-4 and IL-13. The myofibroblast may contribute to the regulation of inflammation via the release of cytokines and to tissue remodeling.
An important step in the inflammatory process is the adhesion of the various cells to each other and the tissue matrix to facilitate infiltration and migration of these cells to the site of inflammation. To promote this, cell membranes express a number of glycoproteins, or adhesion molecules. Adhesion molecules have additional functions involved in the inflammatory process aside from promoting cell adhesion, including activation of cells and cell-cell communication, and promoting cellular migration and infiltration.
REMODELING OF THE AIRWAYS
Acute inflammation is a beneficial, nonspecific response of tissues to injury and generally leads to repair and restoration of the normal structure and function. In contrast, asthma represents a chronic inflammatory process of the airways followed by healing. The end result may be an altered structure referred to as a remodeling of the airways.16 Repair involves replacement of injured tissue by parenchymal cells of the same type and replacement by connective tissue and its maturation into scar tissue. In asthma, the repair process can be followed by complete or altered restitution of airways structure and function, presenting as fibrosis and an increase in smooth muscle and mucus gland mass.
The mucociliary system is the lung’s primary defense mechanism against irritants and infectious agents. Mucus, composed of95%water and 5% glycoproteins, is produced by bronchial epithelial glands and goblet cells.7 The lining of the airways consists of a continuous aqueous layer controlled by active ion transport across the epithelium in which water moves toward the lumen along the concentration gradient. Catecholamines and vagal stimulation enhance the ion transport and fluid movement. Mucus transport depends on the viscoelastic properties of the mucus. Mucus that is either too watery or too viscous will not be transported optimally. The exudative inflammatory process and sloughing of epithelial cells into the airway lumen impair
mucociliary transport. The bronchial glands are increased in size and the goblet cells are increased in size and number in asthma. Expectorated mucus from patients with asthma tends to have a high viscosity.
C L I N I C A L PRESENTATION
CHRONIC AMBULATORY ASTHMA
Asthma is a disease of exacerbation and remission, so the patient may not have any signs or symptoms at the time of exam.
The patient may complain of episodes of dyspnea, chest tightness, coughing (particularly at night), wheezing, or a whistling sound when breathing. These often occur in association with exercise, but also occur spontaneously or in association with known allergens.
Expiratory wheezing on auscultation, dry hacking cough, or signs of atopy (allergic rhinitis and/or eczema) may occur.
Spirometry demonstrates obstruction (FEV1/FVC less than 80%) with reversibility following inhaled β2-agonist administration (at least a 12% improvement in FEV1).
OTHER DIAGNOSTIC TESTS
A fall in FEV1 of at least 20% following 6 minutes of near maximal exercise. Elevated eosinophil count and lgE concentration in blood. Elevated FeNO (greater than 12ppb). Positive methacholine challenge (PC20 FEV1 less than 12.5 mg/mL).