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.
ETIOLOGY:-
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
infection
Respiratory
syncytial virus (RSV), rhinovirus, influenza,
parainfluenza,
Mycoplasma pneumonia
Allergens
Airbone
pollens (grass, trees, weeds), house-dust mites, animal
danders,
cockroaches, fungal spores
Environment
Cold
air, fog, ozone, sulfur dioxide, nitrogen dioxide, tobacco smoke,
wood
smoke
Emotions
Anxiety,
stress, laughter
Exercise
Particularly
in cold, dry climate
Drugs/preservatives
Aspirin,
NSAIDs (cyclooxygenase inhibitors), sulfites, benzalkonium
chloride,
β-blockers
Occupational
stimuli:
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)
PATHOPHYSIOLOGY:-
ACUTE
INFLAMMATION
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.
CHRONIC
INFLAMMATION
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.
EPITHELIAL
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
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.
LYMPHOCYTES
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
CELLS
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.
ALVEOLAR
MACROPHAGES
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.
ADHESION
MOLECULES
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.
MUCUS
PRODUCTION
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
GENERAL
Asthma
is a disease of exacerbation and remission, so the patient may not have any
signs or symptoms at the time of exam.
SYMPTOMS
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.
SIGNS
Expiratory
wheezing on auscultation, dry hacking cough, or signs of atopy (allergic
rhinitis and/or eczema) may occur.
LABORATORY
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).
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