- • Cough, shortness of breath, wheezing, and chest
discomfort, often in association with triggering factors.
- • Wheezing, diminished breath sounds, hyperinflated
lung fields, hyperresonance to percussion; examination can be normal.
- • Variable degrees of airflow limitation, improvement
in airflow following bronchodilator therapy, airtrapping, and airways
Asthma is a chronic inflammatory condition of the lungs. It has
no known distinct etiology, and there are many different clinical
manifestations, making asthma a syndrome rather than a specific disease.
Asthma affects approximately 7% of the U.S. population,
both adults and children, resulting in 17 million people with asthma
in the United States, and over 100 million worldwide. The socioeconomic
burden of asthma is high, with over 11 billion dollars spent in
total costs in 1998, including billions of dollars in indirect costs
from lost productivity. The prevalence of asthma is increasing worldwide,
having risen approximately 75% over the years 1980–1994
in the United States. The reasons for this increase are likely due,
in part, to increased exposure of susceptible individuals to indoor
air pollutants or allergens, and perhaps also to a changing microbiological environment
that impacts immune system development. The National Institutes
of Health (NIH) and World Health Organization (WHO) have issued
disease management guidelines to assist in the consistent diagnosis
and treatment of asthma, but dissemination of these guidelines to
the medical community is incomplete.
The inflammation involved in asthma extends throughout the respiratory
tree (Figure 6–1). The clinical manifestations
of asthma are a consequence of the effects of this inflammation
on the airways and surrounding lung parenchyma, resulting in airway
narrowing, airflow limitation, and alterations in lung mechanics.
Overview of asthma pathophysiology. A: Biology.
The biology of asthma involves the release of mediators, cytokines,
and other signals from activated inflammatory cells, resulting in
airway smooth muscle constriction, pulmonary vascular dilation and
leakage, and mucous gland secretion. Over time, these processes
result in airway remodeling. Macs, macrophages; eos, eosinophils;
pmns, polymorphonuclear leukocytes; lymphs, lymphocytes; TH1, TH2,
T-helper cell type 1, 2. See text for details. B: Anatomy.
Airway remodeling is seen by airway wall thickening from inflammatory
cell infiltration, airway edema, increased mucus secretion, subepithelial
fibrosis and increased smooth muscle mass. In addition, there may
be a loss of the linkage between the airway wall and surrounding tethering
elements of the alveoli. C: Physiology.
The physiological effects of the narrowed, thickened airways are
airflow limitation and gas trapping, resulting in hyperinflation. D: Symptoms. The symptoms arising
from these underlying pathophysiological changes include wheezing,
cough, dyspnea, and chest discomfort.
Many patients with asthma exhibit a two-phase response when exposed
to allergen, and this response pattern serves as a useful paradigm
to characterize the inflammatory events that are thought to occur.
Initially, upon exposure to a sensitizing stimulus in a susceptible
individual, mast cells and epithelial cells within the airway are
activated and release histamine, leukotrienes, tryptase, and other
mediators, which together cause airway smooth muscle constriction,
vasodilation, airway edema, and mucus secretion. These events lead
to acute wheezing, cough, and shortness of breath from airway narrowing
and edema. This is the so-called early asthmatic response that typically
occurs within minutes of exposure, and lasts approximately 1 h.
The early asthmatic response is best treated with β-agonists
that relax airway smooth muscle, and may be prevented by pretreatment
with β-agonists, antileukotrienes, and nedocromil
or cromolyn. Steroid treatment does not appear to substantially
affect this early phase.
Leukotrienes, cytokines, and growth factors released by mast
cells, as well as other mediators, may then initiate a cascade of
inflammation by calling additional cells into the airway, such as eosinophils,
T-lymphocytes, and neutrophils. These cells are then activated to
release further chemokines, cytokines, and other mediators, resulting
in additional inflammatory cell recruitment and further airway smooth
muscle constriction, airway edema, and mucus secretion. A specific type
of T-lymphocyte, the TH2 helper cell, appears to be more common
in asthma based on the pattern of cytokines [interleukin
(IL)-4, 5, 9, and 13, granulocyte-macrophage colony-stimulating factor
(GM-CSF)] found in the syndrome. This TH2 phenotype is
involved in allergic inflammation and defense against parasites,
whereas the TH1-type cell (associated with interferon-γ and
IL-12) is involved in antibody-mediated immunity in response to
viruses and bacteria. A shift of TH1 to TH2 cells appears to be
an important component of allergic airway inflammation, and may
result from a skewing of immune responses that occurs early in life.
In individuals exposed to orofecal infections, mycobacteria, and
other organisms, a TH1-predominant phenotype results, and allergic
asthma is less prevalent. In environments such as those associated
with enhanced hygiene, where there are fewer exposures to infectious
organisms and more widespread use of antibiotics, TH1 responses
are less prevalent and a TH2-type immune response may become more important.
This is the basis of the so-called “hygiene hypothesis” of
asthma, which attempts to explain this skewed TH2 response and subsequent
increased propensity to development of allergic airway inflammation.
However, this paradigm of TH2 predominance in asthma cannot fully explain
all of the pathogenesis of asthma, because, among other reasons,
asthma and allergies need not coexist.
Because of the influx of inflammatory cells that results following
the early response, a second wave of inflammation becomes clinically
manifest 4–6 h after the initial exposure. At this time, the
patient may develop repeated or worsening shortness of breath, cough,
or wheezing. This second wave of symptoms is called the late asthmatic
response, and can be demonstrated in about 50% of individuals
with asthma. The events of the late asthmatic response are thought
to be similar to those that occur on a chronic basis in all patients
with persistent asthma symptoms. These events include additional
inflammatory cell recruitment and activation, with ongoing airway inflammation
and bronchoconstriction. Steroid treatment is the mainstay of therapy
for this ongoing inflammatory phase, although long-acting ...