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Asthma is a disease of the
human respiratory system in which the airways narrow, often
in response to a "trigger" such as exposure to an allergen,
cold air, exercise, or emotional stress. This narrowing
causes symptoms such as wheezing, shortness of breath, chest
tightness, and coughing, which are the hallmarks of asthma.
Between episodes, most patients feel fine.
The disorder is a chronic inflammatory condition in which
the airways develop increased responsiveness to various
stimuli, characterized by bronchial hyper-responsiveness,
inflammation, increased mucus production, and intermittent
airway obstruction. The symptoms of asthma, which can range
from mild to life threatening, can usually be controlled
with a combination of drugs and lifestyle changes.
Public attention in the developed world has recently focused
on asthma because of its rapidly increasing prevalence,
affecting up to one in four urban children. Susceptibility
to asthma can be explained in part by genetic factors, but
no clear pattern of inheritance has been found. Asthma is a
complex disease that is influenced by multiple genetic,
developmental, and environmental factors, which interact to
produce the overall condition.History
The word asthma is derived
from the Greek aazein, meaning "sharp breath." The word
first appears in Homer's Iliad; Hippocrates was the first to
use it in reference to the medical condition. Hippocrates
thought that the spasms associated with asthma were more
likely to occur in tailors, anglers, and metalworkers. Six
centuries later, Galen wrote much about asthma, noting that
it was caused by partial or complete bronchial obstruction.
Moses Maimonides, an influential medieval rabbi,
philosopher, and physician, wrote a treatise on asthma,
describing its prevention, diagnosis, and treatment. In the
17th century, Bernardino Ramazzini noted a connection
between asthma and organic dust. The use of bronchodilators
started in 1901, but it was not until the 1960s that the
inflammatory component of asthma was recognized, and
anti-inflammatory medications were added to the regimen.
Signs and symptoms
An acute exacerbation of
asthma is referred to colloquially as an asthma attack. The
clinical hallmarks of an attack are shortness of breath (dyspnea)
and wheezing, the latter "often being regarded as the sine
qua non." A cough—sometimes producing clear sputum—may also
be present. The onset is often sudden; there is a "sense of
constriction" in the chest, breathing becomes difficult, and
wheezing occurs (primarily upon expiration, but can be in
both respiratory phases).
Signs of an asthmatic episode are wheezing, rapid breathing
(tachypnea), prolonged expiration, a rapid heart rate
(tachycardia), rhonchous lung sounds (audible through a
stethoscope), and over-inflation of the chest. During a
serious asthma attack, the accessory muscles of respiration
(sternocleidomastoid and scalene muscles of the neck) may be
used, shown as in-drawing of tissues between the ribs and
above the sternum and clavicles, and the presence of a
paradoxical pulse (a pulse that is weaker during inhalation
and stronger during exhalation). During very severe attacks,
an asthma sufferer can turn blue from lack of oxygen, and
can experience chest pain or even loss of consciousness.
Severe asthma attacks may lead to respiratory arrest and
death. Despite the severity of symptoms during an asthmatic
episode, between attacks an asthmatic may show few signs of
the disease.
Diagnosis
In most cases, a physician
can diagnose asthma on the basis of typical findings in a
patient's clinical history and examination. Asthma is
strongly suspected if a patient suffers from eczema or other
allergic conditions—suggesting a general atopic
constitution—or has a family history of asthma. While
measurement of airway function is possible for adults, most
new cases are diagnosed in children who are unable to
perform such tests. Diagnosis in children is based on a
careful compilation and analysis of the patient's medical
history and subsequent improvement with an inhaled
bronchodilator medication. In adults, diagnosis can be made
with a peak flow meter (which tests airway restriction),
looking at both the diurnal variation and any reversibility
following inhaled bronchodilator medication.
Testing peak flow at rest (or baseline) and after exercise
can be helpful, especially in young asthmatics who may
experience only exercise-induced asthma. If the diagnosis is
in doubt, a more formal lung function test may be conducted.
Once a diagnosis of asthma is made, a patient can use peak
flow meter testing to monitor the severity of the disease.
Differential diagnosis
Before
diagnosing someone as asthmatic, alternative possibilities
should be considered. A physician taking a history should
check whether the patient is using any known
bronchoconstrictors (substances that cause narrowing of the
airways, e.g., certain anti-inflammatory agents or
beta-blockers).
Chronic obstructive pulmonary disease, which closely
resembles asthma, is correlated with more exposure to
cigarette smoke, an older patient, less symptom
reversibility after bronchodilator administration (as
measured by spirometry), and decreased likelihood of family
history of atopy.
Aspiration, whether direct due to dysphagia (swallowing
disorder) or indirect (due to acid reflux), can show similar
symptoms to asthma. However, with aspiration, fevers might
also indicate aspiration pneumonia. Direct aspiration (dysphagia)
can be diagnosed by performing a Modified Barium Swallow
test and treated with feeding therapy by a qualified speech
therapist. If the aspiration is indirect (from acid reflux)
then treatment directed at this is indicated.
Only a minority of asthma sufferers have an identifiable
allergy trigger. The majority of these triggers can often be
identified from the history; for instance, asthmatics with
hay fever or pollen allergy will have seasonal symptoms,
those with allergies to pets may experience an abatement of
symptoms when away from home, and those with occupational
asthma may improve during leave from work. Occasionally,
allergy tests are warranted and, if positive, may help in
identifying avoidable symptom triggers.
After pulmonary function has been measured, radiological
tests, such as a chest X-ray or CT scan, may be required to
exclude the possibility of other lung diseases. In some
people, asthma may by triggered by gastroesophageal reflux
disease, which can be treated with suitable antacids. Very
occasionally, specialized tests after inhalation of
methacholine - or, even less commonly, histamine — may be
performed.
Asthma is categorized by the NIH Heart Lung and Blood
Institute as falling into one of four categories: mild
intermittent, mild persistent, moderate persistent and
severe persistent. The diagnosis of "severe persistent
asthma" occurs when symptoms are continual with frequent
exacerbations and frequent nighttime symptoms, result in
limited physical activity and when lung function as measured
by PEV or FEV1 tests is less than 60% predicted with PEF
variability greater than 30%.
Pathophysiology
Bronchoconstriction
In essence, asthma is the
result of an abnormal immune response in the bronchial
airways. The airways of asthmatics are "hypersensitive" to
certain triggers, also known as stimuli (see below). In
response to exposure to these triggers, the bronchi (large
airways) contract into spasm (an "asthma attack").
Inflammation soon follows, leading to a further narrowing of
the airways and excessive mucus production, which leads to
coughing and other breathing difficulties.
There are seven categories
of stimuli:
-
allergens, typically inhaled,
which include waste from common household insects, such as
the house dust mite and cockroach, grass pollen, mould
spores and pet epithelial cells;
-
medications, including
aspirin and β-adrenergic antagonists (beta blockers);
-
air pollution, such as ozone,
nitrogen dioxide, and sulfur dioxide, which is thought to
be one of the major reasons for the high prevalence of
asthma in urban areas;
- various industrial
compounds and other chemicals, notably
sulfites;
chlorinated swimming pools generate
chloramines—monochloramine (NH2Cl),
dichloramine (NHCl2) and trichloramine (NCl3)—in
the air around them, which are known to induce asthma:
- early childhood
infections, especially
viral
respiratory infections. However, persons of any age
can have asthma triggered by colds and other respiratory
infections even though their normal stimuli might be from
another category (e.g. pollen) and absent at the time of
infection.
-
exercise,
the effects of which differ somewhat from those of the
other triggers; and
-
emotional stress,
which is poorly understood as a trigger.
Bronchial inflammation
The mechanisms behind
allergic asthma—i.e., asthma resulting from an immune
response to inhaled allergens—are the best understood of the
causal factors. In both asthmatics and non-asthmatics,
inhaled allergens that find their way to the inner airways
are ingested by a type of cell known as antigen presenting
cells, or APCs. APCs then "present" pieces of the allergen
to other immune system cells. In most people, these other
immune cells (TH0 cells) "check" and usually ignore the
allergen molecules. In asthmatics, however, these cells
transform into a different type of cell (TH2), for reasons
that are not well understood. The resultant TH2 cells
activate an important arm of the immune system, known as the
humoral immune system. The humoral immune system produces
antibodies against the inhaled allergen. Later, when an
asthmatic inhales the same allergen, these antibodies
"recognize" it and activate a humoral response. Inflammation
results: chemicals are produced that cause the airways to
constrict and release more mucus, and the cell-mediated arm
of the immune system is activated. The inflammatory response
is responsible for the clinical manifestations of an asthma
attack. The following section describes this complex series
of events in more detail.
The immune response
When an
inhaled antigen becomes trapped in the airways, it is
enzymatically degraded into shorter peptides by APCs such as
dendritic cells. APCs express the peptides derived from the
antigen on the cell surface, in what is known as the binding
groove of the class II major histocompatiblity complex (MHC)
molecule. Now located on the cell surface, the antigen-MHC
complex is presented to T cells, which express a receptor
that is specific to the MHC II peptide.
Presented with the antigen-MHC II complex, T helper 0 (TH0)
cells become activated and start to differentiate into
either T helper type 1 (TH1) or type 2 (TH2) cells. The
selective differentiation of TH0 cells has profound
consequences for the immune system: TH1 cell production
leads to cell-mediated immunity, while the production of
predominantly TH2 cells provides humoral immunity. The
resulting balance of TH1 or TH2 cells is a crucial variable
in the development of asthma; the dominance of the TH2 cell
type appears to be necessary for the development of asthma.
In one study, mice that lacked the ability to create TH1
cells displayed an asthma-like phenotype. The variables that
decide the fate of TH1 vs. TH2 cells are not well
understood, but depend on many factors, including childhood
exposure to infectious agents and the cytokines elicited by
those agents.
One cytokine secreted by TH2 cells—IL-4—combined with the
action of other cytokines induces synthesis by
antigen-stimulated B cells of IgE, an allergen-specific
antibody. IgE binds allergens and then receptors on mast
cells, basophils, and eosinophils in the airway epithelium.
Subsequent exposure of the same antigen to these cells in
the airway epithelium initiates the acute-phase reaction of
asthma. Stimulated mast cells in the airway release
preformed granules of mediators such as histamine,
eicosanoids, and cytokines. These molecules are responsible
for the symptoms of asthma. They affect the mucosa of the
airways, increasing mucosal oedema, and mucus production,
smooth muscle constriction, and recruit other immune cells,
thereby exacerbating the reaction.
The late phase of an asthmatic reaction is characterized by
an influx of inflammatory and immune cells during the first
several hours after antigen exposure. These
cells—particularly eosinophils—secrete a series of
cytokines, leukotrienes, and polypeptides, which contribute
to hyperresponsiveness, mucus secretion, bronchoconstriction,
and sustained inflammation.
Pathogenesis
The
fundamental problem in asthma appears to be immunological:
young children in the early stages of asthma show signs of
excessive inflammation in their airways. Epidemiological
findings give clues as to the pathogenesis: the incidence of
asthma seems to be increasing worldwide, and asthma is now
very much more common in affluent countries.
One theory of pathogenesis is that asthma is a disease of
hygiene. In nature, babies are exposed to bacteria and other
antigens soon after birth, "switching on" the TH1 lymphocyte
cells of the immune system that deal with bacterial
infection. If this stimulus is insufficient—as it may be in
modern, clean environments—then TH2 cells predominate, and
asthma and other allergic diseases may develop. This
"hygiene hypothesis" may explain the increase in asthma in
affluent populations. The TH2 lymphocytes and eosinophil
cells that protect us against parasites and other infectious
agents are the same cells responsible for the allergic
reaction. In the developed world, these parasites are now
rarely encountered, but the immune response remains and is
wrongly triggered in some individuals by certain allergens.
Another theory is based on the correlation of air pollution
and the incidence of asthma. Although it is well known that
substantial exposures to certain industrial chemicals can
cause acute asthmatic episodes, it has not been proved that
air pollution is responsible for the development of asthma.
In Western Europe, most atmospheric pollutants have fallen
significantly over the last 40 years, while the prevalence
of asthma has risen.
Finally, it has been postulated that some forms of asthma
may be related to infection, in particular by Chlamydia
pneumoniae. This issue remains controversial, as the
relationship is not borne out by meta-analysis of the
research. The correlation seems to be not with the onset,
but rather with accelerated loss of lung function in adults
with new onset of non-atopic asthma. One possible
explanation is that some asthmatics may have altered immune
response that facilitates long-term chlamydia pneumonia
infection. The response to targeting with macrolide
antibiotics has been investigated, but the temporary benefit
reported in some studies may reflect just their
anti-inflammatory activities rather than their antimicrobic
action.
Treatment
The most effective treatment
for asthma is identifying triggers, such as pets or aspirin,
and limiting or eliminating exposure to them.
Desensitization is commonly attempted, but has not been
shown to be effective. As is common with respiratory
disease, smoking adversely affects asthmatics in several
ways, including an increased severity of symptoms, a more
rapid decline of lung function, and decreased response to
preventive medications. Asthmatics who smoke typically
require additional medications to help control their
disease. Furthermore, exposure of both nonsmokers and
smokers to secondhand smoke is detrimental, resulting in
more severe asthma, more emergency room visits, and more
asthma-related hospital admissions. Smoking cessation and
avoidance of those who smoke is strongly encouraged in
asthmatics.
The specific medical treatment recommended to patients with
asthma depends on the severity of their illness and the
frequency of their symptoms. Specific treatments for asthma
are broadly classified as relievers, preventers and
emergency treatment. The Expert panel report 2: Guidelines
for the diagnosis and management of asthma (EPR-2) of the
U.S. National Asthma Education and Prevention Program, and
the British guideline on the management of asthma are
broadly used and supported by many doctors. Bronchodilators
are recommended for short-term relief in all patients. For
those who experience occasional attacks, no other medication
is needed. For those with mild persistent disease (more than
two attacks a week), low-dose inhaled glucocorticoids—or
alternatively, an oral leukotriene modifier, a mast-cell
stabilizer, or theophylline—may be administered. For those
who suffer daily attacks, a higher dose of glucocorticoid in
conjunction with a long-acting inhaled β-2 agonist may be
prescribed; alternatively, a leukotriene modifier or
theophylline may substitute for the β-2 agonist. In severe
asthmatics, oral glucocorticoids may be added to these
treatments during severe attacks.
For those in whom exercise can trigger an asthma attack
(exercise-induced asthma), higher levels of ventilation and
cold, dry air tend to exacerbate attacks. For this reason,
activities in which a patient breathes large amounts of cold
air, such as cross-country skiing, tend to be worse for
asthmatics, whereas swimming in an indoor, heated pool, with
warm, humid air, is less likely to provoke a response.
Relief medication
Symptomatic control of
episodes of wheezing and shortness of breath is generally
achieved with fast-acting bronchodilators. These are
typically provided in pocket-sized, metered-dose inhalers (MDIs—see
the image to the right). In young sufferers, who may have
difficulty with the coordination necessary to use inhalers,
or those with a poor ability to hold their breath for 10
seconds after inhaler use (generally the elderly), an asthma
spacer (see top image) is used. The spacer is a plastic
cylinder that mixes the medication with air in a simple
tube, making it easier for patients to receive a full dose
of the drug and allows for the active agent to be dispersed
into smaller, more fully inhaled bits. A nebulizer—which
provides a larger, continuous dose—can also be used.
Nebulizers work by vaporizing a dose of medication in a
saline solution into a steady stream of foggy vapour, which
the patient inhales continuously until the full dosage is
administered. There is no clear evidence, however, that they
are more effective than inhalers used with a spacer.
Nebulizers may be helpful to some patients experiencing a
severe attack. Such patients may not be able to inhale
deeply, so regular inhalers may not deliver medication
deeply into the lungs, even on repeated attempts. Since a
nebulizer delivers the medication continuously, it is
thought that the first few inhalations may relax the airways
enough to allow the following inhalations to draw in more
medication.
Relievers include:
- Short-acting, selective
beta2-adrenoceptor agonists (salbutamol [albuterol],
levalbuterol, terbutaline, bitolterol, pirbuterol,
procaterol, fenoterol, reproterol). Tremors, the major
side effect, have been greatly reduced by inhaled
delivery, which allows the drug to target the lungs
specifically; oral and injected medications are delivered
throughout the body. There may also be cardiac side
effects at higher doses (due to Beta-1 agonist activity),
such as elevated heart rate or blood pressure; with the
advent of selective agents, these side effects have become
less common. Patients must be cautioned against using
these medicines too frequently, as with such use their
efficacy may decline, producing desensitization resulting
in an exacerbation of symptoms which may lead to
refractory asthma and death.
- Older, less selective
adrenergic agonists, such as inhaled epinephrine and
ephedrine tablets, are available over the counter in the
US. Cardiac side effects, although uncommon, occur more
often with these less selective drugs. They also provide a
shorter period of relief than the selective
bronchodilators. Nowadays, they are usually avoided in
patients with heart disease. In emergencies, these drugs
were sometimes administered by injection. Their use in
this situation has declined.
-
Anticholinergic medications,
such as ipratropium bromide may be used instead. They have
no cardiac side effects and thus can be used in patients
with heart disease; however, they take up to an hour to
achieve their full effect and are not as powerful as the
β2-adrenoreceptor agonists.
Prevention medication
Current treatment protocols
recommend prevention medications such as an inhaled
corticosteroid, which helps to suppress
inflammation and reduces the swelling of the lining of
the airways, in anyone who has frequent (greater than twice
a week) need of relievers or who has severe symptoms. If
symptoms persist, additional preventive drugs are added
until the asthma is controlled. With the proper use of
prevention drugs, asthmatics can avoid the complications
that result from overuse of relief medications.
Asthmatics sometimes stop
taking their preventive medication when they feel fine and
have no problems breathing. This often results in further
attacks, and no long-term improvement.
Long-acting β2-agonists
Long-acting bronchodilators
(LABD) give a 12-hour effect, and are used to give a
smoothed symptomatic effect (used morning and night). While
patients report improved symptom control, these drugs do not
replace the need for routine preventers, and their slow
onset means the short-acting dilators may still be required.
In November of 2005,
the American
FDA released a health advisory,
alerting the public to findings that show the use of
Long-acting β2-agonists could lead to a worsening
of symptoms, and in some cases death.
Currently available
long-acting beta2-adrenoceptor agonists include salmeterol,
formoterol, bambuterol, and sustained-release oral albuterol.
Combinations of inhaled steroids and long-acting
bronchodilators are becoming more widespread; the most
common combination currently in use is fluticasone/salmeterol
(Advair in the United States, and Seretide in the UK).
Emergency treatment
When an asthma attack is
unresponsive to a patient's usual medication, other
treatments are available to the physician or hospital:
-
oxygen to
alleviate the hypoxia (but not the asthma per se) that
results from extreme asthma attacks;
nebulized salbutamol (a short-acting beta-2-agonist), often
combined with ipratropium (an anticholinergic);
systemic steroids, oral or intravenous (prednisone,
prednisolone, methylprednisolone, dexamethasone, or
hydrocortisone)
other bronchodilators that are occasionally effective when
the usual drugs fail:
nonspecific beta-agonists, injected or inhaled (epinephrine,
isoetharine, isoproterenol, metaproterenol);
anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate,
atropine);
methylxanthines (theophylline, aminophylline);
inhalation anesthetics that have a bronchodilatory effect (isoflurane,
halothane, enflurane);
the dissociative anaesthetic ketamine, often used in
endotracheal tube induction
magnesium sulfate, intravenous; and
intubation and mechanical ventilation, for patients in or
approaching respiratory arrest. Alternative medicine
Many asthmatics, like those
who suffer from other chronic disorders, use alternative
treatments; surveys show that roughly 50% of asthma patients
use some form of unconventional therapy. There are little
data to support the effectiveness of most of these
therapies. A Cochrane systematic review of acupuncture for
asthma found no evidence of efficacy. A similar review of
air ionizers found no evidence that they improve asthma
symptoms or benefit lung function; this applied equally to
positive and negative ion generators. A study of "manual
therapies" for asthma, including osteopathic, chiropractic,
physiotherapeutic and respiratory therapeutic maneuvers,
found no evidence to support their use in treating asthma;
these manoeuvres include various osteopathic and
chiropractic techniques to "increase movement in the rib
cage and the spine to try and improve the working of the
lungs and circulation"; chest tapping, shaking, vibration,
and the use of "postures to help shift and cough up phlegm."
On the other hand, one meta-analysis found that homeopathy
has a potentially mild benefit in reducing symptom
intensity; however, the number of patients involved in the
analysis was small, and subsequent studies have not
supported this finding. Several small trials have suggested
some benefit from various yoga practices, ranging from
integrated yoga programs—"yogasanas, Pranayama, meditation,
and kriyas"—to sahaja yoga, a form of meditation. A
randomized, controlled trial of just 39 patients suggested
that the Buteyko method may moderately reduce the need for
beta-agonists among asthmatics, but found no objective
improvement in lung function.
See also
Complementary and alternative medicine.
Prognosis
The prognosis for asthmatics
is good, especially for children with mild disease. For
asthmatics diagnosed during childhood, 54% will no longer
carry the diagnosis after a decade. The extent of permanent
lung damage in asthmatics is unclear. Airway remodelling is
observed, but it is unknown whether these represent harmful
or beneficial changes.
Although conclusions from studies are mixed, most studies
show that early treatment with glucocorticoids prevents or
ameliorates decline in lung function as measured by several
parameters.
For those who continue to suffer from mild symptoms,
corticosteroids can help most to live their lives with few
disabilities. The mortality rate for asthma is low, with
around 6000 deaths per year in a population of some 10
million patients in the United States.
Better control of the condition may help prevent some of
these deaths.
Epidemiology
The
prevalence of childhood asthma has increased since
1980, especially in younger children.
Asthma is usually diagnosed
in childhood. The risk factors for asthma include:
- a personal or family
history of asthma or
atopy;
- triggers (see
Pathophysiology above);
- premature birth or low
birth weight;
- viral
respiratory infection in early childhood;
- maternal smoking;
- being male, for asthma in
prepubertal children; and
- being female, for
persistence of asthma into adulthood.
There is a reduced
occurrence of asthma in people who were breast-fed as
babies. Current research suggests that the
prevalence of childhood asthma has been increasing.
According to the
Centers for Disease Control and Prevention's National
Health Interview Surveys, some 9% of US children below 18
years of age had asthma in 2001, compared with just 3.6% in
1980 (see figure). The
World Health Organization (WHO) reports
that some 8% of the Swiss population suffers from asthma
today, compared with just 2% some 25–30 years ago. Although
asthma is more common in affluent countries, it is by no
means a problem restricted to the affluent; the WHO estimate
that there are between 15 and 20 million asthmatics in
India. In the U.S., urban residents, Hispanics, and African
Americans are affected more than the population as a whole.
Globally, asthma is responsible for around 180,000 deaths
annually.
Socioeconomic factors
The incidence of asthma is
higher among low-income populations, which in the western
world are disproportionately minority, and more likely to
live near industrial areas. Additionally, asthma has been
strongly associated with the presence of cockroaches in
living quarters, which is more likely in such neighbourhoods.
The quality of asthma
treatment varies along racial lines, likely because many
low-income people cannot afford health insurance and because
there is still a correlation between class and race. For
example, black Americans are less likely to receive
outpatient treatment for asthma despite having a higher
prevalence of the disease. They are much more likely to have
emergency room visits or hospitalization for asthma, and are
three times as likely to die from an asthma attack compared
to whites. The prevalence of "severe persistent" asthma is
also greater in low-income communities compared with
communities with better access to treatment.
Asthma and athletics
Asthma appears to be more
prevalent in athletes than in the general population. One
survey of participants in the 1996
Summer Olympic Games showed that 15% had been diagnosed
with asthma, and that 10% were on asthma medication.
These statistics have been questioned on at least two bases.
Persons with mild asthma may be more likely to be diagnosed
with the condition than others because even subtle symptoms
may interfere with their performance and lead to pursuit of
a diagnosis. It has also been suggested that some
professional athletes who do not suffer from asthma claim to
do so in order to obtain special permits to use certain
performance-enhancing drugs.
There appears to be a
relatively high incidence of asthma in sports such as
cycling, mountain biking, and long-distance
running, and a relatively lower incidence in
weightlifting and diving. It is unclear how much of these
disparities are from the effects of training in the sport,
and from self-selection of sports that may appear to
minimize the triggering of asthma.
In addition, there exists a
variant of asthma called
exercise-induced asthma that shares many features with
allergic asthma. It may occur either independently, or
concurrent with the latter. Exercise studies may be helpful
in diagnosing and assessing this condition.
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