2. Asthma is a syndrome characterized by airflow obstruction that
varies
markedly, both spontaneously and with treatment. Asthmatics harbor
a special type of inflammation in the airways that makes them more
responsive than nonasthmatics to a wide range of triggers, leading to
excessive narrowing with consequent reduced airflow and
symptomatic
wheezing and dyspnea. Narrowing of the airways is usually
reversible,
but in some patients with chronic asthma there may be an element
of irreversible airflow obstruction. The increasing global prevalence
of asthma, the large burden it now imposes on patients, and the high
health care costs have led to extensive research into its mechanisms
and treatment.
3. Asthma can present at any age, with a peak age of 3
years. In childhood,
twice as many males as females are asthmatic, but by
adulthood
the sex ratio has equalized. Long-term studies that
have followed children
until they reach the age of 40 years suggest that many
with asthma become asymptomatic during
adolescence but that asthma returns in
some during adult life, particularly in those with
persistent symptoms
and severe asthma Adults with asthma, including those
with onset
during adulthood, rarely become permanently
asymptomatic.
4. The
severity of asthma does not vary significantly
within a given patient;
those with mild asthma rarely progress to more
severe disease, whereas
those with severe asthma usually have severe
disease at the onset
Major risk factors for asthma deaths are poorly
controlled disease with
frequent use of bronchodilator inhalers, lack of or
poor compliance
with ICS therapy, and previous admissions to
hospital with near-fatal
asthma.
7. Asthma is a heterogeneous disease with
interplay between genetic and
environmental factors. Several risk factors that
predispose to asthma
have been identified These should be
distinguished
from triggers, which are environmental factors
that worsen asthma in
a patient with established disease.
8. Atopy Atopy is the major risk factor for asthma, and
nonatopic
individuals have a very low risk of developing asthma.
Patients with
asthma commonly suffer from other atopic diseases,
particularly allergic
rhinitis, which may be found in over 80% of asthmatic
patients,
and atopic dermatitis (eczema). This observation suggests
that some
other environmental or genetic factor(s) predispose to the
development
of asthma in atopic individuals Atopy is due to the
genetically determined production
of specific IgE antibody, with many patients showing a family
history of allergic diseases
9. Genetic Predisposition The familial association of
asthma and a
high degree of concordance for asthma in identical
twins indicate
a genetic predisposition to the disease; however,
whether or
not the genes predisposing to asthma are similar
or in addition to those
predisposing to atopy is not yet clear. It now
seems likely that different
genes may also contribute to asthma specifically,
and there is increasing
evidence that the severity of asthma is also
genetically determined.
10. Infections Although viral infections (especially rhinovirus)
are common
triggers of asthma exacerbations, it is uncertain whether
they
play a role in etiology. There is some association between
respiratory
syncytial virus infection in infancy and the development of
asthma, but
the specific pathogenesis is difficult to elucidate because
this infection
is very common in children. Atypical bacteria, such as
Mycoplasma
and Chlamydophila, have been implicated in the
mechanism of severe
asthma, but thus far, the evidence is not very convincing of
a true
association.
11. Diet The role of dietary factors is controversial. Observational studies
have shown that diets low in antioxidants such as vitamin C and vitamin
A, magnesium, selenium, and omega-3 polyunsaturated fats (fish
oil) or high in sodium and omega-6 polyunsaturated fats are associated
with an increased risk of asthma. Vitamin D deficiency may also
predispose to the development of asthma. However, interventional
studies with supplementary diets have not supported an important
role for these dietary factors. Obesity is also an independent risk factor
for asthma, particularly in women, but the mechanisms are thus far
unknown.
Air Pollution Air pollutants, such as sulfur dioxide, ozone, and diesel
particulates, may trigger asthma symptoms, but the role of different
air pollutants in the etiology of the disease is much less certain. Indoor air
pollution may be more important
with exposure to nitrogen oxides from cooking stoves and exposure to
passive cigarette smoke.
12. Allergens Inhaled allergens are common triggers of
asthma symptoms
and have also been implicated in allergic
sensitization. Exposure
to house dust mites in early childhood is a risk
factor for allergic sensitization
and asthma, but rigorous allergen avoidance has
not shown
any evidence for a reduced risk of developing
asthma. Domestic pets, particularly cats, have
also been
associated with allergic sensitization, b
13. Obesity Asthma occurs more frequently in
obese people (body mass
index >30 kg/m2) and is often more difficult
to control. Although mechanical factors may
contribute, it may also be linked to the pro-
inflammatory adipokines and reduced anti-
inflammatory adipokines
that are released from fat stores.
14. Other Factors Several other factors have been
implicated in the etiology
of asthma, including lower maternal age, duration
of breast-feeding,
prematurity and low birthweight, and inactivity, but
are unlikely to
contribute to the recent global increase in asthma
prevalence. There is
also an association with acetaminophen
(paracetamol) consumption in
childhood, which may be linked to increased
oxidative stress.
15. Allergens Inhaled allergens activate mast cells with bound IgE
directly leading to the immediate release of bronchoconstrictor
mediators,
resulting in the early response that is reversed by bronchodilators.
Often, experimental allergen challenge is followed by a late response
when there is airway edema and an acute inflammatory response with
increased eosinophils and neutrophils that are not very reversible with
bronchodilators. The most common allergens to trigger asthma are
Dermatophagoides species, and environmental exposure leads to
lowgrade
chronic symptoms that are perennial. Other perennial allergens
are derived from cats and other domestic pets, as well as cockroaches.
Other allergens, including grass pollen, ragweed, tree pollen, and
fungal
spores, are seasonal. Pollens usually cause allergic rhinitis rather
than asthma, but in thunderstorms, the pollen grains are disrupted and
the particles that may be released can trigger severe asthma
exacerbations
(thunderstorm asthma).
16. Virus infections Upper respiratory tract virus infections such as
rhinovirus, respiratory syncytial virus, and coronavirus are the
most
common triggers of acute severe exacerbations and may
invade epithelial
cells of the lower as well as the upper airways. The mechanism
whereby these viruses cause exacerbations is poorly
understood, but
there is an increase in airway inflammation with increased
numbers of
eosinophils and neutrophils. There is evidence for reduced
production
of type I interferons by epithelial cells from asthmatic patients,
resulting
in increased susceptibility to these viral infections and a
greater
inflammatory response.
17. Pharmacologic agents Several drugs may trigger asthma.
Betaadrenergic
blockers commonly acutely worsen asthma, and their use
may be fatal. The mechanisms are not clear, but are likely
mediated
through increased cholinergic bronchoconstriction. All β blockers
need to be avoided, and even selective β2 blockers or topical
application
(e.g., timolol eye drops) may be dangerous. Angiotensin-
converting
enzyme inhibitors are theoretically detrimental as they inhibit
breakdown
of kinins, which are bronchoconstrictors; however, they rarely
worsen asthma, and the characteristic cough is no more frequent
in asthmatics than in nonasthmatics. Aspirin may worsen asthma
in some patients (
18. EXERCISE Exercise is a common trigger of asthma, particularly in
children. The mechanism is linked to hyperventilation, which
results in increased osmolality in airway lining fluid and triggers
mast cell
mediator release, resulting in bronchoconstriction. Exercise-
induced
asthma (EIA) typically begins after exercise has ended and resolves
spontaneously within about 30 min. EIA is worse in cold, dry
climates
than in hot, humid conditions. It is, therefore, more common in
sports
activities such as cross-country running in cold weather, overland
skiing,
and ice hockey than in swimming. It may be prevented by prior
administration of β2-agonists and antileukotrienes, but is best
prevented
by regular treatment with ICSs, which reduce the population of
surface mast cells required for this response.
19. Physical factors Cold air and hyperventilation
may trigger asthma
through the same mechanisms as exercise.
Laughter may also be a
trigger. Many patients report worsening of
asthma in hot weather
and when the weather changes. Some
asthmatics become worse when
exposed to strong smells or perfumes, but the
mechanism of this
response is uncertain.
20. HORMONES Some women show premenstrual worsening of asthma,
which can occasionally be very severe. The mechanisms are not
completely understood, but are related to a fall in progesterone
and
in severe cases may be improved by treatment with high doses of
progesterone or gonadotropin-releasing factors. Thyrotoxicosis
and
hypothyroidism can both worsen asthma, although the
mechanisms
ARE UNCERTAIN.
GASTROESOPHAGEAL REFLUX Gastroesophageal reflux is common
in asthmatic
patients because it is increased by bronchodilators. Although
acid reflux might trigger reflex bronchoconstriction, it rarely
causes
asthma symptoms, and antireflux therapy usually fails to reduce
asthma symptoms in most patients.
21. STRESS Many asthmatics report worsening of
symptoms with stress.
Psychological factors can induce
bronchoconstriction through cholinergic
reflex pathways. Paradoxically, very severe
stress such as
bereavement usually does not worsen, and may
even improve, asthma
symptoms.
22. PATHOPHYSIOLOGY
Asthma is associated with a specific chronic inflammation of the
mucosa of the lower airways. One of the main aims of treatment is
to
reduce this inflammation. The pathology of asthma has been
revealed through
examining the lungs of patients who have died of asthma and from
bronchial biopsies. The airway mucosa is infiltrated with activated
eosinophils and T lymphocytes, and there is activation of mucosal
mast cells. The degree of inflammation is poorly related to disease
severity and may even be found in atopic patients
without asthma symptoms. This inflammation is
usually reduced by treatment with ICS. There are
also structural changes in the airways (described as
remodeling). A characteristic finding is thickening
of the basement membrane due to subepithelial
collagen deposition.
23. The airway wall itself may be thickened and edematous,
particularly in fatal asthma. Another common
finding in fatal asthma is occlusion of the airway
lumen by a mucous plug, which is comprised of
mucous glycoproteins secreted from goblet cells
and plasma proteins from leaky bronchial vessels There is also
vasodilation and
increased numbers of blood vessels (angiogenesis).
Direct observation by bronchoscopy indicates that
the airways may be narrowed, erythematous, and
edematous. The pathology of asthma is remarkably uniform in
different
phenotypes of asthma, including atopic (extrinsic), nonatopic
(intrinsic), occupational, aspirin-sensitive, and pediatric asthma.
These pathologic changes are found in all airways, but do not
extend
to the lung parenchyma; peripheral airway inflammation is found
particularly
in patients with severe asthma
24. Airway Inflammation There is inflammation in the respiratory
mucosa
from the trachea to terminal bronchioles, but with a
predominance in
the bronchi (cartilaginous airways); however, it is still uncertain as
to
how inflammatory cells interact and how inflammation translates
into
the symptoms of asthma There is good evidence that the
specific pattern of airway inflammation in asthma is associated
with
airway hyperresponsiveness (AHR), the physiologic abnormality of
asthma, which is correlated with variable airflow obstruction. The
pattern of inflammation in asthma is characteristic of allergic
diseases,
with similar inflammatory cells seen in the nasal mucosa in
rhinitis Although most attention has focused on the acute
inflammatory changes seen in asthma, this is a chronic condition,
with inflammation persisting over many years in most patients.
25. MAST CELLS Mast cells are important in initiating the acute
bronchoconstrictor
responses to allergens and several other indirectly acting
stimuli, such as exercise and hyperventilation Activated mucosal
mast cells are found at the airway
surface in asthma patients and also in the airway smooth-muscle
layer,
whereas this is not seen in normal subjects or patients with
eosinophilic
bronchitis. Mast cells are activated by allergens through an
IgE-dependent mechanism, and binding of specific IgE to mast cells
renders them more sensitive to activation by physical stimuli such as
osmolality. The importance of IgE in the pathophysiology of asthma
has been highlighted by clinical studies with humanized anti-IgE
antibodies,
which inhibit IgE-mediated effects, reduce asthma symptoms,
and reduce exacerbations Mast
cells release several bronchoconstrictor mediators, including
histamine,
prostaglandin D2, and cysteinyl-leukotrienes, but also several
cytokines, chemokines, growth factors, and neurotrophins.
26. Macrophages and dendritic cells Macrophages, which are derived
from blood monocytes, may traffic into the airways in asthma and
may be activated by allergens via low-affinity IgE receptors (FcεRII).
Macrophages have the capacity to initiate a type of inflammatory
response via the release of a certain pattern of cytokines, but these
cells also release anti-inflammatory mediators (e.g., IL-10), and thus,
their roles in asthma are uncertain. Dendritic cells are specialized
macrophage-like cells in the airway epithelium, which are the major
antigen-presenting cells. Dendritic cells take up allergens, process
them to peptides, and migrate to local lymph nodes where they present
the allergenic peptides to uncommitted T lymphocytes to program
the production of allergen-specific T cells.
27. EOSINOPHILS Eosinophil infiltration is a characteristic
feature of asthmatic
airways. Allergen inhalation results in a marked increase
in
activated eosinophils in the airways at the time of the
late reaction.
Eosinophils are linked to the development of AHR
through the release
of basic proteins and oxygen-derived free radicals.
Eosinophil recruitment
involves adhesion of eosinophils to vascular endothelial
cells in
the airway circulation due to interaction between
adhesion molecules,
migration into the submucosa under the direction of
chemokines, and
their subsequent activation and prolonged survival.
28. NEUTROPHILS Increased numbers of activated
neutrophils are found in
sputum and airways of some patients with
severe asthma and during
exacerbations, although there is a proportion
of patients even with mild
or moderate asthma who have a predominance
of neutrophils. The roles
of neutrophils in asthma that are resistant to
the anti-inflammatory
effects of corticosteroids are currently
unknown.
29. T LYMPHOCYTES T lymphocytes play a very
important role in coordinating
the inflammatory response in asthma through
the release of specific
patterns of cytokines, resulting in the
recruitment and survival of
eosinophils and in the maintenance of a mast
cell population in the airways.
30. Structural cells Structural cells of the
airways, including epithelial cells, fibroblasts,
and airway smooth-muscle cells,
are also important sources of inflammatory
mediators, such as cytokines
and lipid mediators, in asthma. Indeed,
because structural cells far outnumber
inflammatory cells, they may become
the major sources of mediators driving
chronic inflammation in asthmatic
airways.
31. Inflammatory Mediators Multiple inflammatory
mediators have been implicated in
asthma, and they may have a variety of
effects on the airways that account for
the pathologic features of asthma. Mediators such as
histamine, prostaglandin
D2, and cysteinyl-leukotrienes
contract airway smooth muscle, increase
microvascular leakage, increase airway mucus
secretion, and attract other
inflammatory cells. Because each mediator has many
effects, the role of
individual mediators in the pathophysiology of asthma
is not yet clear.
33. Effects of Inflammation The chronic inflammatory
response has several
effects on the target cells of the airways, resulting
in the characteristic
pathophysiologic and remodeling changes
associated with
asthma. Asthma may be regarded as a disease with
continuous inflammation
and repair proceeding simultaneously, although
the relationship
between chronic inflammatory processes and
asthma symptoms
is often obscure.
34. AIRWAY EPITHELIUM Airway epithelial shedding may be important
in
contributing to AHR and may explain how several mechanisms,
such
as ozone exposure, virus infections, chemical sensitizers, and
allergens
(usually proteases), can lead to its development, as all of these
stimuli
may lead to epithelial disruption. Epithelial damage may contribute
to AHR in a number of ways, including loss of its barrier function to
allow penetration of allergens; loss of enzymes (such as neutral
endopeptidase)
that degrade certain peptide inflammatory mediators; loss
of a relaxant factor (so called epithelial-derived relaxant factor);
and
exposure of sensory nerves, which may lead to reflex neural effects
on
the airway.
35. FIBROSIS In all asthmatic patients, the basement membrane
is apparently
thickened due to subepithelial fibrosis with deposition of
types III and V collagen below the true basement membrane
and
is associated with eosinophil infiltration, presumably
through the
release of profibrotic mediators such as transforming growth
factor-β.
Mechanical manipulations can alter the phenotype of airway
epithelial
cells in a profibrotic fashion. In more severe patients, there
is also
fibrosis within the airway wall, which may contribute to
irreversible
narrowing of the airways.
36. AIRWAY SMOOTH MUSCLE In vitro airway smooth
muscle from asthmatic
patients usually shows no increased
responsiveness to constrictors.
Reduced responsiveness to β-agonists has also
been reported in postmortem
or surgically removed bronchi from asthmatics,
although the
number of β-receptors is not reduced, suggesting
that β-receptors have
been uncoupled. These abnormalities of airway
smooth muscle may be
secondary to the chronic inflammatory process.
37. VASCULAR RESPONSES There is increased airway
mucosal blood flow
in asthma, which may contribute to airway
narrowing. There is an
increase in the number of blood vessels in
asthmatic airways as a result
of angiogenesis in response to growth factors,
particularly vascular
endothelial growth factor. Microvascular leakage
from postcapillary
venules in response to inflammatory mediators is
observed in asthma,
resulting in airway edema and plasma exudation
into the airway lumen.
38. MUCUS HYPERSECRETION Increased mucus
secretion contributes to the
viscid mucous plugs that occlude asthmatic
airways, particularly in
fatal asthma. There is hyperplasia of
submucosal glands that are confined
to large airways and of increased numbers of
epithelial goblet
cells. IL-13 induces mucus hypersecretion in
experimental models of
asthma.
39. NEURAL REGULATION Various defects in autonomic neural control
may
contribute to AHR in asthma, but these are likely to be secondary
to the disease, rather than primary defects. Cholinergic pathways,
through the release of acetylcholine acting on muscarinic receptors,
cause bronchoconstriction and may be activated reflexly in asthma.
Inflammatory mediators may activate sensory nerves, resulting in
reflex cholinergic bronchoconstriction or release of inflammatory
neuropeptides. Inflammatory products may also sensitize sensory
nerve endings in the airway epithelium such that the nerves become
hyperalgesic. Neurotrophins, which may be released from various cell
types in airways, including epithelial cells and mast cells, may cause
proliferation and sensitization of airway sensory nerves. Airway
nerves
may also release neurotransmitters, such as substance P, which have
inflammatory effects.
40. Airway Remodeling Several changes in the structure of the airway are
characteristically found in asthma, and these may lead to irreversible
narrowing of the airways. Population studies have shown a greater
decline in lung function over time than in normal subjects; however,
most patients with asthma preserve normal or near-normal lung
function
throughout life if appropriately treated.
The accelerated decline in lung function occurs in a smaller
proportion
of asthmatics, and these are usually patients with more severe
disease. There is some evidence that the early use of ICS may reduce
the decline in lung function. The characteristic structural changes are
increased airway smooth muscle, fibrosis, angiogenesis, and mucus
hyperplasia.
41. The characteristic symptoms of asthma are wheezing,
dyspnea, and coughing, which are variable, both
spontaneously and with therapy. Symptoms may be
worse at night, and patients typically awake in the
early morning hours. Patients may report difficulty in
filling their lungs with air. There is increased mucus
production in some patients, with typically tenacious
mucus that is difficult to expectorate. There may be
increased ventilation and use of accessory muscles of
ventilation. Prodromal symptoms may precede
an attack, with itching under the chin, discomfort
between the scapulae, or inexplicable fear (impending
doom).
42. Typical physical signs are inspiratory, and to
a greater extent expiratory, rhonchi
throughout
the chest, and there may be hyperinflation.
Some
patients, particularly children, may present
with a predominant nonproductive cough
(cough-variant asthma). There
may be no abnormal physical findings when
asthma is under control.
43. DIAGNOSIS
The diagnosis of asthma is usually apparent
from the symptoms of
variable and intermittent airways obstruction,
but must be confirmed
by objective measurements of lung function.
Hematologic Tests Blood tests are not usually
helpful. Total serum IgE
and specific IgE to inhaled allergens
(radioallergosorbent test [RAST])
may be measured in some patients
44. Imaging Chest roentgenography is usually normal but in
more severe
patients may show hyperinflated lungs. In exacerbations,
there may be
evidence of a pneumothorax. Lung shadowing usually
indicates pneumonia
or eosinophilic infiltrates in patients with bronchopulmonary
aspergillosis. High-resolution computed tomography (CT)
may show
areas of bronchiectasis in patients with severe asthma, and
there may
be thickening of the bronchial walls, but these changes are
not diagnostic
of asthma.
45. Differential Diagnosis It is usually not difficult to differentiate
asthma
from other conditions that cause wheezing and dyspnea. Upper
airway
obstruction by a tumor or laryngeal edema can mimic severe
asthma,
but patients typically present with stridor localized to large airways.
The diagnosis is confirmed by a flow-volume loop that shows a
reduction
in inspiratory as well as expiratory flow, and bronchoscopy to
demonstrate the site of upper airway narrowing. Chronic obstructive
pulmonary disease (COPD) is usually
easy to differentiate from asthma as symptoms show less variability,
never completely remit, and show much less (or no) reversibility to
bronchodilators. Approximately 10% of COPD patients have features
of asthma, with increased sputum eosinophils and a response to
OCSs;
these patients probably have both diseases concomitantly
46. The treatment of asthma is straightforward, and the
majority of
patients are now managed by internists and family
doctors with
effective and safe therapies. There are several aims
of therapy Most emphasis has been placed on
drug therapy,
but several nonpharmacologic approaches have also
been used.
The main drugs for asthma can be divided into
bronchodilators,
which give rapid relief of symptoms mainly through
relaxation of
airway smooth muscle, and controllers, which
inhibit the underlying
inflammatory process.
47. BRONCHODILATOR THERAPIES
Bronchodilators act primarily on airway smooth muscle
to reverse
the bronchoconstriction of asthma. This gives rapid
relief of symptoms
but has little or no effect on the underlying
inflammatory process.
Thus, bronchodilators are not sufficient to control
asthma in
patients with persistent symptoms. There are three
classes of bronchodilators
in current use: β2-adrenergic agonists,
anticholinergics,
and theophylline; of these, β2-agonists are by far the
most effective.
48. β2-Agonists β2-Agonists activate β2-
adrenergic receptors, which are
widely expressed in the airways. β2-Receptors
are coupled through
a stimulatory G protein to adenylyl cyclase,
resulting in increased intracellular cyclic
adenosine monophosphate (AMP), which
relaxes
smooth-muscle cells and inhibits certain
inflammatory cells, particularly
mast cells.
49. Mode of Action The primary action of β2-agonists is to relax airway
smooth-muscle cells of all airways, where they act as functional
antagonists, reversing and preventing contraction of airway
smooth-muscle cells by all known bronchoconstrictors. This
generalized
action is likely to account for their great efficacy as bronchodilators
in asthma. There are also additional nonbronchodilator effects
that may be clinically useful, including inhibition of mast cell
mediator
release, reduction in plasma exudation, and inhibition of sensory
nerve activation. Inflammatory cells express small numbers of β2-
receptors, but these are rapidly downregulated with β2-agonist
activation
so that, in contrast to corticosteroids, there are no effects on
inflammatory cells in the airways and there is no reduction in AHR
50. Aims of Asthma Therapy
• Minimal (ideally no) chronic symptoms,
including nocturnal
• Minimal (infrequent) exacerbations
• No emergency visits
• Minimal (ideally no) use of a required β2-
agonist
• No limitations on activities, including exercise
• Peak expiratory flow circadian variation <20%
• (Near) normal peak expiratory flow
• Minimal (or no) adverse effects from medicine
51. Anticholinergics Muscarinic receptor antagonists such as
ipratropium
bromide prevent cholinergic nerve-induced
bronchoconstriction
and mucus secretion. They are less effective than β2-agonists
in asthma therapy because they inhibit only the cholinergic
reflex
component of bronchoconstriction, whereas β2-agonists
prevent all
bronchoconstrictor mechanisms. Anticholinergics, including
oncedaily
tiotropium bromide, may be used as an additional
bronchodilator
in patients with asthma that is not controlled by ICS and LABA
combinations. High doses may be given by nebulizer in
treating
acute severe asthma but should only be given following β2-
agonists,
because they have a slower onset of bronchodilatation
52. CONTROLLER THERAPIES
Inhaled Corticosteroids ICSs are by far the most effective controllers
for asthma, and their early use has revolutionized asthma therapy
Mode of Action ICSs are the most effective anti-inflammatory
agents
used in asthma therapy, reducing inflammatory cell numbers and
their activation in the airways. ICSs reduce eosinophils in the airways
and sputum and the numbers of activated T lymphocytes and surface
mast cells in the airway mucosa. These effects may account for
the reduction in AHR that is seen with chronic ICS therapy.
The molecular mechanism of action of corticosteroids involves
several effects on the inflammatory process. The major effect of
corticosteroids is to switch off the transcription of multiple activated
genes that encode inflammatory proteins such as cytokines,
chemokines, adhesion molecules, and inflammatory enzymes.
Clinical Use ICSs are by far the most effective controllers in the
management of asthma and are beneficial in treating asthma of any
severity and age.
53. Antileukotrienes Cysteinyl-leukotrienes are potent
bronchoconstrictors,
cause microvascular leakage, and increase eosinophilic
inflammation
through the activation of cys-LT1-receptors. These inflammatory
mediators are produced predominantly by mast cells and, to a
lesser
extent, eosinophils in asthma. Antileukotrienes, such as
montelukast,
block cys-LT1-receptors and provide modest clinical benefit in
asthma. They are less effective than ICS in controlling asthma and
have less effect on airway inflammation, but are useful as an addon
therapy in some patients not controlled with low doses of ICS,
although less effective than LABA.
54. MANAGEMENT OF CHRONIC ASTHMA The
assessment of the frequency of daytime and
nighttime symptoms and limitation of physical
activity determines whether asthma is
intermittent or persistent. There are 4 categories
Therapy is step-wise (Step 1–4) based on the
category of asthma and consists of: Preventing
the inflammation leading to bronchospasm
(controllers) Relieving bronchospasm (relievers)
Controller medicines in asthma Inhaled
corticosteroids e.g. Beclomethasone Reliever
medicines in asthma β2 agonists e.g.
Salbutamol (short-acting)
55. ACUTE SEVERE ASTHMA
Exacerbations of asthma are feared by patients and may be life
threatening. One of the main aims of controller therapy is to prevent
exacerbations; in this respect, ICS and combination inhalers are very
effective.
Clinical Features Patients are aware of increasing chest tightness,
wheezing, and dyspnea that are often not or poorly relieved by their
usual reliever inhaler. In severe exacerbations, patients may be so
breathless that they are unable to complete sentences and may become
cyanotic. Examination usually shows increased ventilation, hyperinflation,
and tachycardia. Pulsus paradoxus may be present, but this is
rarely a useful clinical sign. There is a marked fall in spirometric values
and PEF. Arterial blood gases on air show hypoxemia, and PCO2 is
usually low due to hyperventilation. A normal or rising PCO2 is an
indication of impending respiratory failure and requires immediate
monitoring and therapy. A chest roentgenogram is not usually informative
but may show pneumonia or pneumothorax.
56. high concentration of oxygen should be given by face mask to
achieve oxygen saturation of >90%. The mainstay of treatment are
high doses of SABA given either by nebulizer or via a metered-dose
inhaler with a spacer. In severely ill patients with impending respiratory
failure, IV β2-agonists may be given. A nebulized anticholinergic
may be added if there is not a satisfactory response to β2-agonists
alone, as there are additive effects. In patients who are refractory to
inhaled therapies, a slow infusion of aminophylline may be effective,
but it is important to monitor blood levels, especially if patients
have already been treated with oral theophylline. Magnesium
sulfate given intravenously or by nebulizer is effective when added
to inhaled β2-agonists, and is relatively well tolerated but is not
routinely recommended. Prophylactic intubation may be indicated
for impending respiratory failure, when the PCO2 is normal or rises.
For patients with respiratory failure, it is necessary to intubate and
institute ventilation. These patients may benefit from an anesthetic
such as halothane if they have not responded to conventional
bronchodilators. Sedatives should never be given because they may
depress ventilation. Antibiotics should not be used routinely unless
there are signs of pneumonia.
57. Asthma in the Elderly Asthma may start at any age, including in
elderly
patients. The principles of management are the same as in other
asthmatics, but side effects of therapy may be a problem, including
muscle tremor with β2-agonists and more systemic side effects
with
ICS. Comorbidities are more frequent in this age group, and
interactions
with drugs such as β2-blockers, COX inhibitors, and agents that
may affect theophylline metabolism need to be considered. COPD
is
more likely in elderly patients and may coexist with asthma. A trial
of
OCS may be very useful in documenting the steroid responsiveness
of
asthma.
58. Pregnancy Approximately one-third of asthmatic patients who are
pregnant improve during the course of a pregnancy, one-third deteriorate,
and one-third are unchanged. It is important to maintain
good control of asthma because poor control may have adverse effects
on fetal development. Compliance may be a problem because there
is often concern about the effects of antiasthma medications on fetal
development. The drugs that have been used for many years in asthma
therapy have now been shown to be safe and without teratogenic
potential. These drugs include SABA, ICS, and theophylline; there is
less safety information about newer classes of drugs such as LABA,
antileukotrienes, and anti-IgE. If an OCS is needed, it is better to use
prednisone rather than prednisolone because it cannot be converted to
the active prednisolone by the fetal liver, thus protecting the fetus from
systemic effects of the corticosteroid. There is no contraindication to
breast-feeding when patients are using these drugs
