Asthma

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.
Prevalence
Asthma is one of the most common chronic diseases globally and
currently affects approximately 300 million people worldwide.

The prevalence of asthma has risen in affluent countries over

the last 30 years but now appears to have stabilized, with
approximately 10–12% of adults and 15% of children affected
by the disease.

In developing countries where the prevalence of asthma had been

much lower, there is a rising prevalence, which is associated with
increased urbanization.
The prevalence of atopy and other allergic diseases has also
increased over the same time, suggesting that the reasons for the
increase are likely to be systemic rather than confined to the
lungs.

This epidemiologic observation suggests that there is a maximum

number of individuals in the community, who are likely to be
affected by asthma, most likely by genetic predisposition.

Most patients with asthma in affluent countries are atopic, with

allergic sensitization to the house dust mite Dermatophagoides
pteronyssinus and other environmental allergens.
Because asthma is both common and frequently complicated by
the effects of smoking on the lungs, it is difficult to be certain
about the natural history of the disease in adults.

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.

The commonly held belief that children "grow out of their asthma"
is justified to some extent.
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.
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.
Deaths from asthma are uncommon, and in many affluent
countries have been steadily declining over the last decade.

A rise in asthma mortality seen in several countries during the

1960s was associated with increased use of short-acting B2-
adrenergic agonists (as rescue therapy),
But there is now compelling evidence that the more widespread
use of inhaled corticosteroids (ICS) in patients with persistent
asthma is responsible for the decrease in mortality in recent
years.
Major risk factors for asthma deaths are

1. Poorly controlled disease with frequent use of bronchodilator

inhalers,
2. Lack of corticosteroid therapy, and
3. Previous admissions to hospital with near-fatal asthma.
It has proved difficult to agree on a definition of asthma,
But there is good agreement on the description of the clinical
syndrome and disease pathology.

Until the etiologic mechanisms of the disease are better

understood, it will be difficult to provide an accurate definition.
Etiology
Asthma is a heterogeneous disease with interplay between genetic
and environmental factors.

Several risk factors have been implicated (Table 254-1).

1. 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).
Atopy may be found in 40–50% of the population in affluent
countries, with only a proportion of atopic individuals becoming
asthmatic.

This observation suggests that some other environmental or

genetic factor(s) predispose to the development of asthma in
atopic individuals.
The allergens that lead to sensitization are usually proteins that
have protease activity, and the most common allergens are derived
from house dust mites, cat and dog fur, cockroaches (in inner
cities), grass and tree pollens, and rodents (in laboratory workers).

Atopy is due to the genetically determined production of

specific IgE antibody, with many patients showing a family
history of allergic diseases.
2. Intrinsic Asthma
 A minority of asthmatic patients (approximately 10%) have
negative skin tests to common inhalant allergens and normal
serum concentrations of IgE.

 These patients, with nonatopic or intrinsic asthma, usually show

later onset of disease (Adult-onset Asthma), commonly have
concomitant nasal polyps, and may be aspirin-sensitive.
They usually have More Severe, Persistent Asthma.

Little is understood about mechanism, but the immunopathology

in bronchial biopsies and sputum appears to be identical to that
found in atopic asthma.

There is recent evidence for increased Local Production of IgE

in the airways, suggesting that there may be common IgE-
mediated mechanisms; Staphylococcal Enterotoxins, which
serve as "superantigens," have been implicated.
3. Infections
 Although viral infections are common as 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, as this
infection is very common in children.
More recently, 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.
4. Genetic Considerations
 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.

Genetic screens with classical linkage analysis and single-

nucleotide polymorphisms of various candidate genes indicate
that asthma is polygenic, with each gene identified having a
small effect that is often not replicated in different populations.
This observation suggests that the interaction of many genes is
important, and these may differ in different populations.

The most consistent findings have been associations with

polymorphisms of genes on chromosome 5q, including the T
helper 2 (TH2) cells interleukin (IL)-4, IL-5, IL-9, and IL-13,
which are associated with atopy.

There is increasing evidence for a complex interaction between

genetic polymorphisms and environmental factors that will require
very large population studies to unravel.
Novel genes that have been associated with asthma, including
ADAM-33, DPP-10, and GPRA, have also been identified by
positional cloning, but their function in disease pathogenesis is
not yet clear.

Recent genome-wide association studies have identified further

novel genes, although, again, their functional role is not yet
clear.
Genetic polymorphisms may also be important in determining the
response to asthma therapy.

For example, the Arg-Gly-16 variant in the B 2-receptor has

been associated with reduced response to B2-agonists, and
repeats of an Sp1 recognition sequence in the promoter region
of 5-lipoxygenase may affect the response to antileukotrienes.

However, these effects are small and inconsistent and do not yet
have any implications for asthma therapy.
5. Environmental Factors
 It is likely that environmental factors in early life determine which
atopic individuals become asthmatic.

 The increasing prevalence of asthma, particularly in developing countries,

over the last few decades also indicates the importance of environmental
mechanisms interacting with a genetic predisposition.
Hygiene Hypothesis
 The observation that allergic sensitization and asthma were less
common in children with older siblings first suggested that lower
levels of infection may be a factor in affluent societies that
increase the risks of asthma.

 This "hygiene hypothesis" proposes that lack of infections in early

childhood preserves the TH2 cell bias at birth, whereas exposure to
infections and endotoxin results in a shift toward a predominant protective
TH1 immune response.
Children brought up on farms who are exposed to a high level of
endotoxin are less likely to develop allergic sensitization than
children raised on dairy farms.

Intestinal parasite infection may also be associated with a

reduced risk of asthma.

While there is considerable epidemiologic support for the

hygiene hypothesis, it cannot account for the parallel increase
in TH1-driven diseases such as diabetes mellitus over the same
period.
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 polyunsaturates 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.

 Most evidence argues against an important role for air pollution as

asthma is no more prevalent in cities with a high ambient level of
traffic pollution than in rural areas with low levels of pollution.
Asthma had a much lower prevalence in East Germany compared
to West Germany despite a much higher level of air pollution, but
since reunification these differences have decreased as eastern
Germany has become more affluent.

Indoor air pollution may be more important with exposure to

nitrogen oxides from cooking stoves and exposure to passive
cigarette smoke.

There is some evidence that maternal smoking is a risk factor for

asthma, but it is difficult to dissociate this association from an
increased risk of respiratory infections.
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.
The increase in house dust mites in centrally heated poorly
ventilated homes with fitted carpets has been implicated in the
increasing prevalence of asthma in affluent countries.

Domestic pets, particularly cats, have also been associated with

allergic sensitization, but early exposure to cats in the home
may be protective through the induction of tolerance.
Occupational Exposure
 Occupational asthma is relatively common and may affect up to
10% of young adults.

 Over 200 Sensitizing Agents have been identified.

 Chemicals such as toluene diisocyanate and trimellitic anhydride, may

lead to sensitization independent of atopy.
Individuals may also be exposed to allergens in the workplace
such as small animal allergens in laboratory workers and fungal
amylase in wheat flour in bakers.

Occupational asthma may be suspected when symptoms improve

during weekends and holidays.
6. 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 remains unexplained.
Pathogenesis
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.
1. Pathology
 The pathology of asthma has been revealed through examining the
lungs at autopsy of patients who have died of asthma and from
bronchial biopsies in patients with usually mild asthma.

 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 be found in atopic patients without asthma symptoms.

The inflammation is reduced by treatment with ICS.

A characteristic finding is thickening of the basement membrane

due to subepithelial collagen deposition.

This feature is also found in patients with eosinophilic

bronchitis presenting as cough who do not have asthma and is,
therefore, likely to be a marker of eosinophilic inflammation in
the airway as eosinophils release fibrogenic factors.
The epithelium is often shed or friable, with reduced attachments
to the airway wall and increased numbers of epithelial cells in the
lumen.

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 (Fig. 254-1).
Histopathology of a small airway in fatal asthma.
The lumen is occluded with a mucous plug, there is goblet cell metaplasia, and the airway wall is
thickened, with an increase in basement membrane thickness and airway smooth muscle.
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

types of asthma, including Atopic, Nonatopic, 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.

The involvement of airways may be patchy and this is consistent

with bronchographic findings of uneven narrowing of the airways.
2. Inflammation
 There is inflammation in the respiratory mucosa from the trachea
to terminal bronchioles, but with a predominance in the bronchi
(cartilaginous airways).

 Considerable research has identified the major cellular

components of inflammation, but it is still uncertain how
inflammatory cells interact and how inflammation translates into
the symptoms of asthma (Fig. 254-2).
Inflammation in the airways of asthmatic patients leads to
airway hyperresponsiveness and symptoms. SO2, sulfur dioxide
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.

However, an indistinguishable pattern of inflammation is found in

intrinsic asthma, and this may reflect local rather than systemic
IgE production.
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.

The mechanisms involved in persistence of inflammation in asthma

are still poorly understood.
Superimposed on this chronic inflammatory state are acute
inflammatory episodes, which correspond to exacerbations of
asthma.

Many inflammatory cells are known to be involved in asthma with

no key cell that is predominant (Fig. 254-3).
The pathophysiology of asthma is complex with participation of several interacting inflammatory cells, which
result in acute and chronic inflammatory effects on the airway.
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 (via osmolality or thermal
changes), as well as fog.

 Activated 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.

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.
There are, however, uncertainties about the role of mast cells in
more chronic allergic inflammatory events.

Mast cells release several bronchoconstrictor mediators,

including histamine, prostaglandin D2, and cysteinyl-
leukotrienes, but also several Cytokines, Chemokines, Growth
Factors, and Neurotrophins.
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 (FcRII).

 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.
Immature dendritic cells in the respiratory tract promote TH2 cell
differentiation and require cytokines such as IL-12 and tumor
necrosis factor-a (TNF-a), to promote the normally preponderant
TH1 response.

The cytokine thymic stromal lymphopoietin (TSLP) released

from epithelial cells in asthmatic patients instructs dendritic
cells to release chemokines that attract T H2 cells into the
airways.
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.

Blocking antibodies to IL-5 causes a profound and prolonged

reduction in circulating and sputum eosinophils, but is not
associated with reduced AHR or asthma symptoms, although in
selected patients with steroid-resistant airway eosinophils, there
is a reduction in exacerbations.
Eosinophilic inflammation is also found in patients with chronic
cough (eosinophilic bronchitis) who do not have AHR or clinical
features of asthma.

Increasing evidence suggests that eosinophils may be important

in release of growth factors involved in airway remodeling, in
exacerbations but not in AHR.
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.
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.

 The naïve immune system and the immune system of asthmatics are
skewed to express the TH2 phenotype, whereas in normal airways TH1 cells
predominate.
TH2 cells, through the release of IL-5, are associated with
Eosinophilic Inflammation and, through the release of IL-4 and IL-
13, are associated with increased IgE formation.

Recently, bronchial biopsies have demonstrated a preponderance

of natural killer CD4+ T lymphocytes that express high levels of
IL-4.

Regulatory T cells play an important role in determining the

expression of other T cells, and there is evidence for a reduction
in a certain subset of regulatory T cells (CD4+CD25+) in
asthma that is associated with increased T H2 cells.
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.
 In addition, epithelial cells may have key roles in translating inhaled
environmental signals into an airway inflammatory response, and are
probably major target cells for ICS.
3. Inflammatory Mediators
 Many different mediators have been implicated in asthma, and
they may have a variety of effects on the airways that could
account for the pathologic features of asthma (Fig. 254-4).

 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.

Although the multiplicity of mediators makes it unlikely that

preventing the synthesis or action of a single mediator will have
a major impact in clinical asthma, recent clinical studies with
antileukotrienes suggest that cysteinyl-leukotrienes have
clinically important effects.
Many cells and mediators are involved in asthma and lead to several effects
on the airways.
Cytokines
 Multiple cytokines regulate the chronic inflammation of asthma.

 The TH2 cytokines IL-4, IL-5, and IL-13 mediate allergic

inflammation,
 Whereas proinflammatory cytokines such as TNF-a and IL-1B, amplify
the inflammatory response and play a role in more severe disease.
Thymic Stromal Lymphopoietin is an upstream cytokine released
from epithelial cells of asthmatics that orchestrates the release of
chemokines that selectively attract T H2 cells.

Some cytokines such as IL-10 and IL-12 are anti-inflammatory

and may be deficient in asthma.
Chemokines
 Chemokines are involved in attracting inflammatory cells from
the bronchial circulation into the airways.

 Eotaxin (CCL11) is selectively attractant to eosinophils via CCR3

and is expressed by epithelial cells of asthmatics, whereas CCL17
(TARC) and CCL22 (MDC) from epithelial cells attract T H2 cells
via CCR4 (Fig. 254-5).
Chemokines in Asthma.

Tumor necrosis factor (TNF-a) and

other triggers of airway epithelial cells
release thymus and activationregulated
chemokine (TARC, CCL17) and
macrophage-derived chemokine (MDC,
CCL22) from epithelial cells that attract
TH2 cells via activation of their CCR4
receptors.

These promote eosinophilic

inflammation directly through the release
of interleukin (IL)-5 and indirectly via
the release of IL-4 and IL-13, which
induce eotaxin (CCL11) formation in
airway epithelial cells.
Oxidative Stress
 There is increased oxidative stress in asthma as activated
inflammatory cells such as macrophages and eosinophils that
produce reactive oxygen species.
 Evidence for increased oxidative stress in asthma is provided by the
increased concentrations of 8-isoprostane (a product of oxidized
arachidonic acid) in exhaled breath condensates and increased ethane (a
product of lipid peroxidation) in the expired air of asthmatic patients.
 Increased oxidative stress is related to disease severity, may
amplify the inflammatory response, and may reduce
responsiveness to corticosteroids.
Nitric Oxide
 Nitric oxide (NO) is produced by several cells in the airway by
NO synthases, particularly airway epithelial cells and
macrophages.
 The level of NO in the expired air of patients with asthma is
higher than normal and is related to the eosinophilic inflammation.

 Increased NO may contribute to the Bronchial Vasodilation

observed in asthma.
 Exhaled NO is increasingly used in the diagnosis and monitoring of
asthmatic inflammation, although it is not yet used routinely in clinical
practice.
Transcription Factors
 Proinflammatory transcription factors such as nuclear factor-kB
(NF-kB) and activator protein-1, are activated in asthmatic
airways and orchestrate the expression of multiple inflammatory
genes.

 More specific transcription factors that are involved include

nuclear factor of activated T cells and GATA-3, which regulate the
expression of TH2 cytokines in T cells.
4. Effects of Inflammation
 The chronic inflammatory response has several effects on the
target cells of the airways, resulting in the characteristic
pathophysiologic changes associated with asthma.

 Asthma may be regarded as a disease with continuous

inflammation and repair proceeding simultaneously.
Important advances continue to be made in our understanding of
these changes,
But, despite these new insights, the relationship between
chronic inflammatory processes and asthma symptoms is often
not clear.
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 allergen
exposure, 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
1. Loss of its barrier function to allow penetration of allergens;
2. Loss of enzymes (such as neutral endopeptidase) that degrade
certain peptide inflammatory mediators;
3. Loss of a relaxant factor (so called epithelial-derived relaxant
factor); and
4. Exposure of sensory nerves, which may lead to reflex neural
effects on the airway.
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-B.
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.
Airway Smooth Muscle
 There is still debate about the role of abnormalities in airway
smooth muscle in asthmatic airways.

 In vitro airway smooth muscle from asthmatic patients usually

shows no increased responsiveness to constrictors.

 Reduced responsiveness to B-agonists has also been reported in

postmortem or surgically removed bronchi from asthmatics, although the
number of B-receptors is not reduced, suggesting that B-receptors have
been uncoupled.
These abnormalities of airway smooth-muscle may be secondary
to the chronic inflammatory process.

Inflammatory mediators may modulate the ion channels that

serve to regulate the resting membrane potential of airway
smooth-muscle cells, thus altering the level of excitability of
these cells.
In asthmatic airways there is also a characteristic hypertrophy
and hyperplasia of airway smooth muscle,

Which is presumably the result of stimulation of airway

smooth-muscle cells by various growth factors such as platelet-
derived growth factor (PDGF) or endothelin-1 released from
inflammatory or epithelial cells.
Vascular Responses
 There is increased airway mucosal blood flow in asthma.

 The bronchial circulation may play an important role in regulating

airway caliber, since an increase in the vascular volume may
contribute to airway narrowing.

 Increased airway blood flow may be important in removing

inflammatory mediators from the airway, and may play a role in
the development of exercise-induced asthma.
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.
Mucus Hypersecretion
 Increased mucus secretion contributes to the viscid mucous plugs
that occlude asthmatic airways, particularly in fatal asthma.

 There is evidence for hyperplasia of submucosal glands that are confined

to large airways and of increased numbers of epithelial goblet cells.

 IL-4 and IL-13 induce mucus hypersecretion in experimental

models of asthma.
Neural Effects
 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.
5. 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.
This observation suggests that 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

1. Increased Airway Smooth Muscle,
2. Fibrosis,
3. Angiogenesis, and
4. Mucus Hyperplasia.
Asthma Triggers
Several stimuli trigger airway narrowing, wheezing, and dyspnea
in asthmatic patients.

While the previous view held that these should be avoided, it is

now seen as evidence for poor control and an indicator of the
need to increase controller (preventive) therapy.
1. 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
low-grade 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).
2. 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.
3. Pharmacologic Agents
 Several drugs may trigger asthma.

 Beta-adrenergic 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 beta blockers need to be avoided and even selective B 2 blocker or
topical application (e.g., timolol eye drops) may be dangerous.
ACE 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 (aspirin-sensitive

asthma is discussed below under "Special Considerations").
4. 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 recovers spontaneously within about 30 minutes.

EIA is worse in cold, dry climates than in hot, humid conditions.

It is, therefore, more common in sports such as cross-country

running in cold weather, overland skiing, and ice hockey than in
swimming.
It may be prevented by prior administration of B2-agonists and
antileukotrienes, but is best prevented by regular treatment with
ICS, which reduce the population of surface mast cells required
for this response.
5. 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.
6. Food
 There is little evidence that allergic reactions to food lead to
increased asthma symptoms, despite the belief of many patients
that their symptoms are triggered by particular food constituents.

 Exclusion diets are usually unsuccessful at reducing the frequency of

episodes.
Some foods such as shellfish and nuts may induce anaphylactic
reactions that may include wheezing.

Patients with aspirin-induced asthma may benefit from a

salicylate-free diet, but these are difficult to maintain.
Certain food additives may trigger asthma.

Metabisulfite, which is used as a food preservative, may trigger

asthma through the release of sulfur dioxide gas in the stomach.

Tartrazine, a yellow food-coloring agent, was believed to be a

trigger for asthma, but there is little convincing evidence for this.
7. Air Pollution
 Increased ambient levels of sulfur dioxide, ozone, and nitrogen
oxides are associated with increased asthma symptoms.
8. Occupational Factors
 Several substances found in the workplace may act as sensitizing
agents, as discussed above, but may also act as triggers of asthma
symptoms.

 Occupational asthma is characteristically associated with

symptoms at work with relief on weekends and holidays.
If removed from exposure within the first 6 months of symptoms,
there is usually complete recovery.

More persistent symptoms lead to irreversible airway changes,

and, thus, early detection and avoidance are important.
9. Hormonal Factors
 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.
10. Gastroesophageal Reflux
 Gastroesophageal reflux is common in asthmatic patients as it is
increased by bronchodilators.

 Although acid reflux might trigger reflex bronchoconstriction, it

rarely causes asthma symptoms, and antireflux therapy fails to
reduce asthma symptoms in most patients.
11. Stress
 Many asthmatics report worsening of symptoms with stress.

 There is no doubt that 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.
Pathophysiology
Limitation of airflow is due mainly to bronchoconstriction, but
Airway Edema, Vascular Congestion, and Luminal occlusion with
exudate may also contribute.

This results in a reduction in

1. Forced expiratory volume in 1 second (FEV 1),
2. FEV1/forced vital capacity (FVC) ratio, and
3. Peak expiratory flow (PEF),
As well as an increase in airway resistance.
Early closure of peripheral airway results in lung hyperinflation,
(air trapping) and increased residual volume, particularly during
Acute Exacerbations and in Severe Persistent Asthma.

In more severe asthma, reduced ventilation and increased

pulmonary blood flow result in mismatching of ventilation and
perfusion and in bronchial hyperemia.

Ventilatory failure is very uncommon, even in patients with

severe asthma, and arterial Pco2 tends to be low due to
increased ventilation.
Airway Hyperresponsiveness
 AHR is the characteristic physiologic abnormality of asthma and
describes the excessive bronchoconstrictor response to multiple
inhaled triggers that would have no effect on normal airways.

 The increase in AHR is linked to the frequency of asthma symptoms,

and, thus, an important aim of therapy is to reduce AHR.
Increased bronchoconstrictor responsiveness is seen with direct
broncho constrictors such as histamine and methacholine, which
contract airway smooth muscle,
But is characteristically also seen with many indirect stimuli,
which release bronchoconstrictors from mast cells or activate
sensory nerves.

Most of the triggers for asthma symptoms appear to act indirectly,

including Allergens, Exercise, Hyperventilation, Fog (via mast cell
activation), Irritant Dusts, and Sulfur Dioxide (via a cholinergic
reflex).
Clinical Features and Diagnosis