Chapter 9.

Bronchial Asthma

Khaled O Hadeli MD, FCCP

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98

T he defiinition of bronchial
b a
asthma

t
hass been reviised
since i t was first described by Sir Wi lliam Oslerr in
1892. Duriing the lastt century, the definiti on focused
d on
clinical andd physiolog gical featur es of rever sible bronccho-
spasm and bronchial hyper resp onsiveness . This resullted
in confusioon because the two feeatures mayy be shared d by
other chro onic airwayy disorders such as chronic
c airwway
pulmonaryy disease (C COPD).
The lat est definitiion was repported by t he Global Ini-
tiative for Asthma (G GINA) prog gram in 20 004; a chro onic
inflammato ory disordeer of the airways in n which many
m
cells and cellular ellements pllay a role.. The chro onic
inflammatiion causes an associiated incre ase in airw way
hyper-resp ponsivenesss that leadss to recurreent episode s of
wheezing, breathlessn
b ness, chest tightness, and coughiing,
particularlyy at nightt or in th e early m orning. Th hese
episodes are
a usuallyy associateed with wiidespread but
variable airflow
a obsstruction that
t is oftten revers ible
either sponntaneously or with tre atment.

Air way 
Inflamation

Reversable 
Air wayy hyper‐
responsivness Air way 
obstructio
on

Asthma
A

Figure 1. Definition of Asthma

 199 Asthma

Epidemiology
According to WHO statistics, bronchial asthma affects
300 million people; and 255,000 people died of asthma
in 2005. Asthma prevalence increases globally by 50%
every decade. The most striking increase in asthma
prevalence is seen among children. 80% of asthma
deaths occurred in low and lower-income countries, and
asthma deaths are projected to increase by 20% if ap-
propriate actions are not taken. The prevalence of
asthma in the developed countries ranges from 10.9% in
the United States, to more than 15% in the United King-
dom. In developing countries the prevalence of asthma is
less. The highest prevalence in Africa (8%) is seen in
South Africa, but is increasing at a higher rate in devel-
oping countries as they urbanize and westernize.
Worldwide, the burden of asthma on the economy ex-
ceeds that of tuberculosis and HIV combined. In the
United States, asthma-related treatment cost, cost
related to loss of work, loss of productivity, and early
retirement was estimated to be $12 billion in 2004.
These costs are directly related to the severity of the
disease. Even though patients with severe asthma consti-
tute only 20% of the total asthma population, they are
responsible for 50% of the cost of the disease.

• Industrialized countries have a

higher prevalence of asthma
• Developing countries have a
higher incidence of asthma
• Asthma mortality is higher in
poor countries
• The cost of asthma treatment is
high
 The Oea Review of Medicine 200

Pathophysiology of Asthma
Asthma is a chronic disease with a complex interaction
of cells, mediators, and cytokines that result in inflam-
mation. This interaction causes smooth muscle contrac-
tion, smooth muscle hypertrophy, micro vascular
leakage, bronchial wall oedema, activation of airway
neurons, increase in airway responsiveness, stimulation
of mucus-secreting cells, mucus plugging of the airways,
disruption of the airway epithelium, and ultimately
causes widespread airflow limitation.
The inflammatory cells involved in the path physiol-
ogy of asthma include mast cells, macrophages, eosino-
phils, lymphocytes, neutrophils, basophils, and platelets.
These cells are capable of generating mediators that can
induce bronchospasm “early phase response”, or guide
the activation and migration of the eosinophils and
neutrophils, and cause a “late phase response” that
results in epithelial damage, capillary leak, and mucus
hyper secretion. These mediators include histamine,
platelet activating factors, leukotrienes LTC4, LTD4,
LTE4, prostaglandin D2 and other derivatives of the
arachidonic acid cascade.

• Complex interaction of cells, me-

diators, and cytokines.
• Early or Late phase response
• Widespread airflow limitation is
the ultimate result
 201 Asthma

Risk Factors for Asthma

The Environment: This is the most important risk
factor for asthma attacks. Correlation between the
prevalence of asthma and exposure to allergens is docu-
mented in several epidemiological studies. Indoor
allergens include mites, cat & dog allergens, fungi,
cockroach allergens, insect parts and feces, molds, and
dander. Outdoor air quality is a major contributor to
asthma expression as well. Outdoor allergens (pollens,
weeds, and grass) and outdoor pollution (industrial
smog, ozone, and nitric oxide) are included in the list of
culprits. Another interesting point is that environmental
factors in early life influence the development of asthma.
Children who grow up in large families, go to day care,
or live on farms will have a smaller chance of developing
asthma in later life, despite the fact that these same
environmental factors may have a negative effect on
asthma activity, as described above.
Genetics of asthma: Somewhat complex due
mainly to the heterogeneity of the asthma phenotype,
but is well documented.
Gender, Age, & Race: Females are more prone to
asthma, but in childhood, boys are more affected than
girls. Racial variation in the incidence and mortality of
asthma is proven, but geographic location is more im-
portant as immigrants acquire the risk of the local
population.
Extreme weights: Both over weight and under
weight people are at a higher risk of developing asthma.
In asthmatics, improvement in peak expiratory flow rate
(PEFR) variability is seen in patients who correct their
weight.
 The Oea Review of Medicine 202

Triggers of asthma attacks

• Allergens
• Infections
• Environmental endotoxines and irritants
• Stress
• Pain
• Medications
• Non-selective B-blockers (oral or ophthalmic)
• NSAID
• Steroid or other asthma controller withdrawal
• Food additives
• Gastro-esophageal reflux disease

Clinical Features of Asthma

The most common symptoms of asthma are wheezing,
shortness of breath, and cough. Chest tightness, chest
pain, and nocturnal awakening are less common, but
well described in the literature. Asthmatics may have
multiple symptoms, or may present with cough or
wheeze only. Most attacks of asthma are preceded by
allergen exposure; usually aeroallergens are responsible.
As described above in the Pathophysiology of Asthma
a reaction could be immediate and symptomatic, or
delayed where the patient may not appreciate any symp-
toms even with a similar degree of spirometric decline in
FEV1. The reason for this is thought to be the rapidity of
the decline of FEV1. If the decline is rapid the patient
will be symptomatic, but if the reaction is slow the attack
may pass unnoticed. Patients with a slow decline in their
FEV1 and who have a poor perception of their symptoms
are likely to be under medicated and are more likely to
develop fatal or near-fatal attacks. Cough variant asthma
is a common manifestation of asthma where objective
measurements of airflow limitation may be difficult. In
 203 Asthma

such patients bronchoprovocation testing may be needed

to diagnose the disease.
A constellation of signs can be seen with bronchial
asthma. Most common are tachypnea, prolonged exhala-
tion phase, wheeze, use of accessory muscles, and pulsus
paradoxus. The degree of wheezing does not predict the
severity of the disease; a quiet chest may actually be a
late sign of an acute severe attack. Early in the attack,
hyperventilation leads to decrease in CO2. Later on, in
advanced and severe cases when FEV1 is less than 15%,
VQ mismatch leads to “dead space ventilation”, com-
bined with increased work of breathing and increased
production of CO2 and O2 consumption. Blood levels of
CO2 may “normalize” or even rise to high levels, O2
levels continue to drop.

• Wheeze, breathlessness, and

cough are the most common
asthma symptoms
• Perception of asthma symptom is
variable, depending on the person
and the speed of FEV1 declin.
• Tachypnea and prolonged exhala-
tion phase are the most common
physical signs in asthma
• Hypercarbia, dead space ventila-
tion, and quiet chest in physical
examination are advanced find-
ings suggesting a severe attack
 The Oea Review of Medicine 204

Classification of Asthma
Class Frequency of Night time Lung Function
Attacks attacks

Mild < 2 attacks < Two FEV1 or

Intermittent weekly times per PERF>80%predicted,
month but PERF variability
<20%

Mild > 2 attacks > Two FEV1 or PERF >80%

Persistent per week, times per predicted, but PERF
but < 1 month variability 20-30%
attack daily

Moderate Daily attacks > One FEV1 or PERF >60%-

Persistent time per <80%, >30% PERF
week variability

Severe Continuous Frequent/ FEV1 or PERF <60%,

Persistent attacks Daily >30% PERF variability

Diagnosis and Monitoring of

Asthma
Signs and symptoms of asthma are nonspecific, patients
often poorly perceive symptoms, and there is a poor
correlation between signs and severity, making the
diagnosis and management of asthma challenging.
Several tests are developed to help with the diagnosis
and management of asthma:
Spirometry: FEV1 (forced expiratory volume in 1
second) and FVC (forced vital capacity) are very impor-
tant variables that help to quantify the degree of airway
obstruction. In acute attacks, the FEV1 usually drops by
30% of the baseline. The finding of 15% reversibility or
greater (of FEV1) after the use of short acting bronchodi-
lators is suggestive of asthma.
Peak expiratory flow rate: This is a good tool to
assess the variability in airflow limitation seen in asth-
 205 Asthma

matics. After establishing an individual’s normal range,

the peak flow rates can then be followed to monitor the
progression of the disease. The National Institute of
Health (NIH) has developed guidelines to help patients
monitor disease severity and control (zones of airflow
limitation).

• Green zone (80% and 100% of

person’s best) indicates good con-
trol
• Yellow (50%-80% of person’s
best) indicates poor control and
warrants patient attention, and
possibly a need to increase treat-
ment
• Red (less than 50%) indicates
very poor control and warrants
physician involvement

Arterial Blood Gas (ABG): The most common

finding in an asthma attack is hypoxemia due to ventila-
tion perfusion (VQ) mismatch. In mild to moderate
attacks, hyperventilation leads to hypocarbia and respi-
ratory alkalosis. As previously described, severe asthma
exacerbations may lead to normalization or hypercarbia
and worsening hypoxemia, heralding respiratory failure.
Bronchoprovocation testing: In patients with
typical features of asthma, but without spirometric or
peak flow confirmation, an inhalation challenge test may
be helpful. After giving the patient a dose of short-acting
bronchodilators to ensure normal airway at the start of
the test, standardized escalating doses of inhaled meth-
acholine or histamine are given. A 20% decline in FEV1
is diagnostic of asthma.
Radiological Features: Most commonly, the chest
x-ray of an asthmatic will be normal. The main findings
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with severee airway ob bstruction are hyperin

nflation of the
chest (figurre 2) and a flat diaphrragm.

Figure 2. Hyperinflation in 56 year old female with severe

asthma

Other Clinica
C l Forms
s of As
sthma
Occupa ational a sthma: A particularr occupatio onal
environme nt precipittates attack ks in certaain suscept ible
individualss. Animal handlers, grain han dlers, pou ultry
workers, a nd spray p ainters aree some occu upations assso-
ciated withh this formm of asthm ma. Often, symptoms
s im-
prove in a few days away
a from the occup ation. Seek king
occupationnal history in patientss with asth ma may prrove
to be the most impo ortant step p in the management
m t of
ma.
their asthm
Noctur rnal asthm ma: Attack ks occur m ore frequen ntly
at night, perhaps
p as a differen nt expressiion of gen eric
asthma. Th he nocturn al attacks area though ht to be duee to
circadian rhythm
r variiability in bronchial
b nflammatio n.
in
Exerci se induce ed asthma a: The exa act mechan ism
of this formm of asthmma is not clear.
c Evapo orative losss of
water and heat by inh halation of large volu mes of unccon-
ditioned aiir during ex
xercise mayy provoke b ronchospassm.
 207 Asthma

Couggh varian nt asthma : Cough is the main symp-s

tom, andd diagnosiss can be made
m with bronchopro
b ovoca-
tion tessting. The cough usually
u ressponds weell to
treatmennt with bronnchodilatorrs and sterooids.
Drugg induced d asthma: Main culprrit drugs in nclude
aspirin and
a beta-bloockers.
ABPA A (allergicc bronchop pulmonary aspergillossis or
allergic bronchopu ulmonary mycosis):
m A form of assthma
thought to reflectt hypersen nsitivity to
o fungi u sually
Aspergilllus fumigattus. This foorm is charracterized by
b the
formatioon of thick respiratory
r secretions and mucuss plug
(figure 3),
3 presencce of eosi nophilia, high h IgE levels,
l
antibodiees to asperrgillus, and
d recurrent lung infilttrates.
If untrea
ated this may
m lead to bronchiec tasis. Treattment
includes the use of o steroidss. The rolee of anti-ffungal
medicatiions is less defined.

Figure 3. Mucus plug pulled of 45 year old female with

ABPA
 The Oea Review of Medicine 208

Churg-Strauss syndrome: Is a multisystem dis-

ease characterized by allergic rhinitis, asthma, and blood
eosinophilia. Involvement of other systems could be
seen. The gold standard diagnostic procedure is open
lung biopsy with findings including eosinophilic infil-
trates, giant cell vasculitis, interstitial granulomas, and
eosinophilic lymphadenopathy. Leukotriene modifying
agents were implicated in the development of the dis-
ease, however, it is believed that the tapering off of the
steroids in these patients unmasked the disease rather
than the other way around. Treatment is usually with
high dose steroids.
Fatal or near-fatal asthma: is an important
variant of asthma presentation. Despite better under-
standing of the pathophysiology of asthma and the
availability of effective medications, acute attacks with
significant mortality rates still occur.
According to the British Thoracic Society, risks of devel-
oping near fatal attacks are:
• Previous history of near fatal asthma
• Previous history of hospitalization due to asthma
• Previous history of mechanical ventilation due to
respiratory failure from asthma
• Patient on 3 or more classes of asthma medication
• Heavy use of B-agonist
• Behavioral problems (non-compliance, alcohol
abuse, drug abuse…etc.)
• Social problems (poverty, social isolation, child
abuse…etc.)
• Other risk factors include:
• Marked fluctuations of PERF am/pm readings
• People with blunt response to hypoxemia
• Lack of prophylactic anti-inflammatory treatment
Death is usually due to hypercarbic respiratory fail-
ure. Despite severe hypercarbia and very low pH, severe
attacks can be reversed with appropriate management.
 209 Asthma

When an asthma attack is sudden and respiratory failure

occurs fast, the recovery can be quick and complete,
compared to attacks that are slow to progress.
Patients who require mechanical ventilation pose a
significant challenge to the physician. Severe broncho-
spasm and limitation of airflow make ventilation very
difficult; and old strategies aimed at quick correction of
blood gas derangement may lead to increased mortality
from barotrauma and decreased cardiac output due to
increased intrathoracic pressure and decreased venus
return. The use of mechanical ventilation strategies
leading to permissive hypercarbia has improved the
outcomes.
Proper asthma control can significantly reduce near
fatal attacks and asthma mortality. Measures like the
regular use of peak flow meters, written action plans,
better patient-physician communication, better patient
compliance, and the use of corticosteroids can help in
this regard.

Management of Asthma
Environmental control of asthma
Once a patient is diagnosed with asthma, a detailed
environmental and occupational history is essential.
General or specific advice about environmental changes
is the cornerstone of asthma management and control.
Patients need to appreciate that asthma is a clinical
syndrome, where the clinical manifestation can be
controlled but the condition is likely to be lifelong.
Environmental education is important for the patient for
the rest of his/her life. Occupational exposures and type
of home furnishings, that may influence the disease, may
be difficult to change at the time of diagnosis, but may
be necessary to improve control of the disease.
 The Oea Review of Medicine 210

Pharmacological Treatment of Asthma

Short- term objectives: The use of short acting
bronchodilators to control an acute attack and to manage
a fall in the PERF or FEV1.
Long-term objectives: The use of anti- inflam-
matory medications and long-acting bronchodilators for
daily maintenance and diminished acute exacerbations.

Asthma Treatment By Severity:*

Asthma Short acting Long acting
Severity/ treatment “Rescue medication” “maintainer”

Mild Intermittent SABA as needed NON

Mild Persistent SABA ICS or LMA or Cs

Moderate persistent SABA LABA and ICS vs.

Higher dose ICS with
or without
LMA/Theo

Severe Persistent SABA All the above and

oral steroids

Short acting beta-agonist (SABA), Long Acting beta-agonist

(LABA), Inhaled corticosteroids (ICS), Leukotriene-
modifying agent (LMAs), Cromolyn sodium (Cs), Theophyl-
line (Theo)

*If uncontrolled at any severity level, consider pulse

treatment with oral steroids.
 211 Asthma

Medications
Anti-inflammatory Agents
Corticosteroid
• Mode of action: Prevent migration and activation of
inflammatory cells, interfere with the production of
prostaglandins and leukotrienes, and reduce capil-
lary leak.
• Use: All forms of asthma with severity higher than
mild intermittent.
• Preparations: Oral and inhaled.
• Side effects: Long-term use of inhaled corticostero-
ids is associated with a good safety profile; nonethe-
less local effects such as hoarseness of voice,
dysphonia, cough, and oral candidiasis can be ex-
pected. Hypophyseal-pituitary-adrenal suppression,
osteoporosis, cataract, hypertension, diabetes melli-
tus, and immune suppression can be seen, especially
with long-term use of oral preparations.
Cromolyn Sodium
• Mode of action: Mast cell stabilization
• Use: Allergen-induced asthma
• Preparation: Inhalation.
• Very good safety profile
Leukotriene Modifying Agent
• Mode of action: Inhibit the cysteinyl leukotrienes
and Leukotriene C4, D4, and E4.
• Use: particularly useful in allergen-induced asthma,
exercise- induced asthma, and aspirin- induced
asthma.
• Preparation: Oral
• Side effects: Generally very safe with reports of rare
cases of Churge-strauss vasculitis in patients with
 The Oea Review of Medicine 212

severe steroid-dependent asthma during steroid ta-

per while being on LPMs.
Bronchodilators
Short Acting Beta Agonist (SABA)
• Mode of action: Airway dilation by producing
cAMP, also reduce the release of inflammatory me-
diators and improve mucocilliary transport. Used as
rescue medication and prophylactic in exercise-
induced asthma.
• Use: All levels of severity, preferably on “as needed”
basis.
• Preparation: Oral and inhaled.
• Side effects: Despite selectivity, may have systemic
adrenergic effects like tremors, arrhythmias, palpi-
tation, and paradoxical bronchospasm. Regular use
of Beta 2 agonists is thought to be associated with
increased mortality. So, these medications are bet-
ter used as an “as needed” rescue medication.
Long Acting Beta Agonist (LABA)
• Mode of action: Similar to that of short acting bron-
chodilators, but due to lipophilicity the duration of
action is much longer.
• Use: Moderate persistent severity or higher.
• Preparation: Inhaler.
• Side effects: the safety profile of long acting beta
agonists is controversial. The weight of evidence fa-
vors their use in moderate persistent severity or
higher in combination with corticosteroids.
Methylxanthines
• Mode of action: Not defined. Methylxanthines are
effective bronchodilators with anti-inflammatory
properties.
• Use: Moderate persistent asthma or higher.
 213 Asthma

• Preparation: Oral.
• Side effects: Narrow therapeutic margin, requires
monitoring of therapeutic levels especially in the el-
derly. Side effects include GI upset in mild toxicity
and serious cardiac arrhythmias seen in high blood
levels.
Magnesium Sulfate
• Mode of action: Inhibits calcium channel smooth
muscle and reduce acetylcholine release.
• Use: Acute severe attack.
• Preparation: Intravenous.
• Side effects: circulatory collapse.
An t icho lin erg i cs

• Mode of action: Reduce vagal tone, synergistically

when used with Beta agonists.
• Use: mainly used in COPD, or as a substitute to beta
agonists and methylxanthines in patients with car-
diac arrhythmias.
• Preparation: inhaler.
• Side effect: slow-acting. Caution in patients with
glaucoma or urinary retention.
The Patient–physician Relationship and
its Effect on Asthma Control
The outcome of asthma management and the degree of
asthma control are influenced by the patient-physician
relationship. Best compliance and outcomes are seen
with patient-focused approach, where the physician
interacts with the patient in a friendly and open-minded
way. The physician listens to the patient’s concerns and
develops a trusting two-way communication. This ap-
proach will enable the physician to understand the
patient, not only his illness. Disease-focused approaches
 The Oea Review of Medicine 214

may lead to loss of effective communication with the

patient, and ultimately poor adherence and outcome.
Summary of Asthma Management
• Use of objective measures of lung function to assess
the severity of asthma and to monitor the efficacy of
treatment.
• Identification and elimination of factors that wor-
sen symptoms, precipitate attacks, or promote on-
going airway inflammation (environmental control).
• Comprehensive pharmacological therapy to reverse
bronchoconstriction and prevent airway inflamma-
tion.
• Creating a patient-focused relationship between the
patient and health provider.
Further Reading
1. Bethesda MD. Expert panel 2: guidelines for the diagnosis
and management of asthma. NIH publication 1997; No.
97-4051.
2. Braman SS. Decreasing the global burden of asthma.
Chest 2006; 130(suppl):S4-S12.
3. Masoli M, Fabian D, Holt S, Beasley R, von Hertzen L.
GINA program: The global burden of asthma. Allergy
2004;59:469-478.
4. Canonica GW. Treating asthma as inflammory disease.
Chest 2006;130(suppl):S21-S28.
5. Hall IP. Genetics and pulmonary medicine: asthma.
Thorax 1999;54:65-69.
6. Kay AB. Pathology of mild, severe, and fatal asthma. Am J
Respir Crit Care Med 1996;154(suppl):S66-S69.
7. Graham LM. Classifying asthma. Chest 2006;
130(suppl):S13-S20.
8. Palma-Carlos AG. Correlation between clinical classifica-
tion, PEF and FEV1: guidelines and reality. Allergy Im-
munol (Paris) 2003;35:130-132.
 215 Asthma

9. Corbridge TC, Hall JB. The assessment and management

of patient with status asthmaticus. Am J respire Crit Care
Med 1995;151:1296-1316.
10. Cockrill BA. ABPA. Annual Rev Med 1999;50:303-316.
11. Jimenez-Friedman G, Beckett W, Szeinuk J, Petsonk E.
Clinical evaluation, management, and prevention of work-
related asthma. Am J Ind Med 2000;37:121-141.
12. Greening AP, Ind PW, Northfield M, Shaw G. Added
salmeterol versus high-dose corticosteroids in asthma
patients. Lancet 1994;344:219-224.
13. Salvi SS, Krishna MT, Sampson AP, Holgate ST. The anti-
inflammatory effects of Leukotriene-modifying drugs and
their use in asthma. Chest 2001; 119:1533-1546.
14. Irwin R. Patient-Focused Care. Chest 2006;
130(suppl):S73-S82.
15. The Smart study. Chest. 2006;129:15-26.
Websites
1. http://www.ginasthma.com/
Global Initiative for asthma (GINA).
2. www.who.int/respiratory/gard/en/
Global Alliance against Chronic Respiratory Diseases
(GARD).
3. www.who.int/topics/asthma/en/
World Health Organization: Asthma, Fact Sheet.