CHAPTER VI

BRONCHIAL ASTHMA
Definition: Bronchial asthma is considered (Bethesda Consensus 1995) a chronic inflammation of
the airways, associated with a non-specific bronchial hyper-reactivity to various stimuli, which
clinically determines recurrent paroxysms of dyspnea (expiratory bradypnea), cough, wheezing
and sibilant rales, associated with obstructive-type pulmonary function tests disturbances of
various severity, partially or totally reversible, spontaneously or under appropriate therapy.

General Considerations:
1. The first complete description of the asthma attack was proposed by Trousseau in 1868.
2. Asthma is common in adults (prevalence ~ 5%) and even more common in children (~ 10%).
Men and women are equally affected. A genetic susceptibility to asthma is recognized.
3. Asthma prevalence is greater in industrialized countries but differences with developing
countries are lessening. The prevalence of asthma is increasing worldwide.
4. Mortality rate ~ 2-4%, particularly high in children and teenagers (50% of deaths caused by
asthma happened in children < 10 years).

Major types of asthma: Asthma traditionally has been divided into two forms (table VI-1):
I. Allergic (atopic, extrinsic) asthma:
 Onset usually in childhood and may persist into adulthood, although remission in
adolescence is common
 Atopic susceptibility – personal and/or family history of other allergic diseases
(allergic rhinitis, eczema, urticaria).
 Marked eosinophilia, increased serum Ig E, skin tests to allergens are positive.
 Allergen exposure initiates the asthma attack. Types of allergens: dusts, odors, pollen
grains, milk, fish, eggs, penicillin or serum injections, wool, synthetic cloth, etc.
II. Nonallergic (nonatopic, intrinsic) asthma:
 Onset in adults (late - onset asthma) (> 40 years).
 Often associates with perennial nonallergic rhinitis.
 The disease cannot be classified on the basis of defined immunological mechanisms.
These patients are said to have idiosyncratic asthma.
 There is a special type of intrinsic asthma in which the patient is exquisitely sensitive
to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS).
 These intrinsic asthma individuals may be confused clinically with patients having
chronic bronchitis or emphysema, because asthma exhibits virtually identical
symptoms to these diseases, caused by airflow limitation.

EXTRINSIC ASTHMA INTRINSIC ASTHMA

Type of patient Usually atopic Nonatopic
Age on onset Child and young adult Middle age
Family history Allergy Bronchial asthma
Nasal symptoms Allergic rhinitis ? Nasal polyps ?
Aspirin sensitivity Not a feature Significant association
Course Intermittent Continuous
Bronchitis Uncommon Common
Skin tests + ---
Ig E level Raised Normal or low
Prognosis Good Poor
Table VI-1: Major differentiation features between extrinsic and intrinsic asthma.

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Pathogenesis:
1. Asthma is regarded primarily as an inflammatory disease of airways, leading to bronchiolo-
obstruction, initially transient, but in late stages it becomes permanent, involving fibrosis. The
inflammation is present even in patients with mild asthma who are asymptomatic.

2. Inflammation underlies airway hyperresponsiveness (nonspecific bronchial hyper-reactivity):

an increased airway narrowing in response to a wide range of stimuli (triggers and chemical
mediators):
 Physical and chemical -- TRIGGERS:
1. Allergen 5. Aspirin
2. Exercise 6. Cigarette smoke, industrial fumes
3. Cold air 7. Irritant gases
4. Particulates

Fig. VI-1: Mechanisms of asthma (reproduced from Barnes P.J., Godfrey S., Asthma, Martin Dunitz Ltd,
London, ISBN 1-85317-277-4,1996)

 CHEMICAL MEDIATORS (inflammatory mediators) released by the inflammatory

cells (mast cells, macrophages, eosinophils, neutrophils and T-helper lymphocytes) are
powerful smooth muscle and vasoactive mediators, which cause the immediate
asthmatic reaction:
1. Histamine.
2. Leukotrienes, especially leukotriene C4 (LTC4).
3. Prostaglandins, especially prostaglandin D2 (PGD2).
4. Bradykinin.

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 Adrenergic beta-blockade theory (Szentivanyi). Bronchial mucosa has two types of
receptors:
 Beta-adrenergic receptors, stimulated by the sympathetic nervous system,
activate the adenilate-cyclase, which transform ATP in 3.5 cAMP,
responsible for bronchodilatation.
 Cholinergic receptors, stimulated by parasympathetic vagal fibers, through
cGMP synthesis, determine bronchoconstriction.
According to this theory, allergen inhalation induces a beta-adrenergic receptors
blockade (by linkage with their active sites), resulting a non-balanced cholinergic
(bronchocontrictive) stimulation.

3. Inflammatory mediators effects:

a) Bronchoconstriction.
b) Mucus hypersecretion (mucus gland and goblet cell hyperplasia).
c) Edema, exudation of plasma.
d) Patchy epithelial shedding.
e) Airway hyper-reactivity.
f) Activation of cholinergic reflexes that may amplify the inflammation.

4. The CYTOKINES (multiple intracellular messengers, e.g. interleukin 1, 2, 4, 5) are

responsible for coordinating, amplifying and perpetuating the inflammatory response
and attracting additional inflammatory cells.

Fig. VI-2:
Mechanisms leading
to secretion of
mediators and
epithelial damage in
asthmatic airways
(reproduced from Barnes
P.J., Godfrey S., Asthma,
Martin Dunitz Ltd,
London, ISBN 1-85317-
277-4,1996)

5. Chronic inflammation leads to structural changes, defining the irreversible (fixed)

obstructive syndrome of the airflows (see also fig. VI-1 and VI-2):
 Subepithelial fibrosis (basement membrane thickening).
 Airway smooth muscle hyperplasia and hypertrophy.
 New vessel formation.

6. In extrinsic asthma antibodies of the IgE type are formed in response to the antigen
(common materials present in the environment) and fixed to the bronchial mucous
cells, especially on “mast cells”(fig. VI-2). When the patient is exposed once again to

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 the antigen, an antigen-antibody reaction will occur on the surface of the mast cells,
leading to its stimulation and several chemical mediators are liberated. A gene on
chromosome 11 controls IgE antibody production.

N.B !
1. Airway narrowing in asthma results from a combination of smooth muscle spasm, airway
edema and inflammation, and mucus plugging.
2. The pathophysiologic changes, although are affecting the entire lung parenchyma are not
uniformly distributed. Some airways may display a predominance of bronchospasm, mucous
plugging may occlude others, and still others may appear unaffected.

INDUCERS:
Allergen
Chemical sensitizers BRONCHIAL INFLAMMATION
Virus infections ?
Air pollutants ??

CHEMICAL MEDIATORS OF INFLAMMATION

AIRWAY
HYPERRESPONSIVENES

Triggers:
Allergen, SO2,
Cold air,
Particulates,
Cigarette

Edema Mucus hypersecretion Bronchoconstriction

OBSTRUCTION OF THE BRONCHIOLES

CLINICAL FEATURES:
Paroxysms of dyspnea (expiratory bradypnea),
cough, wheezing and sibilant rales

Fig. VI- 3: Relationship between airway inflammation, airway hyperreactivity and clinical
features of asthma.

Precipitating factors (triggers) (according to Harrison’s Principle of Internal Medicine, 14 th ed.):

The stimuli that interact with airway responsiveness and incite acute episodes of asthma can be
grouped into seven major categories:
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 1. allergenic; 5. infectious;
2. pharmacological; 6. exercise-related;
3. environmental; 7. emotional.
4. occupational;

1. Allergens:
 Allergic asthmatic patients (the great majority of them are children and young adults) have
seasonal attacks, in response to the higher atmospheric concentration of allergens
(especially pollen).
 A nonseasonal form may result from allergy to feathers, animal dander, dust mites, molds,
and other antigens that are present continuously in the environment.
 Exposure to allergen by atopic asthmatic individuals leads to the development of four
types of reactions:
1. Immediate response (immediate asthma) in which airways obstruction develops in
minutes (maximum severity in 15-20 min) and then subsides (after 1 h).
2. Dual asthmatic response is a combination of an immediate response, followed by a
more prolonged, sustained, and relatively resisting to bronchodilator drugs attack of
airflow limitation (late reaction).
3. Isolated late reaction occurs especially in occupational asthma, being related to work-
place exposure to isocyanates. The delay between the moment of inhalation and the
onset of the symptoms may be up to 4-10 hours.
4. Recurrent asthmatic reactions represent repetitive episodes of asthma lasting for
several days after the allergen inhalation.

2. Pharmacological Stimuli:
 The drugs most commonly associated with the induction of acute episodes of asthma are
aspirin, nonsteroidal anti-inflammatory agents (indomethacin, fenoprofen, naproxen,
ibuprofen, and phenylbutazone), coloring agents tartrazine), beta-adrenergic antagonists
(Propranolol), and sulfiting agents (potassium metabisulfite, potassium and sodium
bisulfite, sodium sulfite, and sulfur dioxide).

3. Air pollution:
 Asthmatic patients may experience worsening of symptoms on contact with various kinds
of atmospheric pollution. These conditions tend to develop in heavily industrial or densely
populated urban areas (thermal inversions creating stagnant air masses).
 Air pollutants known to precipitate asthma attacks: ozone, nitrogen dioxide, cigarette
smoke, high concentrations of dust, and sulfur dioxide.

4. Occupational factors. More than 200 materials are known to give rise to occupational asthma.
Atopic individuals develop the symptoms more rapidly, but non-atopic individuals can also
develop asthma, but usually to a higher level of exposure and after a longer period. It is now
very well established that working with, or being exposed to the following substances may
induce occupational asthma (after Harrison’s Principle of Internal Medicine, 14 th ed):
 metal salts (platinum, chrome, and nickel);
 wood and vegetable dusts (those of oak, western red cedar, grain, flour, castor bean,
green coffee bean, mako, gum acacia, karay gum, and tragacanth);
 pharmaceutical agents (antibiotics, piperazine, and cimetidine);
 industrial chemicals and plastics (toluene diisocyanate, phthalic acid anhydride,
trimellitic anhydride, persulfates, ethylenediamine, p-phenylenediamine);
 biologic enzymes (laundry detergents and pancreatic enzymes);
 animal and insect dusts, serums, and secretions.

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5. Infections:
 Respiratory viruses and not bacteria or allergy are the major etiological factors of
bronchial asthma exacerbations: rhinovirus and influenza virus (in adults), respiratory
syncytial virus and parainfluenza virus (in children).
 The mechanism by which viruses induce exacerbations of asthma may be related to the
production of T cell-derived cytokines that potentate the infiltration of inflammatory cells
into already susceptible airways.

6. Exercise:
 In some individuals, an asthmatic attack may occur 5—10 minutes after the onset of
exercise.
 Bronchospasm is related to heat or water loss from the bronchial surface.

7. Emotional stress:
 It is now scientifically demonstrated that emotional factors may influence asthma in terms
of higher severity episodes of airflow obstruction, and longer in duration, in almost all
asthmatics, if they exercise hard enough.
 There are some patients, mostly young adolescents, who have little or no clinical asthma
on a day-to-day basis, but develop severe asthma attacks when they take part in sports.
 The pathophysiology is not fully understood, but it seems that this phenomenon may be
related to endorphins level effects and modification of vagal efferent activity.

Pathophysiology (see also table VI-3):

1. Airway narrowing due to: contraction of the smooth muscle, vascular congestion, edema
of the bronchial wall, and thick bronchial secretions.
2. Increased airway resistance.
3. Decreased forced expiratory volumes and flow rates (FVC < 50% N, FEV 1 < 30% N).
4. Hyperinflation of the lung and thorax.
5. Increased work of accessory respiratory muscles.
6. Changes in elastic recoil.
7. Abnormal distribution of ventilation and pulmonary blood flow.
8. Altered blood gas concentrations (hypoxia).
9. Pulmonary hypertension leading to cor pulmonale.

Clinical Features:

1. Asthmatic attack is characterized by:

 Episodic wheezing.
 Sensation of tightness in the chest.
 Dyspnea (expiratory bradypnea).
 Paroxysmal cough.
2. The frequency of asthma attacks is highly variable. Some patients may have only one or two
attacks a year, that last few hours, whilst others may suffer nearly continuous symptoms (very
frequent attacks or attacks lasting for weeks). Symptoms are usually worst during the night.
Nocturnal asthma is usually most severe after 3–4 AM (morning deepening), due to circadian
variations in bronchomotor tone and bronchial reactivity, leading to bronchoconstriction
(vagal stimulation and accumulation of secretions).
3. The patient gets up suddenly with wheezy chest, marked dyspnea, persistent dry cough, and
anxiety.

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4. In extrinsic asthma, near the end of the attack, the patient expectorates a small amount of
viscid sputum (mucus pellets).
5. The typical asthmatic attack (allergic) usually lasts from few minutes to 1-2 hours.
6. Physical findings vary with the severity of the attack:
 A mild attack may produce only slight tachycardia and bradypnea, with prolonged
expiration and mild diffuse wheezing.
 Moderate attacks are associated with use of accessory muscles of respiration, distant
breath sounds, loud wheezing, sibilant rales extensively spread over the thoracic area,
hyperresonance (“air trapping”), and intercostal retraction.
 Severe asthma attacks include fatigue, pulsus paradoxus (> 20 mm Hg), hypotension,
diaphoresis, inaudible breath sounds with diminished wheezing, inability to maintain
recumbency, and cyanosis, leading to severe hypoxemia and may be hypercapnia.
7. Between the attacks the chest is completely free (unless bronchial asthma is accompanied with
bronchitis).

STATUS ASTHMATICUS is a prolonged (> 24-48 h), very severe asthmatic attack that does
not respond to treatment and involves the risk for ventilatory failure.
1. Causes: sudden stop of corticosteroid therapy, physical trauma, excessive use of 2
adrenergic therapy, prolonged exposure to allergens (or triggers), pneumothorax,
pulmonary infections.
2. Clinical features:
 Tachypnea / bradypnea (rare) ( > 30 respirations/min.)
 Central cyanosis.
 Muscles asthenia.
 Inaudible breath sounds, no wheezing, no cough !
 Hypotension, collapse.
 Acute cor pulmonale: tachycardia, gallop, hepatojugular reflux, Harzer`s sign
positive, pulsus paradoxus.
 Hypercapnic encephalopathy: loss of concentration, somnolence, attacks of
consciousness loss, flapping tremor, and superficial coma.
3. Hypoxemia with hypercapnia
4. Chest X-ray – severe hyperinflation
5. Prognosis – very severe.

Laboratory Findings:

1. Skin tests (“scratch” or “prick”) – positive in extrinsic asthma.

2. Sputum analysis:
 Viscid on gross examination. Excessive eosinophilia.
 Mucus casts of small airways (Curschmann's spirals).
 Elongated rhomboid crystals derived from the eosinophilic cytoplasm
(Charcot-Leyden crystals).

3. Pulmonary function tests -- obstructive dysfunction:

 FVC, FEV1/FVC ratio, FEF25–75, PEFR are reduced.
 RV, TLC, lung compliance and DLCO are increased.
 Partial reversibility (improvement in FVC or FEV 1 of at least 15% or
improvement in FEF25–75 of at least 25%) is often demonstrated after the attack.
 Values of PEFR under 100–200 l/min indicate severe ventilatory dysfunction
(normally 450–650 l/min in men and 350–500 l/min in women).
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 4. Arterial blood gas measurements in asthma may be normal during a mild attack, but
respiratory alkalosis and mild hypoxemia are usually observed.

5. Hematological studies reveal eosinophilia (10-30%) in both the allergic and intrinsic
form of the disease.

6. Immunological studies reveal increased level of Ig E (>250 U – PRIST technique) in

extrinsic asthma and normal, slightly increased or decreased in intrinsic asthma.

7. Chest X-ray reveals hyperinflation during attacks. Unnecessary in acute asthma,

important in differential diagnosis.

8. Methacholine or histamine provocation tests are helpful, particularly when baseline

spirometry is normal. Inhalation of gradually increasing concentrations of these
substances induces a transient episode of airflow limitation in subjects having
bronchial hyperresponsiveness.

Positive Diagnosis:
1. Episodic or chronic wheezing, dyspnea, cough, and feeling of tightness in the chest.
2. Prolonged expiration and diffuse wheezing on physical examination.
3. Limitation of airflow on pulmonary function testing, or positive bronchoprovocation
challenge test.
4. Complete or partial reversibility of obstructive dysfunction after bronchodilator
therapy.

Functional evaluation of asthma attack severity

From the point of view of how severe an asthma attack may be, the clinical features are
helpful, but cannot provide an objective perspective, necessary for an accurate differentiation
(table VI-3). Pulmonary function studies (spirometry) are best fit for this challenge (table VI-2).

Normal Mild attack Moderate attack Severe attack

FEV1 baseline > 80% > 70% > 60% < 60%
FEV1 after bronchodilator no change > 80% > 70% no change
PEFR baseline > 80% > 80% > 60% < 60%
PEFR after bronchodilator no change no change > 70% no change
MMFR baseline > 60% > 50% > 40% < 40%
MMFR after bronchodilator no change > 60% no change no change

Table VI-2: Functional evaluation of severity by spirometry. (modified and adapted after Barnes and
Godfrey, in Asthma, Ed. Martin Dunitz, 1996). See for abreviations the chapter II: Pulmonary Function Studies.

Severity
1. Intermittent asthma attacks
2. Mild perennial, asthma
Symptoms
* Less than 1 attack/week. Long symptom-free periods.
Less than 2 nocturnal attacks/month. Occasional absence
from work or school.
* More than 1 attack/week, but less than 1/day. More than
2 nocturnal attacks/month. Absence from work or school

50

3. Moderate perennial, asthma
4. Severe perennial, asthma
is usual
* Almost daily attacks. More than 1 nocturnal
attack/week. The patients cannot exercise normally and
are prone to miss work or school.
* Very frequent symptoms. Patients are disturbed on most
nights. Patients require continuous medication and
frequent hospitalizations.

Table VI-3: Classification of the bronchial asthma according to the severity and the frequency of
the attacks (adapted and modified from Global Initiative for Asthma, San Francisco, 1997)

Complications (see table VI-4):

Sudden complications Late complications

(during attack) (after years of evolution)
1. Spontaneous Pneumothorax 1. Pulmonary emphysema.
– paroxysmal cough may 2. Bronchial dilatations (bronchiectasis).
induce rupture of a bulla 3. Recurrent airway infections (bacterial, viral, aspergilus)
(hyperresonance, abolished 4. Chronic respiratory failure, leading to pulmonary
vesicular breath and vocal
hypertension and cor pulmonale.
fremitus).
5. Long term cortisone therapy may induce serious side
2. Pneumomediastin (rare)
effects:
3. Vagal syncope (cough  Osteoporosis
syncope).  Systemic hypertension.
4. Localized atelectasis. (due to  Cushing-like syndrome (diabetes mellitus,
viscid mucus accumulation) obesity, hypertension).
 Cortisone-induced diabetes mellitus.
 Growth disturbances during childhood.
*In Status Asthmaticus:  Peptic ulcer
 Severe respiratory failure.  Predisposing factor for infections.
 Dangerous ventricular  Cortisone dependence.
tachyarrhythmias. 6. 2 adrenergic therapy side effects:
 Palpitations.
 Arrhythmias.

Table VI-4: Early and late complications of bronchial asthma.

Differential Diagnosis:
A. Other causes of paroxysmal dyspnea with wheezing:
 Cardiac asthma (see below).
 Recurrent pulmonary embolism (deep venous thrombosis, S1Q3T3,
arteriography).
 Pulmonary vasculitis (complete examination of the patient reveals a systemic
vasculitis).
 Carcinoid syndrome (diarrhea, “flushing”).
B. Other causes of paroxysmal dyspnea:
 Extrinsic allergic alveolitis.
 Foreign body or tumor of the larynx (inspiratory dyspnea, stridor)
 Mediastinal syndrome (chest X-ray).

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  Hysterical dyspnea.
 Anaphylaxis.
 COPD acute phases.
C. Other causes of eosinophilia and reversible bronchial obstruction:
 Strongyloidosis.
 Bronchopulmonary aspergillosis.
 Churg-Strauss syndrome.

Particular attention must be paid to the differentiation of bronchial asthma attacks from some
relatively frequent diseases, clinically often similar, but with totally different treatment.
Cardiac asthma is the most important differential diagnosis (table VI-5)

Features Bronchial asthma Cardiac asthma

1. History Atopic syndrome. Hypertension, CAD, Left heart
Recurrent airway infections. valvulopathy, Dilative
cardiomyopathy.
2. Age All ages. Usually > 50 years.
3. The frequency of Relatively frequent attacks of Rare attacks of paroxysmal dyspnea,
attacks paroxysmal dyspnea with wheezing. usually precipitated by exertion.
4. Provoking factors. Allergy, Broncho-pulmonary Tachyarrhythmias, Exertion,
infections; Although present, the Hypervolemia. Association of attacks
relationship with exertion is reduced. with recumbency is highly suggestive.
5. Dyspnea Paroxysmal expiratory dyspnea, Paroxysmal, expiratory tachypnea.
associated with wheezing (usually
bradypnea).
6. Wheezing Very intense Moderate

7. Cough + +
8. Expectoration Viscid, mucus casts (Curschmann's Fluid, copious, blood-tinged (pink)
spirals) Charcot-Leyden crystals, or expectoration.
muco-purulent.
9. Physical Hyperinflation of the thorax. Fine and medium crackles, climbing
examination of the Hyperresonance. Prolonged expiration. from bases to apex, +/- sibilants.
lung Sibilant rales, +/- fine crackles Prolonged expiration.
(bronchial hypersecretion).
10. Physical +/- Moderate sinus tachycardia. High rate Tachycardia or
examination of the tachyarrhythmia, gallop, murmurs,
heart ECG abnormalities, ENZYMES.
11. Blood pressure Usually normal. Often hypertension.
12. Chest X-ray No cardiomegaly (cardio-thoracic Cardiomegaly, especially due to left
index <0,50). cavities enlargement (CTI> 0,50)
13. Blood analysis Marked eosinophilia. No eosinophilia.

Table VI-5: Differential diagnosis between bronchial asthma and cardiac asthma.

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