BRONCHIAL ASTHMA

Background

Asthma is a chronic reversible airway hyperresponsiveness to a variety of stimuli characterized

by airway inflammation, intermittent airflow obstruction, due to broncho-constriction and
edema. The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the
presence of airway edema and mucus secretion also contributes to airflow obstruction and
bronchial reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus
hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway
remodeling are present.

Airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response

to numerous exogenous and endogenous stimuli. The mechanisms involved include direct
stimulation of airway smooth muscle and indirect stimulation by pharmacologically active
substances from mediator-secreting cells such as mast cells or nonmyelinated sensory neurons.
The degree of airway hyperresponsiveness generally correlates with the clinical severity of
asthma.

Anatomy

The airways of the lungs consist of the cartilaginous bronchi, membranous bronchi, and gas-
exchanging bronchi termed the respiratory bronchioles and alveolar ducts. While the first 2 types
function mostly as anatomic dead space, they also contribute to airway resistance. The smallest
non-gas-exchanging airways, the terminal bronchioles, are approximately 0.5 mm in diameter;
airways are considered small if they are less than 2 mm in diameter. [4]

Airway structure consists of the following:

 Mucosa, which is composed of epithelial cells that are capable of specialized mucous
production and a transport apparatus
 Basement membrane
 A smooth-muscle matrix extending to the alveolar entrances
 Predominantly fibrocartilaginous or fibroelastic-supporting connective tissue.

Cellular elements include mast cells, which are involved in the complex control of releasing
histamine and other mediators. Basophils, eosinophils, neutrophils, and macrophages also are
responsible for extensive mediator release in the early and late stages of bronchial asthma.
Stretch and irritant receptors reside in the airways, as do cholinergic motor nerves, which
innervate the smooth muscle and glandular units. In bronchial asthma, smooth muscle
contraction in an airway is greater than that expected for its size if it were functioning normally,
and this contraction varies in its distribution.

Pathophysiology

The pathophysiology of asthma is complex and involves the following components:

 Airway inflammation
 Intermittent airflow obstruction
 Bronchial hyperresponsiveness

Airway inflammation

The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence
of airway edema and mucus secretion also contributes to airflow obstruction and bronchial
reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus
hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway
remodeling are present. [2] See the image below.

Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and
cytokine response leading to airway inflammation and asthma symptoms.

Some of the principal cells identified in airway inflammation include mast cells, eosinophils,
epithelial cells, macrophages, and activated T lymphocytes. T lymphocytes play an important
role in the regulation of airway inflammation through the release of numerous cytokines. Other
constituent airway cells, such as fibroblasts, endothelial cells, and epithelial cells, contribute to
the chronicity of the disease. Other factors, such as adhesion molecules (eg, selectins, integrins),
are critical in directing the inflammatory changes in the airway. Finally, cell-derived mediators
influence smooth muscle tone and produce structural changes and remodeling of the airway.

The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an

exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms
involved include direct stimulation of airway smooth muscle and indirect stimulation by
pharmacologically active substances from mediator-secreting cells such as mast cells or
nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates
with the clinical severity of asthma.

Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness,

which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and
coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In
some patients with chronic asthma, airflow limitation may be only partially reversible because of
airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and
subepithelial fibrosis) that occurs with chronic untreated disease.

The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain
some of the dramatic increases in asthma prevalence in westernized countries.7This hypothesis is
based on the concept that the immune system of the newborn is skewed toward Th2 cytokine
generation (mediators of allergic inflammation). Following birth, environmental stimuli such as
infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance. 
However, unequivocal support for the "hypgiene hypothesis" has not been demonstrated

Airflow obstruction

Airflow obstruction can be caused by a variety of changes, including acute bronchoconstriction,

airway edema, chronic mucous plug formation, and airway remodeling. Acute
bronchoconstriction is the consequence of immunoglobulin E-dependent mediator release upon
exposure to aeroallergens and is the primary component of the early asthmatic response. Airway
edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic
response. Chronic mucous plug formation consists of an exudate of serum proteins and cell
debris that may take weeks to resolve. Airway remodeling is associated with structural changes
due to long-standing inflammation and may profoundly affect the extent of reversibility of
airway obstruction.

Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates.
These changes lead to a decreased ability to expel air and may result in hyperinflation. The
resulting overdistention helps maintain airway patency, thereby improving expiratory flow;
however, it also alters pulmonary mechanics and increases the work of breathing.

Etiology

Factors that can contribute to asthma or airway hyperreactivity may include any of the following:

 Environmental allergens (eg, house dust mites; animal allergens, especially cat and dog;
cockroach allergens; and fungi)
 Viral respiratory tract infections
 Exercise, hyperventilation
 Gastroesophageal reflux disease
 Chronic sinusitis or rhinitis
 Aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, sulfite
sensitivity
 Use of beta-adrenergic receptor blockers (including ophthalmic preparations)
 Obesity
 Environmental pollutants, tobacco smoke
 Occupational exposure
 Irritants (eg, household sprays, paint fumes)
 Various high- and low-molecular-weight compounds (eg, insects, plants, latex, gums,
diisocyanates, anhydrides, wood dust, and fluxes; associated with occupational asthma)
 Emotional factors or stress
 Perinatal factors (prematurity and increased maternal age; maternal smoking and prenatal
exposure to tobacco smoke; breastfeeding has not been definitely shown to be protective)

Patient Education1

The key points of education include the following:

 Patient education should be integrated into every aspect of asthma care

 All members of the healthcare team, including nurses, pharmacists, and respiratory
therapists, should provide education.
 Clinicians should teach patients asthma self-management based on basic asthma facts,
self-monitoring techniques, the role of medications, inhaler use, and environmental
control measures.
 Treatment goals should be developed for the patient and family.
 A written, individualized, daily self-management plan should be developed.
 Several well-validated asthma action plans are now available and are key in the
management of asthma and should therefore be reviewed: ACT (Asthma Control Test),
 ATAQ (Asthma Therapy Assessment Questionnaire), and ACQ (Asthma Control
Questionnaire).

Clinical presentation

General manifestations of asthma

Typical symptoms include cough, wheezing, shortness of breath, and chest pain or tightness.

Wheezing, a musical, high-pitched, whistling sound produced by airflow turbulence, is one of

the most common symptoms. In the mildest form, wheezing is only end expiratory. As severity
increases, the wheeze lasts throughout expiration. In a more severe asthmatic episode, wheezing
is also present during inspiration. During a most severe episode, wheezing may be absent
because of the severe limitation of airflow associated with airway narrowing and respiratory
muscle fatigue.

Wheezing can be associated with other causes of airway obstruction, such as cystic fibrosis and
heart failure, bronchomalacia, or tracheomalacia also exercise-induced bronchoconstriction

Cough may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal
asthma. Usually, the cough is nonproductive and nonparoxysmal. Children with nocturnal
asthma tend to cough after midnight and during the early hours of morning. Chest tightness or a
history of tightness or pain in the chest may be present with or without other symptoms of
asthma, especially in exercise-induced or nocturnal asthma.

Other nonspecific symptoms in infants or young children may be a history of recurrent

bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or chest
rattling. Most children with chronic or recurrent bronchiolitis have asthma. Asthma is also the
most common underlying diagnosis in children with recurrent pneumonia; older children may
have a history of chest tightness and/or recurrent chest congestion.

Non-pulmonary Manifestations

Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, ocular
shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis,
and pale violaceous nasal mucosa due to allergic rhinitis, may be present in the absence of an
acute episode, such as during an outpatient visit between acute episodes. Turbinates may be
erythematous or boggy. Polyps may be present.

Skin examination may reveal atopic dermatitis/ eczema, or other manifestations of allergic skin
conditions. Clubbing of the fingers is not a feature of asthma and indicates a need for more
extensive evaluation and workup to exclude other conditions, such as cystic fibrosis.
Classification according to Global Iniative for Asthma(GINA) 2013

Asthma severity is defined as "the intensity of the disease process" prior to initiating therapy and
helps in determining the initiation of therapy in a patient who is not on any controller
medications.

The severity of asthma is classified as:

 Intermittent,
 Mild persistent
 Moderate persistent
 Savere Persistent

Intermittent asthma is characterized as follows:

 Symptoms of cough, wheezing, chest tightness, or difficulty breathing less than twice a
week
 Flare-ups are brief, but intensity may vary
 Nighttime symptoms less than twice a month
 No symptoms between flare-ups
 Lung function test FEV 1 is 80% or more above normal values
 Peak flow has less than 20% variability am-to-am or am-to-pm, day-to-day

Mild persistent asthma is characterized as follows:

 Symptoms of cough, wheezing, chest tightness, or difficulty breathing 3-6 times a week
 Flare-ups may affect activity level
 Nighttime symptoms 3-4 times a month
 Lung function test FEV 1 is 80% or more above normal values
 Peak flow has less than 20-30% variability

Moderate persistent asthma is characterized as follows:

 Symptoms of cough, wheezing, chest tightness, or difficulty breathing daily

 Flare-ups may affect activity level
 Nighttime symptoms 5 or more times a month
 Lung function test FEV 1 is above 60% but below 80% of normal values
 Peak flow has more than 30% variability

Severe persistent asthma is characterized as follows:

 Symptoms of cough, wheezing, chest tightness, or difficulty breathing that are continual
  Frequent nighttime symptoms
 Lung function test FEV 1 is 60% or less of normal values
 Peak flow has more than 30% variability

Global Initiative for Asthma (GINA) 2016 guidelines

 Mild asthma: Well controlled with as-needed reliever medication alone or with low-
intensity controller treatment such as low-dose inhaled corticosteroids (ICSs), leukotriene
receptor antagonists, or chromones

 Moderate asthma: Well controlled with low-dose ICS/long-acting beta2-agonists (LABA)

 Severe asthma: Requires high-dose ICS/LABA to prevent it from becoming uncontrolled,
or asthma that remains uncontrolled despite this treatment

The 2016 GINA guidelines stress the importance of distinguishing between severe asthma and
uncontrolled asthma, as the latter is a much more common reason for persistent symptoms and
exacerbations, and it may be more easily improved. The most common problems that need to be
excluded before a diagnosis of severe asthma can be made are the following;

 Poor inhaler technique

 Poor medication adherence
 Incorrect diagnosis of asthma, with symptoms due to alternative conditions such as upper
airway dysfunction, cardiac failure, or lack of fitness
 Comorbidities and complicating conditions such as rhinosinusitis, gastroesophageal
reflux, obesity, and obstructive sleep apnea
 Ongoing exposure to sensitizing or irritant agents in the home or work environment.

MANAGEMENT

The 2016 GINA guidelines include the following stepwise recommendations for medication and
symptom control

 Step 1: As-needed SABA with no controller; other options are to consider low-dose ICS
for patients with exacerbation risks
 Step 2: Regular low-dose ICS plus as-needed SABA; other options are LTRA or
theophylline
 Step 3: Low-dose ICS/LABA plus as-needed SABA or ICS/formoterol maintenance and
reliever therapy; other options are medium-dose ICS or low-dose ICS/LABA
 Step 4: Low-dose ICS/formoterol maintenance and reliever therapy or medium-dose
ICS/LABA as maintenance plus as-needed SABA; add-on tiotropium for patients with
 history of exacerbations; other options are high-dose ICS/LTRA or slow-release
theophylline; refer for expert assessment and advice
 Step 5: Refer for expert investigation and add-on treatment; add-on treatments include
tiotropium by mist inhaler for patients with a history of exacerbations, omalizumab for
severe allergic asthma, and mepolizumab for severe eosinophilic asthma; other options
are that some patients may benefit from low-dose oral corticosteroids but long-term
systemic adverse effects occur

KENNEDY KIAMBATI, Dip. CM, Bsc. CM (Egerton University)