MEDICINE

Asthma
Lecturer: Dr. Labrador | September 25, 2017
Transcribed by: Aguas | Panlilio | Saylo | Tan | Vino

OUTLINE ASTHMA
1. Asthma
 It is a syndrome characterized by airflow obstruction
a. Risk Factors
- Atopy that varies markedly, both spontaneously and with
- Intrinsic Asthma treatment.
- Infections
- Environmental Factors  Asthmatics harbor a special type of inflammation in
- Hygiene Hypothesis the airways that makes them more responsive to a
- Air Pollution
wide range of triggers than non-asthmatics, leading to
- Allergens
- Occupational Exposure excessive narrowing with consequent reduced airflow
b. Pathology and symptomatic wheezing.
- Inflammation
- Inflammatory Cells  Narrowing of the airways is usually reversible, but in
o Mast Cells some patients with chronic asthma there may be an
o Macrophages and Dendritic Cells
element of irreversible airflow obstruction.
o Eosinophils
o Neutrophils
- Structural Cells  Asthma can present at any age with peak age of 3
- Inflammatory Mediators years.
o Cytokines
o Chemokines  Male:female ratio in childhood is 2:1 but in
- Effects of Inflammation
adulthood, it becomes 1:1.
o Fibrosis
o Airway Smooth Muscle
o Vascular Responses  The severity of asthma does not vary significantly
o Mucus Hypersecretion within a given patient.
o Airway Remodeling o mild asthma rarely progress to severe disease
c. Asthma Triggers o severe asthma usually have severe at onset
- Pharmacologic Agents
- Physical Factors
- Occupational Factors Risk Factors
- Hormonal Factors Asthma is a heterogeneous disease with interplay between
d. Pathophysiology genetic and environmental factors.
- Airway Hyperresponsiveness
e. Clinical Features
f. Diagnosis
- Lung Function Tests
o Spirometry
 Post-bronchodilator Test
o Peak Flow Meter
- Hematologic Tests
- Imaging
- Skin Tests
g. Differential Diagnosis
Atopy
h. Treatment
- Aims of Asthma Therapy - is the major risk factor for asthma
- Bronchodilator Therapies - nonatopic individuals have a very low risk of
o β2-adrenergic agonists developing asthma
 SABAs - patients with asthma commonly suffer from other
 LABAs atopic diseases such as:
- Controller Therapies o allergic rhinitis (80% of asthmatic patients)
- Step-wise Approach to Asthma Therapy
o atopic dermatitis or eczema

 The allergens that lead to sensitization are usually

*blue = recording proteins that have protease activity.
*purple = notes from old trans
*green = additional information
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 The concomitant allergens are derived from:
- house dust mites (very common)
- cat and dog fur
- cockroaches
- grass and tree pollens
- rodents (in lab workers)
 Atopy is due to the genetically determined production
of specific IgE antibody, with many patients showing a
family history of allergic diseases.
Intrinsic Asthma
 A minority of asthmatic patients (approximately 10%)
have:
- negative skin test to common inhalant allergens
- normal serum IgE concentrations
 These patients (with nonatopic or intrinsic asthma)
usually:
- show later onset of disease (adult-onset)
- have concomitant nasal polyps
- are aspirin-sensitive
- have more severe, persistent asthma
Infections
 Viral infections are common triggers of asthma
exacerbations but it is uncertain whether they play a
role in etiology.
Viral infections are not known to cause asthma but may
only worsen the symptoms of existing asthma conditions.
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, also indicates the importance of
environmental mechanisms interacting with a genetic
predisposition.
Hygiene Hypothesis
 The hygiene hypothesis proposes that:
- lack of infection in early childhood preserves
the Th2 cell bias at birth
- 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.
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MEDICINE - Asthma
 Intestinal parasite infection may also be associated
with a reduced risk of asthma.
Air Pollution
 Air pollutants, such as sulfur or sulfur dioxide, ozone
and diesel particulates, may trigger asthma symptoms
but the role of different air pollutants in the etiology
of the disease is much less certain.
 Indoor air pollutants 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 from an increased risk of respiratory infections.
Allergens
 Inhaled allergens are common triggers of asthma
symptoms and are also implicated in allergic
sensitization.
Occupational Exposure
 Occupational asthma is relatively common
 It may affect up to 10% of young adults
 There are over 200 sensitizing agents identified
 Some chemicals may lead to sensitization
independent of atopy
e.g. toluene diisocyanate, trimellitic anhydride
 Individuals may also be exposed to allergens in the
workplace
e.g. small animal allergens in laboratory workers
fungal amylase in wheat flour in bakers
Pathology
 The airway mucosa is infiltrated with:
- activated eosinophils
- T lymphocytes
- activation of mucosal mast cells
 The degree of inflammation:
- is poorly related to disease severity
- may be found in atopic patients without asthma
symptoms
 Another common finding in fatal asthma is occlusion
of the airway lumen by a mucus plug which is
composed of mucus glycoproteins secreted from
goblet cells and plasma proteins from leaky bronchial
vessels.
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 There is also vasodilation and increased numbers of Many cells and mediators are involved in asthma and lead
blood vessels (angiogenesis). to several effects on the airways.

Inflammation
 There is inflammation in the respiratory mucosa from
trachea to terminal bronchioles, but with
predominance in the bronchi (cartilaginous airways).

 There is evidence that specific pattern of airway

inflammation in asthma is associated with airway
hyperresponsiveness (AHR) which is the physiologic
abnormality of asthma that is correlated with variable
airflow obstruction.

 The pattern of inflammation in asthma is

characteristic of allergic diseases with similar
Inflammatory Cells
inflammatory cells seen in the nasal mucosa in rhinitis.
Mast Cells
- are important in initiating the acute
 Asthma is a chronic condition, with inflammation
bronchoconstrictor responses to allergens and
persisting over many years in most patients.
several other indirectly acting stimuli, such as:
o exercise and hyperventilation via osmolality or
 Superimposed on this chronic inflammatory state are
thermal changes
acute inflammatory episodes which correspond to
o fog
exacerbations of asthma.
- localized to the airway smooth muscle layer
- are not found in normal subjects or in patients with
 Inflammation in the airways of asthmatic patients
eosinophilic cough
leads to airway hyperresponsiveness and symptoms.
Macrophages and Dendritic Cells
 Macrophages
- are derived from blood monocytes
- may be activated by allergens via low-affinity
IgE receptors

 Dendritic Cells
- are specialized macrophage-like cells in the
airway epithelium which are the major antigen-
presenting cells (APCs)

Eosinophils
- are linked to the development of airway
hyperresponsiveness
- eosinophilic 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
An asthma condition with cough as the only symptom is the late reaction
called cough-variant asthma.
Neutrophils
- increased numbers of activated neutrophils are
found in the sputum and airways of some patients
with severe asthma during exacerbations although
there is a proportion of patients even with mild or
moderate asthma that have a predominance of
neutrophils
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- the role of neutrophils in asthma, which are
resistant to the anti-inflammatory effects of
corticosteroids, is currently unknown
Structural Cells
- are an important source of inflammatory mediators
such as cytokines and lipid mediators
- structural cells of the airways include:
o epithelial cells
o fibroblasts
o airway smooth muscle cells
Inflammatory Mediators
Cytokines
 Multiple cytokines regulate the chronic inflammation
of asthma.
 TH2 cytokines that mediate allergic inflammation are:
- IL-4
- IL-5
- IL-13
 Proinflammatory cytokines that amplify the
inflammatory response and play a role in more severe
disease are:
- tumor necrosis factor (TNF)
- IL-1
Chemokines
- are involved in attracting inflammatory cells from
the bronchial circulation into the airways
Effects of Inflammation
Asthma may be regarded as a disease with continuous
inflammation and repair proceeding simultaneously.
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MEDICINE - Asthma
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.
 In more severe patients, there is also fibrosis within
the airway wall, which may contribute to irreversible
narrowing of the airways.
Airway Smooth Muscle
 In asthmatic airways, there is also a characteristic
hypertrophic and hyperplasia of airway smooth
muscle, which is presumably the result of stimulation
of airway smooth muscle cells by various growth
factors released from inflammatory or epithelial cells.
such as:
- platelet-derived growth factor (PDGF)
- endothelin 1
Vascular Responses
 There is increased airway mucosal blood flow in
asthma.
 Microvascular leakage from post-capillary venules in
response to inflammatory mediators is observed in
asthma, resulting in:
- airway edema
- plasma exudation into the airway lumen
Mucus Hypersecretion
 There is hyperplasia of submucosal glands that are
confined to large airways and of increased numbers of
epithelial goblet cells.
 This occludes asthmatic airways particularly in fatal
asthma.
Airway Remodeling
 Several changes in the structure of the airway may
lead to irreversible narrowing of airways.
 Population studies have shown a greater decline in
lung function over time than in normal subjects,
however, most patients with asthma preserve normal
or near normal lung function throughout life if
appropriately treated.
 The accelerated decline in lung function occurs in
smaller proportion of asthmatics, and these are
usually patients with more severe disease.
 The characteristic structural changes are:
- increased airway smooth muscle
- fibrosis
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- angiogenesis  The mechanisms are not completely understood but

- mucus hyperplasia are related to a fall in progesterone and in severe
cases may be improved by treatment with high doses
Asthma Triggers of progesterone or gonadotropin-releasing factors.

 Thyrotoxicosis and hypothyroidism can both worsen

asthma, although the mechanisms are uncertain.

Pathophysiology
 Limitation of airflow
- is mainly due to bronchoconstriction but airway
edema, vascular congestion, and luminal
occlusion with exudate may also contribute.
Pharmacologic Agents - results in an increase (↑) in:
 β-adrenergic blockers commonly worsen asthma and o airway resistance
their use may be fatal. - results in a reduction (↓) in:
o FEV1
 All β blockers need to be avoided. o FEV1/FVC ratio
o PEF
 Even selective β2 blockers or topical application (e.g.
timolol eye drops) may be dangerous. FEV1 – forced expiratory volume in 1 second
FVC – forced vital capacity
 ACE inhibitors are theoretically detrimental as they PEF – peak expiratory flow
inhibit breakdown of kinins, which are
bronchoconstrictors. They, however, rarely worsen Airway Hyperresponsiveness (AHR)
asthma and the characteristic cough is no more  AHR is the characteristic physiologic abnormality of
frequent in asthmatics than non-asthmatics. asthma.

 Aspirin may worsen asthma in some patients (e.g.  It is the excessive bronchoconstrictor response to
aspirin-sensitive asthma) multiple inhaled triggers that would have effect on
normal airways.
Physical Factors
 hyperventilation  The increase in AHR is linked to the frequency of
 laughter asthma symptoms; thus, an important aim of therapy
 cold air is reduce to AHR.
 hot weather
 weather changes  Increased bronchoconstrictor responsiveness is seen
 exposure to strong smells or perfumes with direct bronchoconstrictors such as:
- histamine
Occupational Factors - methacholine
 Occupational asthma is characteristically associated
with symptoms at work with relief on weekends and  Most of the triggers for asthma symptoms appear to
holidays act indirectly, including:
- allergens, exercise, hyperventilation, fog (via
 If removed from exposure within the first six months mast cell activation)
of symptoms, there is usually complete recovery. - irritant dusts and sulfur dioxide (via cholinergic
reflex)
 More persistent symptoms lead to irreversible airway
changes and therefore early detection and avoidance Clinical Features
are important.  The characteristic symptoms of asthma are:
- wheezing
Hormonal Factors - dyspnea
 Some women show pre-menstrual worsening of - coughing
asthma, which can occasionally be very severe. - chest tightness/pain

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 Symptoms may be worse at night, and the patient is

typically awakened in the early morning hours.

 There is increased mucus production in some patients

with typically tenacious mucus that is difficult to
expectorate.

 There may be increased ventilation and use of

accessory muscles for ventilation.

 Prodromal symptoms may precede an attack :

- itching under the chin
- discomfort between the scapulae
- inexplicable fear (impending doom)

 Typical physical signs are:

- inspiratory, and to a great extent, expiratory
rhonchi throughout the chest (auscultation)
- there may be hyperinflation (percussion)
Rhonchi are low-pitch wheezes. All asthmatics present
with wheezes but not all patients with wheezes are
asthmatic.
 Some patients, particularly children, may present with
a predominant non-productive cough (cough- variant
asthma)
 There may be no abnormal physical findings when
asthma is under control.
Diagnosis
 The diagnosis of asthma is usually apparent from the
symptoms of variable and intermittent airway
obstruction.
 It is usually confirmed by objective measurements of
lung function.
Lung Function Tests
Spirometry
 Simple spirometry confirms airflow limitation with a
reduced (↓):
- FEV1
- FEV1/FVC ratio
- PEF
Post-bronchodilator Test (Post BD)
 This is a test that utilizes spirometry to assess possible
reversibility of bronchoconstriction in diseases such as
asthma. (commonly known as reversibility test)
 Reversibility is demonstrated by an increase of > 12%
and > 200mL in FEV1, 15 minutes after an inhaled
short-acting β2 agonist or in some patients, by a 2 to
4-week trial of oral glucocorticoids (prednisone or
prednisolone 30-40 mg daily).
Each time, we do 3 tests and get the best of 3 then wait for
15 minutes and repeat. We subtract the post from the pre-
bronchodilator results. The test can be repeated for 4 to 5
times. For example:
pre-bronchodilator = 1500
post-bronchodilator = 1700
This is not yet reversible because it needs to be > 12% and
> 200 mL increase in FEV1.
Peak Flow Meter
 Peak flow meter test measures how well your lungs
push out air.

 Measurements of PEF twice daily may confirm the

diurnal variation in airway obstruction.

*Asthma patients may have normal lung function tests.

 Spirometry measures how fast and how much air you The nearer the marker indicates that the obstruction is
breathe out. more severe.

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Hematologic Tests
 Blood tests are not usually helpful.
 Total serum IgE and specific IgE to inhaled allergens
(RAST) may be measured in some patients.
Imaging
Chest Roentgenography
- usually normal
- may show hyperinflated lungs in severe patients
- in exacerbations, rule out pneumothorax
Lung Shadowing
- usually indicate pneumonia or
- eosinophilic infiltrates in patients with
bronchopulmonary aspergillosis
High-Resolution Computed Tomography (HRCT)
- may show areas of bronchiectasis in patients with
severe asthma
- there may be thickening of the bronchial walls, but
these changes are not diagnostic of asthma
Skin Tests
 Skin prick test to common inhalant allergens are:
- positive in allergic asthma
- negative in intrinsic asthma, but are not helpful
in diagnosis
 Positive skin responses may be useful in persuading
patients to undertake allergen avoidance measures.
Differential Diagnosis
 Upper airway obstruction by a tumor (especially in
elderly individuals)
 Laryngeal edema (present with stridor localized to
large airways)
 Endobronchial obstruction with a foreign body
(especially in children)
 Left ventricular failure (patient can go to congestion)
 Eosinophilic pneumonia
 Systemic vasculitis, including Churg-Strauss syndrome
and polyarteritis nodosa may be associated with
wheezing
 COPD (especially when the patient is smoking and in
the elderly)
Treatment
The main drugs for asthma can be divided into:
 bronchodilators, which give rapid relief of symptoms
mainly through relaxation of airway smooth muscle
 controllers, which inhibit the underlying inflammatory
process
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MEDICINE - Asthma
Aims of Asthma Therapy
Bronchodilator Therapies
- act primarily on airway smooth muscle to reverse
the bronchoconstriction of asthma
- gives rapid relief of symptoms
- has little or no effect on the underlying
inflammatory process
 Thus, bronchodilators are not sufficient to control
asthma in patients with persistent symptoms.
 There are three classes three classes of
bronchodilators in current use:
- β2-adrenergic agonist (most effective)
- anticholinergics
- theophylline
β2-Adrenergic Agonists
 β2 agonists are usually given by inhalation to reduce
side effects.
 Effects of β2-Agonists on Airways:
- relaxation of airway smooth muscle
- inhibition of mast cell mediator release
- inhibition of plasma exudation and airway edema
- increased mucociliary clearance
- increased mucus secretion
- decreased cough
- no effect on chronic inflammation
Short-acting B2-Agonists (SABAs)
Examples:
albuterol
terbutaline
- have a duration of action of 3 to 6 hours
- have a rapid onset of bronchodilation and therefore
used as needed for symptom relief
- are also useful in preventing exercise-induced
asthma (EIA) if take prior to exercise
- are used in high doses by nebulizer or via a metered
dose inhaler with a spacer
-
*Increased use of SABAs indicates that asthma is not
controlled.
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Long-acting B2-Agonists (LABAs)

Examples:
salmeterol
formoterol

- have a duration of action of over 12 hours

- given twice daily
- have replaced the regular use of SABAs but should
not be given in the absence of inhaled
corticosteroid (ICS) therapy as they do not control
the underlying inflammation
- are used to improve asthma control and reduce
exacerbations when added to ICS, which allows
asthma to be controlled at lower doses of
corticosteroids

*This observation has led to the widespread use of fixed

combination inhalers that contain a corticosteroid and a
LABA, which have been proven to be highly effective in
the control of asthma.

Controller Therapies
 Inhaled Corticosteroids
- are by far the most effective controllers for
asthma, and their early use has revolutionized
asthma therapy

Step-wise Approach to Asthma Therapy

Step-wise approach to asthma therapy according to the
severity of asthma and ability to control symptoms.

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References:

Doc’s ppt + Batch 2018 Trans

Harrison’s 18th Ed. “Sometimes it’s okay if the only thing
Harrison’s 19th Ed. you did today was breathe”

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