ASTHMA

Dr. LEUL N.
• Asthma is a syndrome characterized by airflow obstruction that varies markedly,
both spontaneously and with treatment.

• Asthma is a heterogeneous disease with several phenotypes recognized, but thus

far these do not correspond well to specific pathogenic mechanisms (endotypes) or
responses to therapy.

• Asthma is a chronic inflammatory disorder characterized by increased

responsiveness of the airways to multiple stimuli.

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 PREVALENCE
• Asthma is one of the most common chronic diseases globally

• ~10–12% of adults and 15% of children affected by the disease.

• 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.

• 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.

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 RISK FACTORS AND TRIGGERS
• Atopy
– Major risk factor for asthma

– Commonly suffer from other atopic diseases, particularly allergic rhinitis,

which may be found in >80% of asthmatic patients, and atopic dermatitis
(eczema)

– Atopy may be found in 40–50% of the population

– 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).

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• Epigenetic mechanisms
– Epigenetic mechanisms may be important, particularly in the early
development of asthma.
– DNA methylation and histone modification patterns may be influenced by
diet, cigarette smoke exposure, and air pollution, and may affect genes
involved in the pathogenesis of asthma.

• Infections
– Although viral infections (especially Rhinovirus) are common as triggers of
asthma exacerbations, it is uncertain whether they play a role in etiology.
– Living in damp houses with exposure to mold spores is now recognized to be a
risk factor, and removal of these factors may improve asthma.

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• 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.

• Diet
– 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.

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• Air Pollution
– Air pollutants such as sulfur dioxide, ozone, and diesel particulates may
trigger asthma symptoms
– Indoor air pollution is also important with exposure to nitrogen oxides from
cooking stoves and exposure to passive cigarette smoke.
• Allergens
– are common triggers of asthma symptoms and have also been implicated in
allergic sensitization
• Occupational Exposure
– Occupational asthma is relatively common and may affect up to 10% of young
adults.
– Chemicals such as toluene diisocyanate and trimellitic anhydride, may lead to
sensitization independent of atopy.
• Obesity
– Asthma occurs more frequently in obese people (BMI >30 kg/m2) and is often
more difficult to control.

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• Other factors
– Lower maternal age, duration of breastfeeding, prematurity and low
birthweight, and inactivity, but are unlikely to contribute to the recent
global increase in asthma prevalence.
• Intrinsic Asthma
– (~10%) have negative skin tests to common inhalant allergens and normal
serum concentrations of IgE

– These patients, with non-atopic 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.

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 Asthma Triggers
• Several stimuli trigger airway narrowing, wheezing, and dyspnea in asthmatic
patients.
• 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.
– The most common allergens to trigger asthma are Dermatophagoides species,
and environmental exposure leads to low-grade chronic symptoms that are
perennial.
– Other allergens, including grass pollen, ragweed, tree pollen, and fungal
spores, are seasonal
• 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.

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• PHARMACOLOGIC AGENTS
– Several drugs may trigger asthma.
– Betaadrenergic 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 β, β2 blockers, or
topical application (e.g., timolol eye drops) may be dangerous.

• 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.

• PHYSICAL FACTORS Cold air and hyperventilation may trigger asthma

through the same mechanisms as exercise.

• FOOD AND DIET 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

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• AIR POLLUTION Increased ambient levels of sulfur dioxide, ozone, diesel
particulates and nitrogen oxides are associated with increased asthma symptoms.

• OCCUPATIONAL FACTORS
– May act as sensitizing agents but may also act as triggers of asthma symptoms.
– Occupational asthma is characteristically associated with symptoms at work with
relief on weekends and holidays.

• HORMONES: -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

• 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 anti-reflux therapy
usually fails to reduce asthma symptoms in most patients.

• STRESS Many asthmatics report worsening of symptoms with stress.

– Psychological factors can induce bronchoconstriction through cholinergic reflex
pathways.

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 PATHOPHYSIOLOGY
• Asthma is associated with a specific chronic inflammation of the mucosa of the lower
airways.

• Pathology
– 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 even be
found in atopic patients without asthma symptoms.
– A characteristic finding is thickening of the basement membrane due to
subepithelial collagen deposition. likely to be a marker of eosinophilic inflammation
in the airway as eosinophils release fibrogenic mediators.
– The airway wall itself may be thickened and edematous, particularly in fatal asthma

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 – 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 vessel

– There is also vasodilation and increased numbers of blood vessels (angiogenesis).

– 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.

• Airway Inflammation
– There is inflammation in the respiratory mucosa from the trachea to terminal
bronchioles, but with a predominance in the bronchi (cartilaginous airways )

– 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

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 – The pattern of inflammation in asthma is characteristic of allergic diseases, with
similar inflammatory cells seen in the nasal mucosa in rhinitis.

– Superimposed on this chronic inflammatory state are acute inflammatory

episodes, which correspond to exacerbations of asthma.

– Although the common pattern of inflammation in asthma is characterized by

eosinophil infiltration, some patients with severe asthma show a neutrophilic
pattern of inflammation that is less sensitive to corticosteroids.
• 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 changes), as well as fog

– 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 by
physical stimuli such as osmolality.

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• 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 (FcεRII).

– 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.

• 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.

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• 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.
• 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.

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• 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.

• Inflammatory Mediators
– CYTOKINES
– CHEMOKINES
– OXIDATIVE STRESS
– NITRIC OXIDE
– TRANSCRIPTION FACTORS

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• Effects of Inflammation
– AIRWAY EPITHELIUM: -Epithelial damage may contribute to AHR in a number
of ways, including loss of its barrier function to allow penetration of allergens;
loss of enzymes (such as neutral endopeptidase/ neprilysin) that degrade certain
peptide inflammatory mediators like bradykinin; loss of a relaxant factor (so-
called epithelial-derived relaxant factor); and exposure of sensory nerves, which
may lead to reflex neural effects on the airway.

– FIBROSIS : - the basement membrane is apparently thickened due to

subepithelial fibrosis with deposition of types III and V collagen below the true
basement membrane

– AIRWAY SMOOTH MUSCLE : - no increased responsiveness to constrictors.

– VASCULAR RESPONSES There is increased airway mucosal blood flow

in asthma, which may contribute to airway narrowing.

– MUCUS HYPERSECRETION Increased mucus secretion contributes to the viscid

mucous plugs that occlude asthmatic airways, particularly in fatal asthma.
– NEURAL REGULATION

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• 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.
– The characteristic structural changes are increased airway smooth muscle,
fibrosis, angiogenesis, and mucus hyperplasia.

• 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.

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 CLINICAL FEATURES
• The characteristic symptoms of asthma are
– Wheezing,
– Dyspnea,
– Coughing

• Symptoms may be worse at night and patients typically awake in the early morning hours.
•
• Difficulty in filling their lungs with air.

• Increased mucus production typically tenacious mucus that is difficult to expectorate .

• Prodromal symptoms may precede an attack, with itching under the chin, discomfort
between the scapulae, or inexplicable fear (impending doom).

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• Complain of a sensation of chest constriction and cough.

• Typical physical signs are inspiratory, and to a greater extent expiratory, rhonchi
throughout the chest, and there may be hyperinflation.

– Severe asthma attack may be in respiratory distress, with rapid breathing and
loud wheezing

– The use of accessory muscles of inspiration indicates diaphragmatic fatigue.

– The appearance of paradoxical respiration, which is chest deflation and abdominal

protrusion during inspiration followed by chest expansion and abdominal deflation
during expiration, is a sign of impending ventilatory failure.

– Alteration in the mental status (e.g., lethargy, exhaustion, agitation, or confusion)

also heralds respiratory arrest.

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• Directed physical examination reveals hyper-resonance to percussion, decreased
intensity of breath sounds, and prolongation of the expiratory phase , usually with
wheezing.

• The “silent chest” reflects very severe airflow obstruction, with air movement
insufficient to promote an audible wheeze.

• A pulsus paradoxus (change in blood pressure during inspiration) >20 mm Hg is also

indicative of severe asthma, although it is not specific for asthma.

• Although tachycardia and tachypnea are usually seen with acute asthma, a normal
heart rate, a normal respiratory rate, and the absence of a pulsus paradoxus do
not indicate complete relief of airway obstruction.

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 DIAGNOSIS
• Lung Function Tests
– Simple spirometry confirms airflow limitation with a reduced FEV 1,
FEV1/FVC ratio, and PEF

– Reversibility is demonstrated by a >12% and 200-mL increase in FEV 1 15 min

after an inhaled short-acting β2-agonist (SABA; such as inhaled albuterol
400 μg) or in some patients by a 2–4 week trial of oral corticosteroids (OCS)
(prednisone or prednisolone 30–40 mg daily).

– Measurements of PEF twice daily may confirm the diurnal variations in

airflow obstruction.

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• Airway Responsiveness
– The increased AHR is normally measured by methacholine or histamine challenge
with calculation of the provocative concentration that reduces FEV1 by 20% (PC20).

– This is rarely useful in clinical practice, but can be used in the differential diagnosis
of chronic cough and when the diagnosis is in doubt in the setting of normal
pulmonary function tests.

• Hematologic Tests
– Blood tests are not usually helpful.

– Total serum IgE and specific IgE to inhaled allergens (radioallergosorbent test
[RAST]) may be measured in some patients.

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• Imaging

– Chest roentgenography

• Is usually normal but in more severe patients may show hyperinflated lungs.
• In exacerbations, there may be evidence of a pneumothorax.
• Lung shadowing usually indicates pneumonia or eosinophilic infiltrates in
patients with bronchopulmonary aspergillosis (BPA).

– High-resolution CT
• May show areas of bronchiectasis in patients with severe asthma, and there
may be thickening of the bronchial walls, but these changes are not diagnostic
of asthma.

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• Skin tests
– To common inhalant allergens (house dust mite, cat fur, grass pollen) are positive
in allergic asthma and negative in intrinsic asthma, but are not helpful in
diagnosis.

– Positive skin responses may be useful in persuading patients to undertake allergen

avoidance measures

• Exhaled NO
– Fractional exhaled nitric oxide (FENO) is now being used as a noninvasive test to
measure eosinophilic airway inflammation.

– The typically elevated levels in asthma are reduced by ICS, so this may be a test
of compliance with therapy.

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 TREATMENT

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• The treatment of asthma is straightforward

• COMPONENTS OF ASTHMA MANAGEMENT —

– Routine monitoring of symptoms and lung function
– Patient education to create a partnership between clinician and patient
– Controlling environmental factors (trigger factors) and comorbid conditions
that contribute to asthma severity
– Pharmacologic therapy

• GOALS OF ASTHMA TREATMENT — The goals of chronic asthma management

may be divided into two domains: reduction in impairment and reduction of risk

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• Reduce impairment — Specific goals for reducing impairment include:
– Freedom from frequent or troublesome symptoms of asthma (cough, chest
tightness, wheezing, or shortness of breath)
– Minimal need (≤2 days per week) of inhaled short acting beta agonists (SABAs) to
relieve symptoms
– Few night-time awakenings (≤2 nights per month) due to asthma
– Optimization of lung function
– Maintenance of normal daily activities, including work or school attendance and
participation in athletics and exercise
– Satisfaction with asthma care on the part of patients and families

• Reduce risk — Specific goals for reducing risk include:

– Prevention of recurrent exacerbations and need for emergency department or
hospital care
– Prevention of reduced lung growth in children, and loss of lung function in adults
– Optimization of pharmacotherapy with minimal or no adverse effects

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 PHARMACOLOGIC 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

• Pharmacologic treatment is the mainstay of management in most patients with asthma

• The stepwise approach to pharmacotherapy is based on increasing medications until

asthma is controlled, and decreasing medications when possible to minimize side
effects.

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 • Categories of asthma severity — Asthma severity is determined by considering
the following factors
– Reported symptoms over the previous two to four weeks

– Current level of lung function (PEFR or FEV 1 and FEV1/FVC values)

– Number of exacerbations requiring oral glucocorticoids in the previous year

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• Intermittent — Intermittent asthma is characterized by the following
– Daytime asthma symptoms occurring two or fewer days per week
– Two or fewer nocturnal awakenings per month
– Use of short-acting beta agonists to relieve symptoms two or fewer days per
week
– No interference with normal activities between exacerbations
– FEV1 measurements between exacerbations that are consistently within the
normal range (ie, ≥80 percent of predicted normal)
– FEV1/FVC ratio between exacerbations that is normal (based on age-adjusted
values)
– One or no exacerbations requiring oral glucocorticoids per year

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 • Mild persistent — Mild persistent asthma is characterized by the following

– Symptoms more than twice weekly (although less than daily)

– Approximately three to four nocturnal awakenings per month due to asthma

(but fewer than every week)

– Use of SABAs to relieve symptoms more than two days out of the week (but
not daily)

– Minor interference with normal activities

– FEV1 measurements within normal range (≥80 percent of predicted normal)

and normal FEV1/FVC ratio

– Two or more exacerbations requiring oral glucocorticoids per year

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• Moderate persistent — The presence of any of the following is considered an
indication of moderate disease severity:
– Daily symptoms of asthma

– Nocturnal awakenings more than once per week

– Daily need for SABAs for symptom relief

– Some limitation in normal activity

– FEV1 between 60 and 80 percent of predicted and FEV 1/FVC below normal

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• Severe persistent — Patients with severe persistent asthma experience one or
more of the following:

– Symptoms of asthma throughout the day

– Nocturnal awakenings nightly

– Need for SABAs for symptom relief several times per day

– Extreme limitation in normal activity

– FEV1 <60 percent of predicted and FEV1/FVC below normal

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 BRONCHODILATOR THERAPIES

• Bronchodilators act primarily on airway smooth muscle to reverse the

bronchoconstriction of asthma.

• This gives rapid relief of symptoms but 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 of bronchodilator in current use:

– β2-adrenergic agonists,
– Anticholinergics
– Theophylline

• β2-agonists are by far the most effective.

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• Beta2-Agonists
– Relaxes smooth muscle cells and inhibits certain inflammatory cells, particularly
mast cells.

– Mode of Action
• The primary action of β2-agonists is to relax airway smooth-muscle cells of
all airways, where they act as functional antagonists, reversing and
preventing contraction of airway smooth-muscle cells by all known
bronchoconstrictors.

• There are also additional non-bronchodilator effects that may be clinically

useful, including inhibition of mast cell mediator release, reduction in plasma
exudation, and inhibition of sensory nerve activation.

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• Clinical Use: - given by inhalation to reduce side effects.
•
– SABA, such as albuterol and terbutaline, have a duration of action of 3–6 h.
They have a rapid onset of bronchodilatation and are, therefore, used as
needed for symptom relief (relievers). Increased use of SABA indicates
that asthma is not controlled.

– Long-acting β2-agonists (LABA) include salmeterol and formoterol, both

of which have a duration of action over 12 h and are given twice daily by
inhalation; and indacaterol, olodaterol, and vilanterol, which are given once
daily. LABA have replaced the regular use of SABA, but LABA should not be
given in the absence of ICS therapy as they do not control the underlying
inflammation.

• Side Effects
– The most common side effects are muscle tremor and palpitations, which are
seen more commonly in elderly patients.

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• Anticholinergics

– Muscarinic receptor antagonists, such as ipratropium bromide, prevent

cholinergic nerve-induced bronchoconstriction and mucus secretion.

– They are less effective than β2-agonists in asthma therapy as they inhibit
only the cholinergic reflex component of bronchoconstriction, whereas β2-
agonists prevent all bronchoconstrictor mechanisms.

– Long-acting muscarinic antagonists (LAMA), including tiotropium bromide or

glycopyrronium bromide, may be used as an additional bronchodilator in
patients with asthma that is not controlled by maximal doses of ICS-LABA
combinations

– Side effects are not usually a problem as there is little or no systemic

absorption. The most common side effect is dry mouth; in elderly patients,
urinary retention and glaucoma may also be observed

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• Theophylline
– was widely prescribed as an oral bronchodilator several years ago, especially as
it was inexpensive.
– It has now fallen out of favor as side effects are common, and inhaled β2-
agonists are much more effective as bronchodilators.
– Clinical Use
• Oral theophylline is usually given as a slow-release preparation once or
twice daily as this gives more stable plasma concentrations than normal
theophylline tablets.
– Low doses of theophylline, giving plasma concentrations of 5–10 mg/L, have
additive effects to ICS and are particularly useful in patients with severe
asthma.
– Side Effects: - The most common side effects are nausea, vomiting, and
headaches and are due to phosphodiesterase inhibition. Diuresis and
palpitations may also occur, and at high concentrations cardiac arrhythmias,
epileptic seizures, and death may occur due to adenosine A1-receptor
antagonism.

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 CONTROLLER THERAPIES

• Inhaled corticosteroids

– Most effective controllers for asthma

– Mode of action: -
• Most effective anti-inflammatory agents used in asthma therapy, reducing
inflammatory cell numbers and their activation in the airways
• ICS reduce eosinophils in the airways and sputum, and numbers of activated T
lymphocytes and surface mast cells in the airway mucosa.

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• Clinical Use
– ICS are usually given twice daily, but some may be effective once daily in mildly
symptomatic patients.

– ICS rapidly improve the symptoms of asthma, and lung function improves over
several days. They are effective in preventing asthma symptoms, such as EIA and
nocturnal exacerbations, but also prevent severe exacerbations.

– ICS reduce AHR, but maximal improvement may take several months of therapy.

– Early treatment with ICS appears to prevent irreversible changes in airway

function that occur with chronic asthma.

– Withdrawal of ICS results in slow deterioration of asthma control, indicating that

they suppress inflammation and symptoms, but do not cure the underlying
condition.

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• ICS are now given as first-line therapy for patients with persistent asthma, but
if they do not control symptoms at low doses, it is usual to add a LABA as the
next step.

• Side Effects
– Local side effects include hoarseness (dysphonia) and oral candidiasis, which
may be reduced with the use of a large volume spacer device.
– ICS have minimal systemic effects

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• Systemic Corticosteroids
– Corticosteroids are used intravenously (hydrocortisone or methylprednisolone)
for the treatment of acute severe asthma, although several studies now show
that OCS are as effective and easier to administer.

– A course of OCS (usually prednisone or prednisolone 30–45 mg once daily for 5–

10 days) is used to treat acute exacerbations of asthma; no tapering of the dose
is needed.

– Approximately 1% of asthma patients may require maintenance treatment with

OCS; the lowest dose necessary to maintain control needs to be determined.

– Systemic side effects, including truncal obesity, bruising, osteoporosis, diabetes,

hypertension, gastric ulceration, proximal myopathy, depression, and cataracts,
may be a major problem

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• Antileukotrienes
– Cysteinyl-leukotrienes are potent bronchoconstrictors; they cause
microvascular leakage and increase eosinophilic inflammation through the
activation of cys-LT1-receptors.

– These inflammatory mediators are produced predominantly by mast cells

and, to a lesser extent, eosinophils in asthma.

– Antileukotrienes, such as montelukast and zafirlukast, block cys-LT1-

receptors and provide modest clinical benefit in asthma.

– They are less effective than ICS in controlling asthma and have less effect
on airway inflammation

– They are given orally once or twice daily and are well tolerated.

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• Cromones
– Cromolyn sodium and nedocromil sodium are asthma controller drugs that
appear to inhibit mast cell and sensory nerve activation and are, therefore,
effective in blocking trigger-induced asthma such as EIA and allergen- and
sulfur dioxide-induced symptoms.

– Cromones have relatively little benefit in the long-term control of asthma due to
their short duration of action (at least four times daily by inhalation).
–
• Steroid-Sparing Therapies
– Various immunomodulatory treatments have been used to reduce the
requirement for OCS in patients with severe asthma, who have serious side
effects with this therapy.

– Methotrexate, cyclosporin A, azathioprine, gold, and IV gamma globulin have all

been used as steroid-sparing therapies, but none of these treatments has any
long-term benefit and each is associated with a relatively high risk of side
effects.

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• Anti-IgE
– Omalizumab is a blocking antibody that neutralizes circulating IgE without
binding to cell-bound IgE and, thus, inhibits IgE-mediated reactions.

– reduce the number of exacerbations in patients with severe asthma and may
improve asthma control.

– Very expensive and is only suitable for highly selected patients who are not
controlled on maximal doses of inhaler therapy and have a circulating IgE
within a specified range.

– Patients should be given a 3- to 4-month trial of therapy to show objective

benefit.

– Omalizumab is usually given as a subcutaneous injection every 2–4 weeks and

appears not to have significant side effects, although anaphylaxis is very
occasionally seen

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• Anti-IL-5
– Antibodies that block IL-5 (mepolizumab, reslizumab) or its receptor
(benralizumab) markedly reduce blood and tissue eosinophils and reduce
exacerbations in patients who have persistently increased sputum eosinophils
despite maximal ICS therapy.

• Immunotherapy
– Specific immunotherapy using injected extracts of pollens or house dust mites has
not been very effective in controlling asthma and may cause anaphylaxis.

• Alternative Therapies
– Nonpharmacologic treatments, including hypnosis, acupuncture, chiropraxis,
breathing control, yoga, and speleotherapy, may be popular with some patients.
However, placebo-controlled studies have shown that each of these treatments
lacks efficacy and cannot be recommended.

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 MANAGEMENT OF CHRONIC ASTHMA

• There are several aims of chronic therapy in asthma .

• Important to establish the diagnosis objectively using spirometry or PEF

measurements at home.

• Triggers that worsen asthma control hould be avoided,

• It is important to assess asthma control, assessed by symptoms, night

awakening, need for reliever inhalers, limitation of activity and lung function

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• Stepwise Therapy
– Mild, Intermittent Asthma
• SABA is all that is required
• Use of a reliever medication more than twice a week indicates the need for
regular controller therapy.

– The treatment of choice for all patients is an ICS given twice daily.

– It is usual to start with an intermediate dose (e.g., 200 [μg] bid of

[beclomethasone dipropionate] BDP) or equivalent and to decrease the
dose if symptoms are controlled after three months.

– If symptoms are not controlled, a LABA should be added, which is most

conveniently given by switching to a combination inhaler

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• The dose of controller should be adjusted accordingly, as judged by the need for
a rescue inhaler.

• Low doses of theophylline or an antileukotriene may also be considered as an

add-on therapy, but these are less effective than LABA.

• If asthma is not controlled despite the maximal recommended dose of inhaled

therapy, it is important to check adherence and inhaler technique.

• In these patients, maintenance treatment with an OCS may be needed and the
lowest dose that maintains control should be used.

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• Intermittent (Step 1)
– Patients with mild intermittent asthma are best treated with a quick-acting
inhaled beta-2-selective adrenergic agonist, taken as needed for relief of
symptoms.

– Patients for whom triggering of asthmatic symptoms can be predicted (eg,

exercise-induced bronchoconstriction) are encouraged to use their inhaled beta
agonist approximately 10 minutes prior to exposure in order to prevent the onset
of symptoms.

– Inhaled beta agonists — The currently available inhaled SABAs

(eg, albuterol and levalbuterol in the United States) have a rapid onset of action
(within five minutes), an intermediate duration of effect (approximately four to
six hours), and relative beta-2 selectivity. The inhaled route of administration is
preferred over tablet or liquid formulations because of the shorter time to
relief, greater potency of bronchodilation, and fewer side effects

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• Delivery mechanisms — SABAs are available in metered-dose inhalers (MDIs), a
dry powder inhaler (DPI), and in solution for nebulization

• Other bronchodilators — Ipratropium and oral beta agonists are generally less
effective than inhaled beta agonists for symptom relief in intermittent asthma.

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• MILD PERSISTENT (STEP 2)
– the preferred long-term controller is a low dose inhaled glucocorticoid (GC)

– Regular use of inhaled glucocorticoids reduces the frequency of symptoms (and

the need for SABAs for symptom relief), improves the overall quality of life, and
decreases the risk of serious exacerbations.

– Alternative strategies included leukotriene receptor antagonists theophylline

and cromoglycates.
– Among these alternatives, we favor the leukotriene blockers.

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• Moderate persistent (Step 3)
– The preferred therapies are either low-doses of an inhaled glucocorticoid
plus a long-acting inhaled beta agonist (LABA), or medium doses of an
inhaled glucocorticoid

– Alternative strategies include adding a leukotriene modifier (leukotriene

receptor antagonist or lipoxygenase inhibitor) or theophylline to low-dose
inhaled GCs. We favor use of leukotriene modifiers and rarely initiate
theophylline in the modern treatment of asthma.

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• SEVERE PERSISTENT (STEP 4 OR 5)
– The preferred treatments are medium (Step 4) or high (Step 5) doses of
an inhaled glucocorticoid, in combination with a long-acting inhaled beta-
agonist
– In treating severe asthma, many providers add a leukotriene modifier to the
combination inhaled GC and LABA, so-called "triple-controller therapy.“
– When severe asthma remains poorly controlled, oral glucocorticoids may be
needed on a daily or alternate-day basis.
– For patients whose asthma is inadequately controlled on high-dose inhaled
GCs and LABAs, the anti-IgE therapy omalizumab may be considered if there
is objective evidence of sensitivity to a perennial allergen (by allergy skin
tests or in vitro measurements of allergen-specific IgE) and if the serum
IgE level is within the established target range

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• The preferred long-term controller agents for mild persistent asthma are low-
dose inhaled glucocorticoids. Alternative agents are leukotriene modifying drugs,
mast cell stabilizing agents (cromoglycates), and sustained-release theophylline,
although the latter two therapies are increasingly obsolete
• Inhaled glucocorticoids — Inhaled glucocorticoids (commonly called inhaled
steroids) are now considered the agents of choice in all patients with persistent
asthma
– Initial dosing —should be in the low-dose range
• Mometasone is approved for once-daily dosing.
• The other inhaled glucocorticoids have traditionally been administered
twice daily,

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 ACUTE SEVERE ASTHMA
• Exacerbations of asthma are feared by patients and may be life threatening.
• Clinical features
– Increasing chest tightness, wheezing, and dyspnea that are often not or poorly
relieved by their usual reliever inhaler.
– Breathless that they are unable to complete sentences
– Cyanotic.
– Increased ventilation, hyperinflation, and tachycardia.
– Pulsus paradoxus
– There is a marked fall in spirometric values and pef.
– Arterial blood gases on air show hypoxemia, and pco2 is usually low due to
hyperventilation.
– A normal or rising pco2 is an indication of impending respiratory failure and
requires immediate monitoring and therapy.
– A chest roentgenogram is not usually informative, but may show pneumonia or
pneumothorax.

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• TREATMENT
– A high concentration of oxygen should be given by face mask to achieve oxygen
saturation of >90%.
– The mainstay of treatment are high doses of SABA given either by nebulizer or via
a MDI with a spacer.
– In severely ill patients with impending respiratory failure, IV β2-agonists may be
given.
– A nebulized anticholinergic may be added if there is not a satisfactory response to
β2-agonists alone, as there are additive effects.
– In patients who are refractory to inhaled therapies, a slow infusion of aminophylline
may be effective, but it is important to monitor blood levels, especially if patients
have already been treated with oral theophylline.
– Magnesium sulfate given intravenously or by nebulizer is effective when added to
inhaled β2-agonists, and is relatively well tolerated but is not routinely
recommended.

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• Prophylactic intubation may be indicated for impending respiratory failure, when
the PCO2 is normal or rises.

• Antibiotics should not be used routinely unless there are signs of pneumonia.

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 Refractory Asthma
• ~5% of the case
• Important to check adherence to therapy and inhaler technique.
• There are two major patterns of difficult asthma:

– Some patients have persistent symptoms and poor lung function, despite
appropriate therapy, whereas

– Others may have normal or near normal lung function but intermittent,
severe (sometimes life-threatening) exacerbations.

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• MECHANISMS
– Poor adherence with medication, particularly ICS
• Compliance may be improved by giving the ICS as a combination with a LABA
that gives symptom relief.

• Adherence with OCS may be measured by suppression of plasma cortisol and

the expected concentration of prednisone/prednisolone in the plasma.

– Exposure to high, ambient levels of allergens or unidentified occupational agents.

– Severe rhino-sinusitis may make asthma more difficult to control; upper airway
disease should be vigorously treated.

– Drugs such as beta-adrenergic blockers, aspirin, and other cyclooxygenase (COX)

inhibitors may worsen asthma.
– Few systemic diseases make asthma more difficult to control, but hyper- and
hypothyroidism may increase asthma symptoms and should be investigated if
suspected.

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• Corticosteroid-Resistant Asthma
– It is defined by a failure to respond to a high dose of oral
prednisone/prednisolone (40 mg once daily over 2 weeks)

– Complete resistance to corticosteroids is extremely uncommon and affects

<1 in 1000 patients.

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• TREATMENT
– Check adherence and the correct use of inhalers
– Identify and eliminate any underlying triggers.
– Low doses of theophylline may be helpful in some patients, and theophylline
withdrawal has been found to worsen in many patients.
– Many of these patients will require maintenance treatment with OCS, and
the minimal dose that achieves satisfactory control should be determined by
careful dose titration.

– Steroid-sparing therapies are rarely effective.

– In some patients with allergic asthma, omalizumab is effective, particularly

when there are frequent exacerbations.

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• Pregnancy
– One-third of asthmatic patients who are pregnant improve during the course
of a pregnancy, one-third deteriorate, and one-third are unchanged.

– The drugs that have been used for many years in asthma therapy have
now been shown to be safe and without teratogenic potential.

– These drugs include SABA, ICS, and theophylline; there is less safety
information about newer classes of drugs such as LABA, antileukotrienes, and
anti-IgE.

– If an OCS is needed, it is better to use prednisone rather than prednisolone as

it cannot be converted to the active prednisolone by the fetal liver, thus
protecting the fetus from systemic effects of the corticosteroid.
– There is no contraindication to breast-feeding when patients are using these
drugs

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