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1 10/19/20
 Asthma TTT:
Asthma phenotypes:
By:
Prof Mohammad Khairy El Badrawy
Prof pf chest medicine
Mansoura university
2019- 2020
Manchester undergraduate
 Definition of Asthma
A chronic inflammatory disease of the airways with the
following clinical features:
1. Episodic and/or chronic symptoms of airway
obstruction
2. Bronchial hyperresponsiveness to triggers.
3. Evidence of at least partial reversibility of the airway
obstruction.
4. Alternative diagnoses are excluded.
Asthma inflammation: cells and mediators:
Mechanisms of airway inflammation:
Pathology of BA: TTT of BA:
Bronchospasm Bronchodilation
Airway inflammation Anti inflammation
 Goals of BA treatment:
1. Control of BA:
A. Improve symptoms.
B. Improve pulmonary function.
2. Decrease or prevent complications of asthma.
3. Decrease mortality of asthma.
4. Decrease side effects and mortality from the
drugs used.
 1. Allergen avoidance
•Dust
•Odors and fumes.
•Chemicals.
•Drugs,
•Smoking
Asthma Treatment is guided with:
1. Severity of the patient’s asthma
2. Patient’s current treatment
3. Economic considerations
4. Drug availability.
a. Bronchodilation is done by:
1.Increased sympathetic activity:
sympathomimetic:
1.Increased intracellular (sm ms) cAMP.
2.Decreased intracellular (sm ms) cGMP.
2.Vagal paralysis: parasympatholysis.
 Increased sympathetic activity:
sympathomimetic:
• Alpha receptors:1 and 2 (sm ms
contraction).
• Beta receptors: Beta 1 and 2
• Beta 1 in the heart
• Beta2 in the smooth muscles.
Stimulation of Beta2 receptors:
increase cAMP by stimulation of
adenyl cyclase that transform ATP
into cAMP and decrease cGMP and
bronchodilatation
Beta 2 agonists: BA
Parasympatholytics:
lead to
bronchodilatation
Muscarinic receptor
anatagonists: MA
1. Sympathomimetics: (BA)
Short acting: Long acting:
1. Salbutamol. 1. Salmetrol.
2. Terbutaline. 2. Formetrol.
3. Fenoterol. 3. Bambuterol.
4. Olodaterol
5. Indacaterol.
 2. Parasympatholytics:
•Ipratropium bromide. (short acting)
•Glycopyrronium (long acting)
•Tiotropium (long acting)
 3. Theophylline:
•Inhibit phosphodiestrase: leads to
accumulation of cAMP in Sm Ms
•Its use nowadays is rare and declining.
•B. Antiinflammatory drugs:
1. Steroids:
1. Inhaled
2. Systemic: parenteral or oral.
2. Antileukotreins: montelukast and xafirlukast.
3. Anti-IgE: omalizumab
4. Steroid sparing drugs: azathioprine and
methotrexate, gold, cyclosporine A.
5. Anti IL5
6. Anti IL13
 Steroids:
•Inhaled steroids: Systemic steroids:
1. Predinisone.
1. Beclomethasone. 2. Prednisolone.
2. Budesonide. 3. Methylprednisol
3. Flutecasone. one.
4. Ceclesonide. 4. Betasone.
5. Triamcinolone.
6. Dexasone.
 Single or combined
• SABA
• LABA.
• SAMA.
• LAMA.
• ICS
• Combined SABA+ICS.
• Combined LABA and ICS.
• Combined SABA and SAMA
• Combined LABA and LAMA
• Tripple: LABA, LAMA and ICS.
 Asthma severity grades:
1. Intermittent asthma.
2. Mild persistent asthma.
3. Moderate persistent asthma.
4. Severe persistent asthma.
 Asthma severity grades:
Daytime Symptom Nighttime Sympt FEV1 %

• Intermittent ≤2 days/week ≤2 nights/month ≥80%

• Mild Persistent > 2/w but < 1/d 2 nights/month ≥80%

• Moderate Persistent Daily > 1 night/week > 60% - < 80%

• Severe Persistent Continual Frequent ≤60%

 Stepwise Approach for Optimal Asthma
management
Step 5
Step 4
Step 3 Refer for
Step 1 Step 2
Preferred controller add-on
choice Med/high treatment
Low dose
ICS/LABA ICS/LABA e.g.
Anti-IgE
low dose ICS

Med/high
dose ICS High dose
Other controller Consider low dose
Leukotriene receptor antagonist Low dose ICS+LTRA Add low
choice ICS ICS+LTRA
(LTRA) (or + theo.) dose OCS
(or + theo.)
Low dose theophylline
As needed SABA or low dose
Reliever As-needed short-acting beta2-agonist (SABA)
ICS/Formoterol
Before stepping up, always check inhaler technique,
adherence and key issues first
Global strategy for Asthma management and prevention guidelines 2014.
 Step 1 treatment:
• Low dose Inhaled steroids
• SABA when needed
 Step 2:
•Medium dose Inhaled steroids + LABA
•Leukotriene receptor antagonists
•Slow release theophylline
 Step 3:
•High dose Inhaled steroids + LABA
•Leukotriene receptor antagonists
•Slow release theophylline
 Step 4:
• High dose of Inhaled steroids + LABA
• Leukotriene receptor antagonists
• Slow release theophylline
• Systemic low dose steroids.
 Step 5:
•High dose of Inhaled steroids + LABA
•Leukotriene receptor antagonists
•Slow release theophylline
•Systemic low dose steroids.
•Tiotropium
•Anti IGE.
ICS with or without LABA, continue to be the
mainstay of pharmacological treatment for mild
to moderate asthma.
Fernando D Martinez et al, Lancet 2013; 382: 1360–72
 ICS in Asthma
•ICS are by far the most effective controllers used in
the treatment of asthma.
•The only drugs that can effectively suppress the
characteristic inflammation in asthmatic airways,
even in low doses.
•First-line therapy for all asthma severities and
patients of all ages and are the most effective
asthma medications currently available.
Peter J.Barnes et.al,Pharmaceuticals 2010, 3, 514-540
 Role of ICS in Asthma
•Reverse chronic airway inflammation.
•Reduce the number of mast cells, macrophages,
T-lymphocytes and eosinophils in the sputum,
broncho-alveolar lavage and bronchial wall.
•Reverse the shedding of epithelial cells, goblet-cell
hyperplasia and basement-membrane thickening
characteristic of the airway mucosa of patients
with asthma.
Kian Fan Chung et.al,Eur J Clin Pharmacol 2009 65:(9)853–871
 ICS in Asthma
Cellular Effects

Peter J.Barnes et.al,Pharmaceuticals 2010, 3, 514-540

 ICS in Asthma (cont.)

• Inhaled corticosteroids are better than leukotriene

receptor antagonists, such as montelukast, at :
• Controlling symptoms
• Improving lung function
• Reducing exacerbations

Fernando D Martinez et al, Lancet 2013; 382: 1360–72

Adding LABA is better than increasing ICS dose
•Patients respond better to adding LABAs than to
doubling the dose of inhaled corticosteroids or adding
a leukotriene receptor antagonist.

Fernando D Martinez et al,Lancet 2013; 382: 1360–72

 Interactions between
corticosteroids and ß2 agonists

Peter J. Barnes et al, Pharmaceuticals 2010, 3(3), 514-540

 A Relationship Exists Between Mortality and SABA or ICS Use

250 2.5
Asthma Deaths/10,000 Patient-years

Rate Ratio for Death From Asthma

200 2.0

150 1.5

100 1.0

50 0.5

0.0 0.0
0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 8 9 10 11 12
Canister units (20,000mcg) of SABA/month Canisters of ICS Per Year2

Risk of asthma death was associated with Use of ≥6 ICS canisters per year was
rapid increase when >1-2 SABA canisters associated with a 50% reduction in asthma
are used per month1 mortality2

ICS = inhaled corticosteroid; SABA = short-acting β2-agonist.

1. Suissa S et al. Am J Respir Crit Care Med. 1994;149:604–10; 2. Suissa S et al. N Engl J Med. 2000;343:332–336.
Veeva ID: Z4-14571 Date of Preparation: October 2018 Date of Expiration October 2020
Proprietary and Confidential ©AstraZeneca Pharmaceuticals • This document is intended for educational purposes to be used when proactively reaching out to Healthcare Professionals.
 Levels of Asthma Control
Assessment of current clinical control (preferably over 4 weeks)

Controlled Partly controlled

Characteristics (All of the following) (Any measure present)
Uncontrolled

1. Daytime symptoms None (twice or More than twice/week

less/week)
2. Limitation of activities None Any
3. Nocturnal symptoms/ None Any
Awakening Three or more
4. Need for reliever/rescue None (twice or less/ More than twice/week features of partly
treatment week) controlled asthma

5. Lung function (PEF or Normal <80% predicted or

FEV1) personal best (if known)

Adapted from Global strategy for Asthma management and prevention 2014.
 Acute severe asthma
Status asthmatics
“Defined as wheezing which does not
respond to initial treatment with inhaled
bronchodilators “

Mannix R, Bachur R: Status asthmaticus in children. Curr Opin Pediatr 2007, 19:281-7.
Werner HA: Status asthmaticus in children. Chest 2001, 119:1913-29.
 Management of acute severe
asthma:
•DX:
1. Pulse: more than 130/ min
2. RR: more than 30/ min.
3. Intercostal indrowing.
4. Cyanosis.
5. Unable to complete a sentence.
6. Pulsus paradoxicus.
 Treatment of ASA:
1. Open IV line.
2. O2 inhalation.
3. 200 mg of hydrocortisone.
4. IV theophylline slowly over 30 min.
5. Inhaled salbutamol with or without ipratropium with nebulizer.
6. Inhaled high doses of budesonide with nebulizer.
7. Mechanical ventilation if the patient is:
• Exhausted,
• Hypercapnea.
 Acute Asthma Management – Adults
In-ED management
MV

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s pons IV MgSO4,
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histo
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t hera
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Ad

Systemic corticosteroid (SCS)

Controlled O 2 + Fast-acting beta-agonist and ipratropium bromide

Treat complications
Confirm Diagnosis
Severe exacerbation Mild exacerbation
 Nebulizer
• Machine produces a mist of
the medication

• Used for small children or for

severe asthma episodes

• No evidence that it is more

effective than an inhaler used
with a spacer
 Other drugs:
•Omalizumab: anti IGE.
•Methotrexate.
•Azathioprine.
•Anti IL5
•Anti IL13
 Occupational Asthma
• “Work-sensitized” (high MW >5000 daltons)
IgE-mediated “asthma with latency”
• “Irritant-induced” (low MW <5000 daltons)
Non IgE-mediated “asthma without latency”
Irritant asthma
Reactive airways dysfunction syndrome (RADS)
“Low-dose RADS”
• “Work-exacerbated” (aggravated)
• > 250 workplace culprit substances
• Estimated 16% of all adult onset asthma
Toren and Blanc 2009
What do these have in common?
 When to do obstruction testing for
Occupational Asthma?
• Preferably performed toward the end of a typical work
week and within 24 hr of the occurrence of symptoms
 Treatment of occupational asthma:
•Change work environment.
•Desensitization if it is not possible.
•Combination LABA and ICS and LTRA.
 Dx of aspirin induced asthma:
•Triad of:
1. Asthma,
2. Chronic rhinosinusitis with nasal polyps, and
3. Precipitation of asthma and rhinitis attacks in
response to aspirin and other NSAIDs.
• A number of theories regarding its pathogenesis have been
proposed:
1. The shunting hypothesis proposes that inhibition of COX-1 shunts
AA metabolism away from production of protective prostanoids
and towards cysteinyl leukotriene (cys-LT) biosynthesis, resulting
in bronchoconstriction and increased mucus production.
2. The COX-2 hypothesis proposes that aspirin causes a structural
change in COX-2 that results in the generation of products of the
lipoxygenase pathway.
 Treatment of AIA:
• AIA patients have an aggressive form of disease, and
treatment should include combination therapy with:
1. Inhaled corticosteroids,
2. Beta(2)-adrenoceptor agonists and
3. LT modifiers.
• Furthermore, recently developed inhibitors of COX-2
may be safer in patients with AIA.
 Obese Asthma Phenotype

Leiria, 2014
 Severe/refractory asthma (ATS workshop)
Major • Continuous or near-continuous oral steroids
(≥1) • High-dose ICS
• Additional daily controller
• Use of SABA on a near-daily basis
• Persistent airway obstruction
• FEV1 < 80%
Minor • Diurnal variation in PF ≥ 25%
(2) • ≥ 1 urgent care visit per year
• ≥3 or more steroid bursts per year
• Prompt deterioration with 25% reduction in steroid dose
• Episode of near-fatal asthma
 Exercise induced asthma:
• Signs and symptoms of exercise-induced bronchoconstriction may
begin during or soon after exercise. These symptoms may last for 60
minutes or longer if left untreated.
• The signs and symptoms may include:
1. Coughing
2. Wheezing
3. Shortness of breath
4. Chest tightness or pain
5. Fatigue during exercise
6. Poorer than expected athletic performance
7. Avoidance of activity (a sign primarily among young children)
 Treatment of EIA:
• Warming.
• SABA inhalation 15 min before exercise.
• Ipratropium bromide 15 min before exercise.
• Inhaled corticosteroids.
• Combination inhalers: LABA and ICS.
• Leukotriene modifiers.
Treatment of eosinophilic
asthma
TARGETED AT Th2 (ALLERGIC) ASTHMA
 Treatments based on Phenotypes -
Omalizumab
• Best Candidates:
• High IgE
• Known Allergen
• BMI
Treatments based on Phenotypes -
Omalizumab
Asthma Exacerbations

Hanania Ann Intern Med 2011, Busse NEJM 2011

 Treatments based on Phenotypes -
Mepolizumab
IL-5: Key cytokine in eosinophil
o Differentiation
o Recruitment
o Activation
o Survival

• Best Candidates:
o - High Eosinophils
o - 2 or greater exacerbations/yr
o - On high dose ICS

Fulkerson Nature Review Drug Discovery 2013

Treatments based on Phenotypes -
Mepolizumab
MENSA trial (RCT), selected for high eosinophils, mod-high dose ICS •
Asthma Exacerbations and FEV1 at 32 Weeks.

Ortega NEJM 2014 (Sponsored by Glaxo-Smith Kline)

Side Effects and Adverse Reactions
• Omalizumab • Mepolizumab
• Anaphylaxis (must have epi-pen)
• 0.1-0.2%
• No observed risk of
• Can occur as late as 1 year anaphylaxis
• ? Malignancy (0.5 vs. 0.2% in RCT) • Muscle pain
• Longer observation trials underway
• Fatigue
• Pain and arthralgia
• Injection site bruising/pain • Injection site
bruising/pain
 Side effects of drugs used:
• Beta agonists.
• Inhaled steroids.
• Systemic steroids.
• Theophyllines.
• Anticholinergics
• Antileukotriens.
• Side effects of leukotriene modifiers include behavior and
mood changes and suicidal thoughts.