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Asthma for a better control • • Definition Epidemiology of asthma Pathophysiology and asthma Asthma for a better control • • Definition Epidemiology of asthma Pathophysiology and asthma evolution Diagnosis of asthma Asthma classification Treatment of asthma Clinical Scenarios and discussion

Definition A chronic inflammatory disorder of the airways in which many cells play a Definition A chronic inflammatory disorder of the airways in which many cells play a role that causes recurrent episodes of wheezing, breathlessness, chest tightness and cough ic but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes. These symptoms associates with widespread and associated increase in airway responsiveness to variety of stimuli.

Emphysema Chronic Bronchitis Venn diagram of obstructive lung disease Airflow limitation Asthma Emphysema Chronic Bronchitis Venn diagram of obstructive lung disease Airflow limitation Asthma

Epidemiology and Risk Factors • • For all age group : incidence 2. 65 Epidemiology and Risk Factors • • For all age group : incidence 2. 65 -4/1000 per year. Children : 4. 3 -18/1000 per year Adult : 2. 1/1000 per year Mortality (1985 -1987) between 1. 3 -9. 3 /100, 000 of total population • Danish follow-up study showed cigarette smoking, age, presence of blood eosinophilia, impairment of lung function and degree of reversibility contribute to asthma mortality

Age and Sex Distribution of Asthma 16 14 Individuals per 1000 12 10 8 Age and Sex Distribution of Asthma 16 14 Individuals per 1000 12 10 8 6 4 2 0 0 10 20 Male 30 40 50 60 70 Female 80

Prevalence of self-reported asthma, children aged 13 -14 years 12 months prevalence of self-reported Prevalence of self-reported asthma, children aged 13 -14 years 12 months prevalence of self-reported asthma with a written questionnaire, for children aged 13 -14 years. International Study of Asthma and Allergies in Childhood (ISAAC) including 463, 801 children in 56 countries

Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Airway Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Airway Inflammation Hyperresponsiveness + Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

Asthma Evolution Hypothesis Genetic Predisposition Asthma Evolution Hypothesis Genetic Predisposition

The Genetic of Asthma • 20 -25% Increase in prevalence of asthma among first The Genetic of Asthma • 20 -25% Increase in prevalence of asthma among first degree relative of asthmatics compare to general population (4%) • Monozygotic twins (50%) dizygotic twins (33%) • Doesn’t follow any medelian pattern • Genetic researches provided evidence of several atopic phenotypes (eosinophil count, skin testing, atopic cytokines)

Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens

Risk factors for development of asthma Factors that contribute to asthma Inherent factors Causal Risk factors for development of asthma Factors that contribute to asthma Inherent factors Causal factors Contributing factors Atopy Gender Hyperresponsiveness Genetic abnormalities Smoking Respiratory Infection Small birth weight Diet Air pollution Lung function Indoor allergens Outdoor allergens Occupational sensitizer

Atopy • Atopy is characterized by – Elevated Ig. E level – Detection of Atopy • Atopy is characterized by – Elevated Ig. E level – Detection of Ig. E against common allergens – Positive skin test against common allergen • Asthmatic are more atopic than non-asthmatic • Increase airway hyperresponsiveness is associated with increase in atopy

Atopy in asthma • House dust mite is the most common allergens • Increases Atopy in asthma • House dust mite is the most common allergens • Increases in prevalence of asthma in New Guinea when adult exposed to house dust mite. • Association between the level of house dust mite in the bed room of babies during the first year of life and asthma in at 8 years of age. • Cats more than any other animals is a risk for asthma • Children expose to furry cat are at twice the risk for • developing asthma • Other allergens including grass, tree pollen, and cockroaches

Asthma risk factors • Exercise: occur because of water loss from the airway wall Asthma risk factors • Exercise: occur because of water loss from the airway wall • Occupation: e. g. ; wood dust, formaldehyde, latex, animal allergens • Drugs: NSAID, possible biphosphonate, ßblocker • Premenstrual asthma : associated with late luteal phase

Smoking and asthma risk • Passive smoking – It the second major risk after Smoking and asthma risk • Passive smoking – It the second major risk after atopy – Parental , especially maternal, smoking is associated with increase risk of asthma in children – Smoking >10 cig/day increase asthma by 2. 5 times at 12 years of age – Increase four-fold of the level of Ig. E from cord blood of newborn of mothers who smoke (even in absence of atopy)

Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation

Th 1 and Th 2 Balance Widespread use of antibiotics Western lifestyle Diet Sensitisation Th 1 and Th 2 Balance Widespread use of antibiotics Western lifestyle Diet Sensitisation to allergens Parasitic infection Bacterial Infection TB, Measles, Hep. A Rural Environment Th 1 Protective immunity Th 0 Th 2 Allergic disease

Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Airway Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Airway Inflammation

Mast cell PGD 2, LTC 4/D 4 Histamine, Tryptase Cytokin es Mast cell Acute Mast cell PGD 2, LTC 4/D 4 Histamine, Tryptase Cytokin es Mast cell Acute Asthma Chronic Asthma APS TH 2 Smooth Muscle Eosinophils B-cell

Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Airway Asthma Evolution Hypothesis Genetic Predisposition + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Airway Inflammation Hyperresponsiveness + Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

Diagnosis of Asthma Diagnosis of Asthma

Case 1 • 22 years old lady came to your office with cough for Case 1 • 22 years old lady came to your office with cough for several weeks with no associated sputum. She deny any other symptoms but remember she use to have similar symptoms when she was young. She also noticed that she get tired slighter sooner that her class mate in sports event. • Examination was normal and her PEF was normal • Does this patient have asthma?

Diagnosis of asthma Wheeze Chest tightness Nocturnal symptoms Cough Asthma Difficulty In breathing Diagnosis of asthma Wheeze Chest tightness Nocturnal symptoms Cough Asthma Difficulty In breathing

Canadian Asthma Consensus Diagnosis and Evaluation of Asthma in Adult • Spirometry: improvement of Canadian Asthma Consensus Diagnosis and Evaluation of Asthma in Adult • Spirometry: improvement of FEV 1 by – 12% and 200 ml from the base line after inhalation of short acting ß 2 agonist – 20% and 250 ml after 10 -14 days on inhaled or systemic glucocorticosteroid – 20% and 250 ml with spontaneous variability • Peak Expiratory Flow – 20% or more variability between highest and lowest values ( morning and afternoon, before and after bronchodilator)

Spirometry in asthma Normal FVC Normal FEV 1 Normal Ratio Normal or mild low Spirometry in asthma Normal FVC Normal FEV 1 Normal Ratio Normal or mild low FVC low FEV 1 low Ratio Asthma

Canadian Asthma Consensus Diagnosis and Evaluation of Asthma in Adult • Airway Hyperresponsiveness – Canadian Asthma Consensus Diagnosis and Evaluation of Asthma in Adult • Airway Hyperresponsiveness – Methacholine neubelizer provocation test to evaluate the airway response – Positive test is there is a drop of more than 20% of FEV 1 in a methacholine concentration of less than 8 mg/ml – Negative methacholine can exclude asthma

Methacholine Provocation Test FEV 1 Base line PC 20 FEV 1 20% Drop Normal Methacholine Provocation Test FEV 1 Base line PC 20 FEV 1 20% Drop Normal Saline 0. 25 mg/ml 0. 5 mg/ml 1 mg/ml 2 mg/ml 4 mg/ml Methacholine Concentration 8 mg/ml

Primary Prevention Asthma Evolution Secondary Prevention + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Primary Prevention Asthma Evolution Secondary Prevention + Environmental Factors Maternal Smoking Indoor/outdoor Allergens Sensitisation Secondary Prevention Regular Anti-inflammatory treatment Genetic Predisposition Secondary Prevention Avoidance Treatment of exacerbation Airway Inflammation Hyperresponsiveness + Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

Current therapy for asthma Relievers (bronchodilators) ß 2 -Agonist Controllers (anti-inflammatory) Corticosteroids Theophylline Cromones Current therapy for asthma Relievers (bronchodilators) ß 2 -Agonist Controllers (anti-inflammatory) Corticosteroids Theophylline Cromones Anticholinergics Antileukotrienes Steroid-sparing agents -Methotrexate -Gold -Cyclosporin A

ß 2 agonist • ß 2 receptors are present in all smooth muscles of ß 2 agonist • ß 2 receptors are present in all smooth muscles of the airways • Direct effect causing – – Smooth muscle relaxation Reduction in neurotransmitter Increase ciliary clearance Decrease the microvascular leak decrease edema • Salbutamol, terbutaline, fenoterole, metaprotanole • Does not have anti inflammatory effect • Drug of choice in both children and adult for the relief of acute asthma symptoms

ß 2 agonist • Side effects – Mild tremor (affect on skeletal muscle receptors) ß 2 agonist • Side effects – Mild tremor (affect on skeletal muscle receptors) – Tachycardia( affect on cardiovascular) – Hypokalemia ( increase K+ entry to skeletal muscle) • No evidence that it increase or induce serious arrhythmias or other cardiac abnormalities

ß 2 agonist • No evidence that regular four times a day with SAß ß 2 agonist • No evidence that regular four times a day with SAß 2 is better than as needed approach in any degree of asthma severity • Regular SAß 2 is associated with masking underlying inflammation increase hyperresponsiveness worsening severity

Long acting ß 2 • • It have more sustained action It enhance the Long acting ß 2 • • It have more sustained action It enhance the effect of inhaled steroids Salmeterol and formoterol Not recommended for relief of acute symptoms and exacerbation • Does not increase airway hyperresponsiveness and it have some antiinflammatory effect

Theophylline • Phosphodiestterase inhibitors increase in c. AMP bronchodilators • Adenosine receptors antagonist CNS Theophylline • Phosphodiestterase inhibitors increase in c. AMP bronchodilators • Adenosine receptors antagonist CNS stimulation, cardiac arrhythmias, diuresis • Stimulation of adrenaline release • Less effective than ß 2 agonist in acute exacerbation and it is more recommended in chronic asthma (especially if nocturnal symptoms present)

Anticholiergics • Muscarinic receptors antagonist and inhibit cholinergic receptors that cause bronchoconstrection • Less Anticholiergics • Muscarinic receptors antagonist and inhibit cholinergic receptors that cause bronchoconstrection • Less effective than ß 2 but it has additative effect • Are more effective in acute than chronic asthma • More effective in asthmatic who have element of fixed airway • Ipratropium, oxitropium and tiotropium bromide

Affect of anticholinergic on smooth muscle Vagus Nerve Acetylcholine Anticholinergic Affect of anticholinergic on smooth muscle Vagus Nerve Acetylcholine Anticholinergic

Cromones • It may affect chloride channels that expressed in mast, nerve and some Cromones • It may affect chloride channels that expressed in mast, nerve and some inflammatory cells • Inhibit mediators release from mast cells by membrane stabilization • Effect on sensory nerve ending in the airways • Prophylactic treatment and should be given regularly • Preferred agent in children

Antileukotrienes • LTC 4, LTE 4 and LTD 4 are products of inflammatory cells Antileukotrienes • LTC 4, LTE 4 and LTD 4 are products of inflammatory cells that cause bronchoconstrition • 40 times more potent that histamine or methacholine to cause bronchoconstriction • Blocking leukotriens receptors cause bronchodilatation and decrease eosinophils • Zafirlukast, pranlukast and montelukast • Reduce allergen-exercise-cold induced asthma by 50 -70% • Complete response in aspirin-induced asthma

Corticosteroids • Action occur through activation of glucocoticosteroid receptors (GCSr) which found in all Corticosteroids • Action occur through activation of glucocoticosteroid receptors (GCSr) which found in all body cells • When bound to receptors it decreases gene production for many pro and inflammatory cytokines • Systemic (parental/oral) or inhaled are the two major form

Systemic corticosteroids • Reserved for moderate to sever cases • Oral bio availability is Systemic corticosteroids • Reserved for moderate to sever cases • Oral bio availability is very high with complete GI absorption. • Parental route reserved if oral rout can’t be tolerated

Inhaled corticosteroid • They are as effective as low to moderate dose of systemic Inhaled corticosteroid • They are as effective as low to moderate dose of systemic steroids with much lesser side effects • Lipophilic: very high binding affinity and fast first pass liver metabolism • five inhaled corticosteroids (ICS) currently available – – – Fluticasone propionate (Flexotide, Flovent) Beclomethasone 17, 21 -dipropionate ( Beclovent, QVAR) Triamcinolone (Azmacort) Flunisolide (Aero. Bid) Budesonide (Pulmicort)

Corticosteroids side effects • Local side effect: – oral candidiasis occur in 10% – Corticosteroids side effects • Local side effect: – oral candidiasis occur in 10% – Increase risk with poor technique, concomitant use of antibiotics and reduce by use of spacer and rinsing mouth. – Dysphonia (30%) in people who use their voice a lot – Doesn't have any effect on airway mucosa

ICS side effects • Hypothalamic-pituitary-adrenal axis – No effect was seen with doses of ICS side effects • Hypothalamic-pituitary-adrenal axis – No effect was seen with doses of BDP<1500 g/day or budesonide <1600 g/day – Only 2 cases reported with adrenal insufficiency ( very high dose of budesonide of 6400 g/day)

ICS side effects • Osteoporosis – ICS shown to have some effect on osteocalcin ICS side effects • Osteoporosis – ICS shown to have some effect on osteocalcin (bone formation) and hydroxyproline (bone resorption) in doses of budesonide>2000 g/day – Bone densitometry carried out in adult asthmatic on various doses of ICS and it showed no increase bone loss • Does not cause growth retardation in children • Children on ICS were shorter on average than children not on ICS at 2 years of age, but all of them had the same height at 6 years of age

ICS side effects • Posterior subcapsular cataract – Usually there is no risk – ICS side effects • Posterior subcapsular cataract – Usually there is no risk – Risk slightly increase with high doses of ICS and use of MDI • Risk of lung infection – Risk of lung infection is not increased – Does not increase the risk of TB re-activation • Risk of skin bruising increase with height doses of ICS ( from 22% to 47%) in older population

Delivery of medication Delivery of medication

Case 2 • 64 years old gentleman who was known to have asthma for Case 2 • 64 years old gentleman who was known to have asthma for several years on inhaled corticosteroids ( MDI). • You are seeing him for the first time, history and exam revealed moderate persistent asthma not will controlled because he claim he can’t use the apparatus. Throat exam showed oral condidiasis and chest exam.

Pressurized metered-dose inhaler • Pressurized in a crystal suspension in liquid mixture of chloroflucarbones(CFC) Pressurized metered-dose inhaler • Pressurized in a crystal suspension in liquid mixture of chloroflucarbones(CFC) • The mixture boil off rabidly as soon as they leave the container with velocity of 30 m/sec • Newer form ban the CFC and use non-CFC solution • Laryngeal deposition is 25% with some MDI

Laryngeal deposit with MDI Laryngeal deposit with MDI

Dry-powder inhaler • Depends on patient inspiratory effort • DPI – Spinhalers – Rotahaler Dry-powder inhaler • Depends on patient inspiratory effort • DPI – Spinhalers – Rotahaler – Diskhalers – Reservoir dry-powder inhalers

Neubelizers • Two type of neubelizer; Jet and ultrasonic • Ultrasonic use sound wave Neubelizers • Two type of neubelizer; Jet and ultrasonic • Ultrasonic use sound wave vibration through liquid to form fountain of droplets • Jet neubelizer result from steam of compressed air or oxygen that push liquid drug through small capillaries to become like steam • Usually 50% of neubelized solution is left in apparatus and can’t be utilized

Deposition% Loss in air Apparatus GI Lung MDI DPI Nebulizer Deposition% Loss in air Apparatus GI Lung MDI DPI Nebulizer

Chronic asthma Chronic asthma

Case 3 • 29 years old male was diagnosed to have asthma for several Case 3 • 29 years old male was diagnosed to have asthma for several years that was controlled in budesonide 200 mcg bid with MDI. In the last week he noticed that he is having more cough and occasionally awaking up in the middle of the night with cough. After assessing possible excerbating factors what will be your next step?

Chronic asthma Classification of asthma severity Days with symptoms Night with symptoms FEV 1 Chronic asthma Classification of asthma severity Days with symptoms Night with symptoms FEV 1 or PEF % PEF variability Mild 2/wk intermittent Mild 3 -6/wk persistent Moderate Daily persistent Sever Continual persistent 2/month 80% <20 3 -4/months 80% 20 -30 5/months >60<80 >30 Frequent 60 >30 step

Treatment Goals • • • Achieve and maintain control of symptoms Minimize frequency of Treatment Goals • • • Achieve and maintain control of symptoms Minimize frequency of asthma attacks Prevent emergency visits to doctors or ER Achieve and maintain normal activity level Optimise asthma therapy with minimum side effects – Minimize the need of ß 2 agonist – Step down use of ICS

Sever Persistent Rescue medication with Short ß 2 agonist Moderate Persistent If symptoms>2/week, nocturnal Sever Persistent Rescue medication with Short ß 2 agonist Moderate Persistent If symptoms>2/week, nocturnal >2/month Go to next step Mild Persistent Mild intermittent Asthma

Short ß 2 agonist is needed Inhaled corticosteroid Beclomethasone or budesonide 200 -800 g Short ß 2 agonist is needed Inhaled corticosteroid Beclomethasone or budesonide 200 -800 g Or fluticasone 100 -400 g Or Sodium cromolyn Sever Persistent Mild intermittent If symptoms>6/week, nocturnal >4/month Go to next step Moderate Persistent Mild persistent asthma

Moderate persistent asthma Short ß 2 agonist is needed double Inhaled corticosteroid Beclomethasone or Moderate persistent asthma Short ß 2 agonist is needed double Inhaled corticosteroid Beclomethasone or budesonide 800 -2000 g Or fluticasone 400 -1000 g Or Inhaled corticosteroids with long acting ß 2 agonist Sever Persistent Mild intermittent If symptoms continual, nocturnal daily Go to next step

Moderate Persistent Mild intermittent Sever persistent asthma Short ß 2 agonist is needed double Moderate Persistent Mild intermittent Sever persistent asthma Short ß 2 agonist is needed double Inhaled corticosteroid Beclomethasone or budesonide 800 -2000 g Or fluticasone 400 -1000 g Or Inhaled corticosteroids with long acting ß 2 agonist With Theophylline or antileukutriens or high dose Anticholinergic If worse symptoms Systemic steroid

Acute Asthma Acute Asthma

Case 4 • 33 years old male presented to emergency with 3 days of Case 4 • 33 years old male presented to emergency with 3 days of progressive dyspnea. He could not sleep the night before because of cough and breathlessness. He is known to have asthma but he is not taking regular treatment. He smoke a pack aday. He deny fever, chest pain or previous history of heart disease • Exam showed patient in moderate distress, BP 130/90, pulse 120/min, O 2 90% • Chest exam showed decrease air entry at right with wheeze bilaterally • What is your management?

Clinical Features of Acute Asthma • History of exacerbating factors ( infection, allergens) • Clinical Features of Acute Asthma • History of exacerbating factors ( infection, allergens) • History of previous symptoms could be absent but mostly with history of uncontrolled asthma. Dyspnoea, orthopnea and PND could be present • Presence of chest pain could indicate asthma complication ( pneumothorax, collapse , CAD or pneumomediastinum) • History of previous ICU or intubations considered high risk

Severity of asthma exacerbation Respiratory arrest Symptoms Mild Moderate Sever Dyspnea Walking Can lie Severity of asthma exacerbation Respiratory arrest Symptoms Mild Moderate Sever Dyspnea Walking Can lie down Talking Prefers sitting At rest Hunched forward Talks in Sentences Phrases Words Alertness May be agitated Agitated RR Increase >30 Accessory Muscles Not Usually Paradoxical Wheeze Moderate at end of expiration Loud Absent Pulse <100 100 -120 >120 Bradycardia PEF >80 60 -80 <60 PO 2 PCO 2 Normal <45 >60 <45 <60 >45 O 2 sat >95 91 -95 <90 Drowsy or confuse

Hospital management in acute asthma Assess severity, ß 2 agonist, O 2, systemic steroids Hospital management in acute asthma Assess severity, ß 2 agonist, O 2, systemic steroids Repeat assessment improvement Continue treatment Partial or no improvement admit Response maintain improvement discharge Life threatening asthma worsening ICU

Case 5 • 26 years old lady 12 weeks pregnant came to you regarding Case 5 • 26 years old lady 12 weeks pregnant came to you regarding her asthma treatment. She have mild persistent asthma taking fluticason 250 mcg bid • She is worry about her baby as she was told that steroids is not good during pregnancy. • What will be your advice