Asthma Better Control

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 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

Venn Chronic Emphysediagram of obstructive Bronchitis ma lung disease

Airflow limitation

Asthm a

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

Individuals per 1000

14 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 35

30

25

20

15

10

5

0 UK

CANADA

USA

Kuwait

S.Africa

Oman

Moroco

Indonesia

Ethiopia

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 Inflammation

Hyperresponsiveness

+ Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

Asthma Evolution Hypothesis Genetic Predisposition

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

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 factors

Contributing factors

Atopy Gender Hyperresponsivene ss 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 IgE level – Detection of IgE 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 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 • Occupation: e.g.; wood dust, formaldehyde, latex, animal allergens • Drugs: NSAID, possible biphosphonate, ß-blocker • Premenstrual asthma : associated with late luteal phase

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 >10cig/day increase asthma by 2.5 times at 12 years of age – Increase four-fold of the level of IgE from cord blood of newborn of mothers who smoke (even in absence of atopy)

Asthma evolution hypothesis Acute Inflammation Su sc G epta en b e le

Cytokines Th2 immune deviation

ly ent r Ea nm iro v En

Allergen Viruses Pollution Diet

Mediators

Symptoms Growth Factors Tissue Remodeling

Chronic Inflammation Cytokines

Cytokines

Asthma Evolution Hypothesis Genetic Predisposition

+ Environmental Factors Maternal Smoking Indoor/outdoor Allergens

Sensitisation

Th1 and Th2 Balance Bacterial Infection TB, Measles, HepA Rural Environment

Th1 Protective immunity

Widespread use of antibiotics Western lifestyle Diet Sensitisation to allergens Parasitic infection

Th0

Th2 Allergic disease

Asthma Evolution Hypothesis Genetic Predisposition

+ Environmental Factors Maternal Smoking Indoor/outdoor Allergens

Sensitisation

Airway Inflammation

Mast cell

PGD2, LTC4/D4 Histamine, Tryptase Cytokin es

Mast cell

Acute Asthma Chronic Asthma APS TH2

Smooth Muscle

Eosinophils

B-cell

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

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

Canadian Asthma Consensus

Diagnosis and Evaluation of Asthma in Adult

• Spirometry: improvement of FEV1 by – 12% and 200ml from the base line after inhalation of short acting ß2 agonist – 20% and 250ml 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 FEV1 Normal Ratio

Normal

Normal or mild low FVC low FEV1 low Ratio

Asthma

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 FEV1 in a methacholine concentration of less than 8mg/ml – Negative methacholine can exclude asthma

Methacholine Provocation Test FEV1 Base line PC20

FEV1

20% Drop

Normal Saline

0.25mg/ml

0.5 mg/ml

1mg/ml

2mg/ml

4mg/ml

Methacholine Concentration

8mg/ml

Primary Prevention

Asthma Evolution Secondary Secondary Secondary Prevention Prevention Prevention

Genetic Predisposition

+ Environmental Factors Maternal Smoking Indoor/outdoor Allergens

Regular Anti-inflammatoryAvoidance treatment

Sensitisation

Airway Inflammation

Hyperresponsiveness

+ Environmental Factors Smoking, cold air Indoor/outdoor Allergens, viral infection

Treatment of exacerbation

Current therapy for asthma Relievers (bronchodilators) ß2-Agonist

Controllers (anti-inflammatory) Corticosteroids

Theophylline

Cromones

Anticholinergics

Antileukotrienes Steroid-sparing agents -Methotrexate -Gold -Cyclosporin A

ß2 agonist • ß2 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 leakdecrease edema

• Salbutamol, terbutaline,fenoterole, metaprotanole • Does not have anti inflammatory effect • Drug of choice in both children and adult

ß2 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

ß2 agonist • No evidence that regular four times a day with SAß2 is better than as needed approach in any degree of asthma severity • Regular SAß2 is associated with masking underlying inflammation  increase hyperresponsiveness  worsening severity

Long acting ß2 • 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 anti-inflammatory effect

Theophylline • Phosphodiestterase inhibitors inhibitors increase in cAMP cAMP bronchodilators • Adenosine receptors antagonist  CNS stimulation, cardiac arrhythmias,diuresis • Stimulation of adrenaline release • Less effective than ß2 agonist in acute exacerbation and it is more recommended in chronic asthma (especially if nocturnal

Anticholiergics • Muscarinic receptors antagonist and inhibit cholinergic receptors that cause bronchoconstrection • Less effective than ß2 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

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 • LTC4,LTE4 and LTD4 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

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 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 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 (AeroBid)

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 BDP<1500µ BDP<1500µ g/day or budesonide <1600 µ g/day – Only 2 cases reported with adrenal insufficiency ( very high dose of budesonide of 6400 µ g/day)

ICS side effects • Osteoporosis – ICS shown to have some effect on osteocalcin (bone formation) and hydroxyproline (bone resorption) in doses of budesonide>2000 µ 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

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 reactivation

• Risk of skin bruising increase with height doses of ICS ( from 22% to 47%) in older population

Delivery of medication

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, his 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

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 30m/sec • Newer form ban the CFC and use non-CFC solution • Laryngeal deposition is 25% with some MDI

Laryngeal deposit with MDI

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 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

Deposition%

Loss in air Apparatus GI Lung

MDI

DPI

Nebulizer

Chronic asthma

Case 3 • 29 years old male was diagnosed to have asthma for several years that was controlled in budesonide 200mcg 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

Chronic asthma Classification of asthma severity Days Night

with step sympto Mild ms intermitt ≤ 2/wk ent Mild persiste 3-6/wk Moderat nt e Daily persiste Sever nt Continua persiste l nt

with sympto ≤ms 2/month 34/month s ≥ 5/month s Frequen t

≥ 80%

PEF variabili ty <20

≥ 80%

20-30

>60<80

>30

≤ 60

>30

FEV1 or PEF %

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

Sever Persistent

Rescue medication with Short ß2 agonist

Moderate Persistent

If symptoms>2/week, nocturnal >2/month Go to next step 

Mild Persistent

Mild intermittent Asthma

Mild intermittent

If symptoms>6/week, nocturnal >4/month Go to next step  Short ß2 agonist is needed Inhaled corticosteroid Beclomethasone or budesonide 200-800µ g Or fluticasone 100-400 µ g Or Sodium cromolyn

Sever Persistent

Moderate Persistent

Mild persistent asthma

Moderate persistent asthma If symptoms continual, nocturnal Sever Persistent

Mild Persistent

Mild intermittent

daily Go to next step 

Short ß2 agonist is needed double Inhaled corticosteroid Beclomethasone or budesonide 800-2000µ g Or fluticasone 400-1000 µ g Or Inhaled corticosteroids with long acting ß2 agonist

Short ß2 agonist is needed double Inhaled corticosteroid Beclomethasone or budesonide 800-200 Or fluticasone 400-1000 µ g

Moderate Persistent

Mild Persistent

Mild intermittent

Sever persistent asthma

Or Inhaled corticosteroids with long acting ß2 agonist With Theophylline or antileukutriens or high d Anticholinergic If worse symptoms Systemic steroid

Acute Asthma

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, BP130/90, pulse 120/min, O2 90% • Chest exam showed decrease air

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 down

Talking Prefers sitting

At rest Hunched forward

Talks in

Sentences

Phrases

Words

Alertness

May be agitated

Agitated

Agitated

RR

Increase

Increase

>30

Accessory Muscles

Not

Usually

Usually

Paradoxical

Wheeze

Moderate at end of expiration

Loud

Loud

Absent

Pulse

<100

100-120

>120

Bradycardia

PEF

>80

60-80

<60

PO2 PCO2

Normal <45

>60 <45

<60 >45

O2 sat

>95

91-95

<90

Drowsy or confuse

Hospital management in acute asthma

ssess severity,ß2 agonist,O2, systemic steroid Repeat assessment improvement Continue treatment

Partial or no improvement

Life threatening asthma

admit

Response maintain

discharge

improvementworsening

ICU

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