L12 Asthma

Question 1

Asthma is a very old disease.

Answer 1

From the Greek word Άσθμα a’sthma meaning gasp
It was first reported about
3500 years ago.
In traditional Chinese medicine, the botanical ma huang has been used for more than 3000 years for the short‐ term treatment of respiratory symptoms.

Question 2

Some traditional treatments for Asthma

Answer 2

Roman: blood from chicken or owls and mix with red wine

-worked for some patients

Question 3

What is asthma?

Answer 3

Asthma is a chronic inflammatory disease of the airways, characterized by airflow obstruction, and bronchospasm.
Symptoms:
wheezing, cough, sputum production, chest tightness, and shortness of breath associated with airway hyperresponsiveness.
Variable episodic airflow obstruction: reversible either spontaneously or with treatment.

Question 4

Facts about asthma

Answer 4

Asthma is one of the most common chronic diseases in the world. (300mil globally effected)
In NZ: 1/6 of adults and 1⁄4 of children have asthma symptoms. More than 600,000 Kiwis
Over 500,000 New Zealanders take asthma medication
$800Million annual economic burden of asthma (direct and indirect cost)
The most common cause of admission to hospital for children
Hospitalization rates: doubled in the past 30 years.
YLD: The highest‐ranking disease in terms of Years Lost to Disability in males, 3rd for females

Question 5

Prevalance of asthma differing b/w countries

Answer 5

NZ is has one of the top prevalance rates in the world (30%)
Countries with higher prevalance rates (UK, AUS, ireland, Canada) are all developed countries
-Indonesia, Romania, Georgia are developed countries

Question 6

Cost burden for Asthma

Answer 6

Annual Direct cost: $125.2mil per year

Annual Indirect cost: $699mil

Question 7

Age distribution for Asthma

Answer 7

under 17yrs: male have higher rates
older than 18yrs: females have higher
1998–>2008: trend increasing rates of asthma

Question 8

Overall change in asthma rates

Answer 8

Percentage distribution of current asthma by sex, age, ethnic origin and Geographic region, 2009
Current Asthma: 24,566,689
Sex: Female 58%. Male 42%
Age:

Question 9

Effectivity of treatment for asthma

Answer 9

Asthma can be effectively treated and most patients can achieve good control of their disease

Question 10

Features of Asthma

Answer 10

Episodic (normally) -dont have symtpoms between different episodes. sometimes seasonally acute.
Chronic- persisitent (pot daily) airflow obstruction
Life-threatening- if not treated possible. keep bronchodilator handy.

Question 11

Symptoms of asthma

Answer 11

Wheezing
Dyspnea
Chest tightness
Coughing
Sputum production
Airflow obstruction
Become worse during night time

Question 12

Diagnosis of Asthma

Answer 12

1. Physical Examination: Wheezing—high‐ pitched whistling sounds, (But, wheezing is not specific for asthma) (episodic may not see symptoms of wheezing b/w attacks) (loudness of wheezing doesnt reflect severity of obstruction)
2. Patient History (specific..)
3. Lung function test (gold standard): evidence of variable airflow obstruction.
4. Symptoms occur or worsen due to certain acitivities (specific…)
5. Other things
   Family history of asthma
   History of atopic disease: allergic rhinitis, urticaria or eczema

Question 13

Patient’s Asthma history

Answer 13

2. History of any of the following:
• Cough, Recurrent wheeze
• Recurrent dyspnea,
• Recurrent chest tightness
• Reversible airflow limitation and diurnal variation
-very important

Question 14

Activities that may worsen asthma symptoms

Answer 14

Exercise
Viral infection
Animals with fur or feathers House‐dust mites
-common allergin for NZ asthma
Moulds,
Smoke ,
Pollen Changes in weather,
-pine tree pollen triggering asthma symptoms
Strong emotional expression (laughing or crying hard, breathing heavily),
Airborne chemicals or dusts

Question 15

Atypical Presentation of Asthma

Answer 15

Dyspnea without wheezing (wheezing doesnt occur in all asthma patients)
Chronic cough
Increased shortness of breath at nighttime
Allergic rhinitis with wheezing

Question 16

Laboratory studies re Asthma

Answer 16

Lung function tests.
Skin allergy test and serologic studies
Radiographic Studies

Question 17

Lung function tests

Answer 17

1. Peak expiratory flow (PEF) (peak flow metre)
   - help to montiro progress of treatment
   - easy to perform
   - cheap
   - difficult to use as a ghost indicator for diagnosis as variation is too large and different from patient-patient
2. Spirometry: FEV1 is a better measure for asthma.
   - diagnoser for asthma
   - FEV1 used to distinguish b/w COPD and asthma
   - not very suitable to patients younger than 6yrs

Question 18

Lung Function Test Spirometry

Answer 18

Asthma:
Very decreased FEV1
Decreased FVC
Decreased FEV1/FVC
Post-bronchodilator Reversibility Testing:
-used to distinguish b.w asthma and COPD.
-see if their lung function can be restored
-FEV1 Increase(after bronchodilator) > 400ml - asthma

Question 19

Atopic Asthma Blood Test

Answer 19

1. Eosinophil count:
   >4 % or 300 ‐ 400/mm3
   > 800 /mm3, suggest the presence of other disorders.
2. Increased Serum IgE level

Question 20

Asthma Allergy Tests

Answer 20

Tree, grass, weed and flower pollens
Dust mites
Mold and mold spores 
Animal Dander 
Insect allergens 
Smoking

Question 21

Current pathogenesis of asthma

Answer 21

Two major models: allergy and non‐ allergy pathways models.

Up to 90% of early‐ onset asthma could be allergic.

Question 22

Atopic Asthma 5 main links

Answer 22

1. The most common type of asthma.
2. Usually begins in childhood, early-onset.
3. Trigged by environmental antigens
4. A positive family history
5. Often preceded by allergic rhinitis, urticaria or eczema.

Question 23

Principle cells identified in airway inflammation re Asthma

Answer 23

arise in the progress of asthma
different cells have different roles in the progress of asthma
Eosinophils: late phase response to allergin. cause chronic asthma.
Mast cells: exercise induced asthma + acute phase responses to allergin
Macrophages: activated + releases pro-inflammatory mediators (over-response of inflammatory responses)
T cells: central role in control of inflammatory responses (esp. late phase responses)
Neutrophils: related to corticosteroid resistance
Basophils: late phase responses to allergin exposure
Dendritic cells: present the allergin to the inflammatory cells

Question 24

Other cells in asthma

Answer 24

1. Airway smooth muscle cells-thicker
2. Epithelial cells- damaged layer
3. Goblet cells
4. Increased/dense number of inflammatory cells

Question 25

Response to an allergen challenge

Answer 25

1. The Acute-Phase Response: In the acute-phase response (APR), inhalation of allergen causes an immediate fall in lung function (as short as 5-10 min). (duffer from shortness of breath in a few mins, and sometimes functions will recover itself w/o interference) 2. Late-phase response (LPR): beginning about 4 to 6 hours after allergen challenge. function is lower and consistent. could cause chronic airway obstruction. 3. Dual-phase: - contains both acute and late phase - worse than acute (50% lung function) and late response (40% lung function). 30% and is persistent/chronic.

Question 26

Graphs

Answer 26

Isolated Immediate: within 1 hr Lung function 100-->50%. after 2 hours lung function recovers to almost 100% Isolated Late: after 4 hours lung function as started to drop 100% --> 40%. 18-20 hrs until near 100% lung function returned Dual Response: within 1 hour lung function has decreased 100-->30%. can recover, but if exposed to allergen again it will drop even further. Recovery can take up to 24hours

Question 27

What causes chronic asthma symptoms?

Answer 27

chronic asthma is related to late phase or dual phase responses

Question 28

Mechanism of Asthma

Answer 28

draw at diagram

Question 29

Why do some people develop asthma from exposure to agents and other's dont?

Answer 29

- we are all exposed to the same antigens - if we knew the answer we wouldnt need research, - -> Asthma genetic (SNPS, polymorphisms, the variations. nothing is dominant/certain) 1. The major etiology factors of allergic asthma are genetic predisposition to Th2 rather than Th1. (2x airway responses to allergin exposure) 2. Th Cells: Helper T cells, T lymphocytes that belong to the CD4+ subset. 3. Th1 cells: produce IFN-γ , IL-2 and TNF-beta 4. Th2 cells: secrete cytokines (eg. IL-4, IL-5, IL-9, IL13, etc.)

Question 30

TH1

Answer 30

Main partner: Macrophage Cytokines produced: IFN-y, IL-2 and tumour necrosis factor-beta Immune stimulation promoted: -cellular immune system. Maximises the killing efficacy of the macrophages and the proliferation of cytotoxic CD8+ T cells. also produces opsonizing antibodies Other functions: the Type 1 cytokine IFN-y increases the production of IL-12 by dendritic cells and macrophages, and via positive feedback, IL-12 stimulates the production of IFN-y in helper T cells, thereby promoting the Th1 profile. IFN-gamma also inhibits the production of cytokines such as IL-4, an important cytokine associated with the Type 2 response, and thus it also acts to preserve its own response

Question 31

TH2

Answer 31

Main partner: B cell Cytokines produced: IL-4, 5, 6, 10, 13 Immune stimulation promoted: Humoral immune system. Stimulates B-cells into proliferation, to induce B-cell antibody class switching, and to increase neutralizing antibody production Other functions: The Type 2 response promotes its own profile using two different cytokines. IL-4 acts on helper T cells to promote the production of Th2 cytokines (including itself; its autoregulatory), while IL-10 inhibits a variety of cytokines including IL-2 and IFN-y in helper T cells and IL-12 in dendritic cells and macrophages

Question 32

Antigen Presenting cels

Answer 32

The TH1 pathway will naturally inhibit the TH2 pathway (and vice versa) - pathway taken is determined by the genes - diagram - cell mediated by antibody mediated immunity

Question 33

TH2 cells pathway

Answer 33

1. Causes type 1 hypersensitivity/atopy: such as eczema (atopic dermatitis), hay fever (allergic rhinitis), asthma. - 90% of early onset asthma is atopic asthma 2. Chronic airway inflammation 3. Bronchial hyper-responsiveness.

Question 34

Nonatopic asthma

Answer 34

1. The majority of late‐onset asthma are nonatopic. (develop symptoms as adults) 2. It may be associated with respiratory tract infections, such as (infection) Mycoplasma pneumoniae and Chlamydia pneumoniae. 3. Other risk factors: medications induced asthma (eg. NSAIDs, beta blockers and aspirin). (drug induced asthma)

Question 35

Key mediators in asthma

Answer 35

1. Leukotrienes 2. Prostanoids 3. ACh 4. Chemokines 5. IgE 6. Nitric Oxide 7. Granule Protein 8. Adhesion molecules inflammation - call can be potential targets for treatments

Question 36

Key mediators in asthma: Leukotrienes

Answer 36

1. De novo synthesis of Mast cells (5-10min), Eosinophils. 2. Very potent mediator (eg., LTC4, LTB4) cause prolonged bronchioconstriction 3. Increase mucus secretion and vascular permeability which generates edema in the airway. 4. Leukotriene receptor Antagonists (e.g., Singulair) is currently recommended as a Second‐ line in the treatment of asthma.

Question 37

Key mediators in asthma: Prostanoids

Answer 37

> Potent bronchoconstrictors (PGD2, PGF2, and TxA2) prolonged bronchoconstriction. > Produced by eosinophils and mast cells. -directly cause smooth muscle contraction

Question 38

Key mediators in asthma: ACh

Answer 38

1. Released from intrapulmonary motor nerves 2. Causing smooth muscle constriction in 3. Stimulating muscarinic receptors.

Question 39

Key mediators in asthma: Chemokines

Answer 39

The function of chemokines is to recruit or chemotaxis of inflammatory cells. Chemokine receptor inhibitors for CCR3 and CCR4 and others are in development as potential therapy for asthma.

Question 40

Key mediators in asthma: IgE

Answer 40

Role of IgE in the late phase response:TH2 cells release IL13 that stimulates the B cells which produces IgE. IgE binds with mast cell receptor and acitvate mast cells which release histamine, PGD2 or leukatines and cause bronchial constirction **--if you can block the function of IgE you can prevent/treat the asthma attack Triggering mast cell Causing airway inflammation. airways Therapy: Humanized monoclonal antibody targeting IgE is developed for asthma therapy (Xolair).

Question 41

Key mediators in asthma: Nitric Oxide

Answer 41

Higher levels of NO in asthma. The production of NO reflects the level or severity of airway inflammation. Exhaled NO measurement has been used to monitor the extent of airway inflammation for asthma control.

Question 42

Key mediators in asthma: Granule Protein

Answer 42

1. Mast cells, basophils, eosinophils, and neutrophils can release granule proteins. 2. Major basic protein (MBP) 3. Eosinophil cationic protein (ECP) - MBP and ECP can darkly damage/attack eosinophil cells/ayers

Question 43

Key mediators in asthma: Adhesion molecules inflammation

Answer 43

>Integrins are the primary mediators of cell- extracellular matrix adhesion. > Integrins are important for transendothelial migration of inflammatory cells into the airways.