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Flashcards in L12 Asthma Deck (43):

Asthma is a very old disease.

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.


Some traditional treatments for Asthma

Roman: blood from chicken or owls and mix with red wine
-worked for some patients


What is asthma?

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


Facts about asthma

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


Prevalance of asthma differing b/w countries

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


Cost burden for Asthma

Annual Direct cost: $125.2mil per year
Annual Indirect cost: $699mil


Age distribution for Asthma

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


Overall change in asthma rates

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


Effectivity of treatment for asthma

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


Features of Asthma

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.


Symptoms of asthma

Chest tightness
Sputum production
Airflow obstruction
Become worse during night time


Diagnosis of Asthma

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


Patient's Asthma history

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


Activities that may worsen asthma symptoms

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


Atypical Presentation of Asthma

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


Laboratory studies re Asthma

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


Lung function tests

1. Peak expiratory flow (PEF) (peak flow metre)
-help to montiro progress of treatment
-easy to perform
-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


Lung Function Test Spirometry

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


Atopic Asthma Blood Test

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


Asthma Allergy Tests

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


Current pathogenesis of asthma

Two major models: allergy and non‐ allergy pathways models.
Up to 90% of early‐ onset asthma could be allergic.


Atopic Asthma 5 main links

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.


Principle cells identified in airway inflammation re Asthma

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


Other cells in asthma

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


Response to an allergen challenge

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.



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


What causes chronic asthma symptoms?

chronic asthma is related to late phase or dual phase responses


Mechanism of Asthma

draw at diagram


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

-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.)



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



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


Antigen Presenting cels

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


TH2 cells pathway

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.


Nonatopic asthma

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)


Key mediators in asthma

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


Key mediators in asthma: Leukotrienes

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.


Key mediators in asthma: Prostanoids

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


Key mediators in asthma: ACh

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


Key mediators in asthma: Chemokines

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.


Key mediators in asthma: IgE

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.
Therapy: Humanized monoclonal antibody targeting IgE is developed for asthma therapy (Xolair).


Key mediators in asthma: Nitric Oxide

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.


Key mediators in asthma: Granule Protein

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


Key mediators in asthma: Adhesion molecules inflammation

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