Asthma - Patho Mod

two ways asthma control is approached

1. through control factors contributing to asthma severity 2. through pharamcological treatment

september

20-25% of asthma exacerbations in ontario occur in

genes that have a role in asthma

IL-4, IL-5, IL-13, esinophils, mast cells, adrenergic receptors, leukotrienes, bronchial hyper-responsiveness and ADAM 33

alveolar ventilation

Mucus also inhibits

red zone

PEF<50% of personal best -- medical alert, this person should take their short acting bronchodilator and increase if needed, they should seek medical attention and/or call 911.

yellow zone

Peak Flow Monitoring Score: PEF 50-80* of personal best -- caution should be taken, the pt should use SA bronchodilator and repeat PEF measurement.

green zone

Peak Flow Monitoring Score: PEF>80% of personal best

Inspection

Physical Assessment Findings: increased work of breathing, use of accessory muscles, prolonged expiration, wheezing, cough, inability to maintain a conversation

vital signs

Physical Assessment Findings: tachypnea, tachycardia, dec. o2 sat

aucultation

Physical Assessment Findings: wheezing, distant breath sounds, other adventitious breath sounds such as crackles

IL4

TH2 release

B cell activation, proliferation and production of antigen specific IgE.

What does the release of IL4 from TH2 cells cause?

Methacoline

a cholinergic agonist which means that it acts on the parasympathetic nervous system and causes bronchoconstriction.

asthma

a chronic reactive airway disorder characterized by increase resistance to airflow due to episodic airway obstructions involves inflammation of the airways, bronchospasm, increased mucus secretion and injury to the mucosal lining of the airways can be characterized by extrinsic or intrinsic based on the factors that trigger the disorder

asthma

a chronic, reactive aiway disorder characterized by increased resistance to airflow due to obstruction of the airway passages

mucus hyper secretion

a major pathophysiological feature of asthma Submucosal glands and goblet cells produce muscus in the airways. Both these sources are affected in patients with asthma resulting in goblet cell hyperplasia and submucosal glance hypertrophy. triggered by the inflammatory response leukotrienes stimulate Th2 release IL-9 & IL-13 -> upregulate mucus production in asthmatic patients Airway obstruction by mucus plugs d/t mucus hypersecretion + increased plasma exudation -> increased airway hyperresponsiveness

histamine

a potent vasodilator that causes increased vascular permeability though retraction of endothelial cells. also causes smooth muscle to contract causing bronchoconstriction when stimulated in the bronchi. This is particularly important in the pathogenesis of asthma.

mast cell degranulation

a trigger in the form of an allergen or irritant exposure causes...

extrinsic asthma (atopic/allergy asthma)

a type 1 hypersensitivity reaction resulting from exposure to allergen/antigen type 1 IgE mediated hypersensitivity reaction

the winter months

adults tend to experience more exacerbations in

cysteinyl leukotrienes

although we have discussed the role of leukotrienes it is important to note that__________ leukotrienes which are mostly produced by mast cells, eosinophils and basophils are the leukotrienes that play a major role in the pathophysiology of asthma. They were initially called "slow reacting substance of anaphylaxis" due to their effect on bronchial smooth muscle of slow and prolonged contraction and hence bronchoconstriction

monoclonal antibody subcut injections

anti-IgE antibody that prevents binging of IgE to basophils and mast cells.

leukocytes

are also known as white blood cells. Neutrophils, eosinophils and basophils are also known as granulocytes. Neutrophils are first on scene and the predominant phagocytes in the early inflammatory phase. IN the pathogenesis of allergic asthma eosinophils have an important role by controlling the release of specific mediators from mast cells. Like mast cells, basophils bind to IgE which is secreted by plasma cells and release histamine and mediators of inflammation such as 1L-4. Remember that lymphocytes are T and B cells. Macrophages arrive after neutrophils, which means that in the pathogenesis of asthma they arrive in the late phase response.

chemotactic chemokines

are cytokines that attract immune and inflammatory cells. They are primarily function to attract leukocytes

alveolar hypoventilation

as hyperinflation progresses ___________ ________ occurs as gas exchange is impeded by increasing intrapleural and alveolar gas pressures causing ventilation perfusion mismatch.

peak flow monitoring

assesses peak expiratory flow (PEF) by compaing to patient's personal best PEF is to measured around the same time each day

common manifestations of severe asthma

asthma goblet cell hyperplasia, smooth muscle hypertrophy, mucus plugging.

extrinsic asthma

atopic/allergy asthma

further bronchoconstriction and mucus secretion epithelial injury and airway remodelling

autonomic dysregulation results in local nerve ending stimulation which causes

relief medications

beta agonist and anticholinergic inhalation medications resulting in bronchodilation used when you are having an attack

quick relief medications

bronchodilators, anticholinergics, systemic corticosteroids.

impaired muccociliary function

caused because of toxic effects of cellular products, specifically from eosinophils such as major basic protein

Hyperventilation

causes a decrease in serum carbon dioxide resulting in respiratory alkalosis usually accompanied with hypoxemia

prostaglandin D2

causes vasodilation, increased vascular permeability and bronchoconstriction.

mast cells

cellular bags of granules found in large numbers in the skin and linings of the GI and respiratory tract. They are activated by several means including physical injury, chemical agents, immunological and infectious means. As discussed previously, they degranulate releasing histamine, chemotactic factors and cytokines which cause an immediate effect. The activated mast cell also begins synthesizing inflammatory mediators derived from plasma membrane lipids such as platelet activating factor, prostaglandin D2 and leukotrienes as well as cytokines and growth factors which results in the long-term response.

asthma

charcterized by paroxysomal or persistent symptoms, such as dyspnea, chest tightness, wheezing, sputum production and cough associated with variable airflow limitation and airway hyperresponsiveness to endogenous or exogenous stimuli. Inflammation and its resultants effects of airway structure are considered the main mechanisms leading to the development and persistence of asthma.

pharmacological treatment

corticosteroids, bronchodilators, mast cell stabilizers, beta agonists and anticholinergic drugs

late phase response

develops four to eight hours after exposure than asthmatic trigger inflammatory cells: basophils, eosinophils and neutrophils. involves inflammation, increased airway responsiveness and renewed bronchospasm these symptoms lead to further airflow limitation and continued, heightened airway responsiveness. this sequence prolongs the asthma attack and sets into motion a vicious cycle of exacerbation including additional edema, epithelial injury, and impaired mucociliary function.

respiratory alkalosis

early in the asthma process hyperventilation will cause

triggers of childhood asthma

family history of allergy and allergic disorders high exposure to airborne allergens exposure to tobacco smoke low birthweight and RDS

leukotrienes

functions are similar and complementary to that of histamine. are more potent and stimulate slower and more prolonged effects compared to histamine. Cysteinyl leukotrienes cause slow and sustained constriction of the bronchioles which is important in the pathogenesis of asthma.

ADAM 33

gene that has been highly associated with asthma and bronchial hyper responsiveness

bronchospasms

happen as a result of: Histamine (early phase) Leukotrienes (late phase) PAF Prostaglandins Autonomic nervous system dysregulation (PNS) Cholinergic mediators responsiveness Also the parasympathetic control of airway function appears to not function appropriately due to heightened responsiveness to cholinergic mediators. This is caused by an alteration of muscarinic receptor function by TNF-alpha and IL-1 leading to an increase in acetylcholine which causes bronchial smooth muscle contraction and further mucus secretion.

early phase response inflammatory mediators

histamine chemotactic chemokines leukotrienes prostaglandin D2 cytokines platelet activation factor

ventilation perfusion mismatch

hyperinflation progresses alveolar hypoventilation occurs as gas exchange is impeded by increasing by intrapleural and alveolar gas pressures causing

platelet activating factor

induces platelet aggregation, increases vascular permeability though endothelial cell retraction, activates neutrophils and is a potent eosinophil chemoaatractant. In the respiratory system, causes bronchospasm, eosinophil infiltration and nonspecific bronchial hyperreavtivity.

intrinsic, non-atopic asthma

initiated by diverse, non-immune mechanisms however many people have overlapping symptoms triggered by vagal reflex and irritant receptors triggered by viral infections, inhaled irritants, NSAIDs, sulphites and emotional stress.

extrinsic, atopic asthma

initiated by type 1 hypersensitivity response to an extrinsic antigen antigen binds with a mast cell and causes mast cell degranulation with release of histamine, leukotrienes, interleukins, and prostaglandins resulting in inflammation and bronchospasm the airway inflammation in turn produces airway edema, epithelial injury and impaired mucociliary function

leukotiene modifiers

interfere with leukotriene action

asthma

involves a hypersensitivity reaction to stimuli and the release of chemical mediators from pre-sensitized mast cells, leading to a vicious cycle of edema, epithelial injury, and impaired mucociliary function.

Hyperventilation

is triggered by lung receptors responding to increaing lung colume and alveolar hypoxia.

vasoactive mediators

leukotrienes, prostaglandin D2, platelet activating factor

beta 2 agonists

like sabultamol act on the beta 2 pulmonary receptors increasing levels of cyclic adenosine monophosphate (cAMP) and relaxing smooth muscle -- possible they may result in tachycardia

vasoactive mediators and chemotactic mediators

mast cell degranulation causes

immediately

mast cells release histamine

vasoactive mediators

mast cells synthesize what for later release?

anticholinergics

medications such as ipratopium that inhibit muscarinic cholinergic receptors reducing vagal tone of the airway which results in bronchodilation.

extrinsic and intrinsic

most asthma is a combination of

intrinsic asthma

non-atopic asthma

22-26

normal HCO3

35-45

normal pCO2

7.35-7.45

normal pH

80-100

normal pO2

intrinsic asthma (non-atopic asthma)

not as well understood -- there are different explanations for why a non-atopic trigger may cause bronchospasm and subsequently an accute asthma exacerbation. respiratory tract infections exercise hyperventilation cold air, weather changes drugs and chemicals irritants hormonal changes and emotional upsets airborne pollutants GERD

adult onset asthma

occupational exposures to low molecular weight sensitizers exposures to infections agents, allergens or pollution women-smoking, obesity, hormonal influences

late phase response

occurs 4-8 hours after triggering stimuli, may persist for days or even weeks release of inflammatory mediators causes recruitment of neutrophils, eosinophils, basophils, T lymphocytes (TH2*) These inflammatory cells cause epithelial injury and edema, increased mucus, changes in mucociliary function -> accumulation of mucus and increased airway responsiveness Epithelial damage and impaired mucociliary function is caused because of direct toxic effects of cellular products, specifically from eosinophils such as major basic protein. In turn, this injury causes local nerve endings to be stimulated through autonomic pathways which may cause further bronchoconstriction and mucus secretion. Macrophages are also activated in the respiratory tract during the late phase.

early phase, or acute response of asthma

occurs within ten to twenty minutes of exposure to a trigger 1. mast cells, in people with asthma are in a pre-sensitive state, react to antigens and release histamine, leukotienes, interleukins and prostaglandins 2. with airborne antigens, the antigen wings to the mast cells on the mucosal surface of the airway 3. the release of inflammatory mediators leads to infiltration of inflammatory cells and allows the antigens to reach the submucosal mast cells. 4. in addition, direct stimulation of parasympathetic receptors cause bronchospasm 5. increased vascular permeability causes mucosal edema and increased mucus secretions.

airway remodelling

one of the major contributors in the pathogenesis of asthma these appear in parallel with inflammation begins early on in the disease process of asthma and declining lung function which is attributed to airway remodelling is found in children as well as new asthmatics

respiratory acidosis + hypoxemia

originally you have respiratory alkalosis, hyperventilation and hypoxemia, you then progress to...

Bronchial provocation tests

patient is given histamine, methacholine or non-pharmacologic agent (i.e. cold air) to cause bronchoconstriction -- people with asthma will react to smaller gases of the drug and therefore you know they have asthma

T Lymphocytes (Th2)

play an important role in the pathogenesis of extrinsic asthma. TH2 lymphocytes act as growth factors for mast cells as well as recruiting and activating eosinophils by stimulating the differentiation of B cells into IgE-producing plasma cells. In asthmatic patients, T cell differentiation is skewed towards Th2 phenotype cells.

Submucosal glands and goblet cells

produce mucus in the airways - both these sources are affected in patients with asthma resulting in goblet cell hyperplasia and submucosal gland hypertrophy

cytokines

proteins that modulate the function of other cells. TNF-alpha, IL-4, 5, 8 & 13 are key mediators in the pathogenesis of asthma. TNF-alpha increases the activation and migration of inflammatory cells (specifically eosinophils and neutropils) and contributes to airway remodeling. TNF-alpha also causes endothelial cells to express adhesion molecules. TNF-alpha and IL-1 alter muscarinic receptor function resulting in increased levels of acetylcholine which causes bronchial contraction and mucus secretion. IL-4, 5, 8 and 13 are T-helper 2 cytokines. IL-4 stimulates activation, proliferation and production of antigen-specific, IgE by B cells. IL-5 activates and promotes eosinophil activity. IL-8 causes more exaggerated inflammatory response through activation of basophils, neutrophils and eosinophils. IL-13 impairs the clearance of mucus, contributes to bronchoconstriction and increases fibroblast secretion.

TH2 cells

release Il4 which stimulates B cell activation, proliferation and production of antigen specific IgE. IgE also causes mast cell degranulation.

hypercapnia or retention of CO2

respiratory acidosis will be accompanied by

hypozemia or a low pO2

respiratory alkalosis may be accompanied by

wheezing

result of the passing of airway through narrowed airways. Initially wheezing will be expiratory as the obstruction is the lower airways

Cough

results as the asthmatic patient tries to clear his or her airway of mucus. In the absence of a respiratory infection, the cough will initially be non-productive during an asthma attack.

Chest tightness

results from air trapping and resultant hyperinflation of the lungs

autonomic dystregulation

results from: alteration to muscarinic receptor function by TNF-alpha and ILI

systemic coricosteroids

sometimes used in extreem asthma exacerbations -- they block the COX and lipoxygenase pathways in the inflammatory process -- the mechanism of action is to decrease inflammation by suppression of polymorphonuclear leukocytes and fibroblasts as well as reducing capillary permeability

mast cell stabilizers

stabilize the membrane of a sensitized mast cell after an antigen IgE interaction preventing the release of inflammatory mediators such as histamine.

respiratory system

the airway passages, the lungs and the associated blood vessels

family history of allergy and allergic disorders

the genetic bassi of asthma is complicated and multifactorial as there have been several genetic loci on a variety of different chromosomes implicated in the pathogenesis of asthma 100+ genes identified as playing a role in asthma -- IL-4, IL-5, IL-13, esinophils, mast cells, adrenergic receptors, leukotrienes, and bronchial hyper-responsiveness ADAM 33 has been highly associated with asthma and bronchial hyper responsiveness

ventilation

the movement of air from the atmosphere into and out of the lungs

perfusion

the movement of blood through the lungs

diffusion

the movement of gases between the roughly one million alveoli or air filled sacs within the lungs and the capillaries that supply the alveoli gases move across the alveolar-capillary membrane oxygen moves from the air that is the alveoli to the blood flowing through the pulmonary capillaries carbon dioxide passes from the blood into the alveoli

upper airways

the nose, nasal passages, mouth, pharynx and larynx.

inspirtation

the process of taking air in

the late phase response

the release of other inflammatory mediators, recruitment of neutrophils, eosinophils, and basophils; increased vascular permeability, epithelial cell injury with decreased mucociliary function and increased airway responsiveness and bronchospasm

Dyspnea/SOB

the result of an inability to adequately ventilate and an abnormal ventilation- perfusion relationship where parts of the lungs are not adequately ventilated.

spirometry

the single most objective measurement of lung function available

lower airways

the trachea, the bronchi, and the bronchioles of the lungs

chest x-ray

this will display: hyperinflation +/- flattening of the hemidiaphragms are common radiological findings note any signs of infection

long term contol of asthma goals

to address inflammation and airway obstruction and quick relief medications that reverse acute airflow obstruction

purpose of the respiratory system

to provide oxygen and carbon dioxide exchange between air and blood.

immune activation and TH2 cell activation

trigger/allergen also causes (along with mast cell degranulation)

immediate or early phase response

triggered by activation of presensitized IgE-coated mast cells mast cell degranulation results in the release of inflammatory mediators that increase mucus production, open mucosal intercellular junctions with exposure of submucosal mast cells to the antigen and cause bronchospasm

vagal reflex and irritant receptors

triggers of intrinsic, non-atopic asthma

bronchoconstriction and mucuse secretion epithelial damage

what do TNF-alpha and ILI cause?

vasodilation, increased capillary permeability, bronchoconstriction

what do vascoactive mediators cause?

spirometry

what type of pulmonary function test may be used in the initial diagnosis, to monitor response to therapy, and to asses the airway function and to validate peak flow monitring? of asthma?

respiratory acidosis

with persistent worsening of ventilation and ventilation perfusion mismatch the patient will progress to

early phase response

within 10-20mins of triggering stimuli and can last up to 2 hours allergen binds to preformed IgE on sensitized mast cells on mucosal surface of airways mast cell activation releasing inflammatory mediators increase mucus secretion, increased vascular permeability and bronchoconstriction dendritic cells may recieve antigen at this time that will be processed and preseneted later in the late phase response to naive T lymphocytes in the lymph nodes or memory Th2 cells in the airway mucosa. This will result in further immune activation

long acting beta 2 agonists (LABA)

work the same as SABAs but last longer