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Flashcards in 24 Asthma Deck (29)
1

Asthma

  • Disorder of...
  • Accompanied by...
  • The different clinical expressions of asthma involve...
  • Heterogeneity of asthma also relates to...
  • Asthma is considered a good example of...

  • Disorder of the conducting airways, which contract too much and too easily spontaneously and in response to a wide range of exogenous and endogenous stimuli
  • This airway hyperresponsiveness is accompanied by enhanced sensory irritability of the airways and increased mucus secretion
  • The different clinical expressions of asthma involve...
    • Varying environmental factors that interact with the airways to cause acute and chronic inflammation
    • The varying contributions of smooth muscle contraction, edema and remodeling of the formed elements of the airways
  • Heterogeneity of asthma also relates to the different response to therapies
  • Asthma is considered a good example of gene–environment interactions, although no single gene or environmental factor accounts for the disease

2

Epidemiology of asthma

  • Asthma and related allergic diseases have increased markedly in...
    • This has been attributed to...
  • The urban-rural gradient in prevalence has been demonstrated most strongly in...
  • This protective effect against the onset of asthma in children is even more apparent if...

  • Asthma and related allergic diseases have increased markedly in...
    • Western countries over the past 50 years
    • This has been attributed to urbanization and associated changes to diet and lifestyle
  • The urban-rural gradient in prevalence has been demonstrated most strongly in children...
    • Who grow up in environments with a wide range of microbial exposures
      • Such as traditional livestock farms or in families who have adopted a more 'naturalistic' diet and lifestyle
    • Who are protected from childhood asthma and atopy (the predisposition to develop IgE against common environmental allergens) in proportion to their level of exposure to bacterial and fungal microbes
  • This protective effect against the onset of asthma in children is even more apparent if...
    • The microbial exposure (for example, working with animals or drinking unpasteurized milk) occurred throughout the mother's pregnancy

3

Pathophysiology of asthma

  • Most asthma begins...
  • In most cases, this occurs through...
  • TH2-type cytokines
  • A similar inflammatory response is triggered in response to...

  • Most asthma begins in childhood in association with sensitization of the airways to common aeroallergens
    • Especially those derived from house dust mites, cockroaches, animal dander, fungi and pollens
  • In most cases, this occurs through the selective expansion of T lymphocytes (particularly of the TH2 type) that secrete a cluster of cytokines, including...
    • Interleukins IL-3, IL-4, IL-5, IL-9, IL-13
    • Granulocyte macrophage colony–stimulating factor (GM-CSF)
  • TH2-type cytokines orchestrate the allergic inflammatory cascade that occurs in asthma, including...
    • TH2 cell survival (regulated by IL- 4)
    • B cell isotype switching to IgE synthesis (IL-4 and IL-13)
    • Mast-cell differentiation and maturation (IL-3, IL-9 and IL-13)
    • Eosinophil maturation and survival (IL-3, IL-5 and GM-CSF) 
    • Basophil recruitment (IL-3 and GM-CSF)
  • A similar inflammatory response is triggered in response to...
    • Parasitic infection, suggesting that, in some way, allergy is a manifestation of 'frustrated' parasite elimination

4

Pathophysiology of asthma

  • The asthmatic epithelium is intrinsically defective in its...
  • Related to this defect, a proportion of the asthma-related allergens have intrinsic biological properties that...
  • Components of house dust mite, cockroach, animal and fungal allergens...
  • Beyond proteolytic allergens, additional environmental stimuli...

  • The asthmatic epithelium is intrinsically defective in its...
    • Physical barrier function within complete formation of tight junctions, thereby facilitating penetration of inhaled allergens into the airway tissue
  • Related to this defect, a proportion of the asthma-related allergens have intrinsic biological properties that...
    • Increase their capacity to penetrate the epithelial barrier and trigger a danger signal to DCs
  • Components of house dust mite, cockroach, animal and fungal allergens...
    • Are proteolytic
    • Can disrupt epithelial tight junctions and activate protease-activated receptors
  • Beyond proteolytic allergens, additional environmental stimuli...
    • Such as respiratory viruses and air pollutants (for example, ozone, particulates and environmental tobacco smoke)
    • Also disrupt tight junctions to impair barrier function

5

Pathophysiology of asthma

  • Main cause of asthma exacerbation
  • The greatest risk factor for developing asthma at 6 years of age n those genetically at risk of asthma
  • What enables rhinovirus and other viruses to replicate
  • Such events provide...

  • Main cause of asthma exacerbation
    • Infection with rhinoviruses
  • The greatest risk factor for developing asthma at 6 years of age n those genetically at risk of asthma
    • Rhinovirus-induced wheezing in the first three years of life
  • What enables rhinovirus and other viruses to replicate
    • Reduced primary IFN-gamma production by lower-airway epithelial cells
    • Leads to cytotoxic cell death (rather than apoptosis), release of inflammatory products, and enhanced viral shedding
  • Such events provide...
    • A strong stimulus for recruitment of immature DCs and their priming for allergen sensitization

6

Pathophysiology of asthma

  • Once established, airway inflammation in asthma is a multicellular process involving mainly...
  • The inflammatory process is largely restricted to...
  • As the disease becomes more severe and chronic, the inflammatory infiltrate...
  • The inflammatory response in the small airways appears to be predominantly...
  • This Th2 type of inflammation 

  • Once established, airway inflammation in asthma is a multicellular process involving mainly...
    • Eosinophils
    • Neutrophils
    • CD4+ T-lymphocytes
    • Mast cells
    • Eosinophilic infiltration (the most striking feature)
  • The inflammatory process is largely restricted to...
    • The conducting airways
  • As the disease becomes more severe and chronic, the inflammatory infiltrate...
    • Spreads both proximately and distally to include the small airways and in some cases adjacent alveoli
  • The inflammatory response in the small airways appears to be predominantly...
    • Outside the airway smooth muscle whereas in the large airways inflammation of the submucosa dominates
  • This Th2 type of inflammation
    • Common to chronic allergic inflammatory responses at multiple tissue sites
    • Seen at these sites in patients with asthma who frequently express comorbidities such as chronic rhinitis, sinusitis, atopic dermatitis, and food allergy

7

Pathophysiology of asthma:
Role of mast cells

  • The allergic response in asthma is characterized by...
  • Allergens...
  • Mast cells
  • Mast cell activation

  • The allergic response in asthma is characterized by...
    • An immediate or early allergic response (EAR) and a late allergic response (LAR)
    • EAR develops within 10 minutes of allergen exposure, reaching a maximum at 30 minutes, and resolving within 1-3 hours
  • Allergens...
    • Initiate EAR through IgE-dependent mechanisms and the cell that initiates EAR is mast cell
  • Mast cells
    • Present as resident cells in all tissues capable of mounting allergic responses
    • Bind IgE with high affinity to FcERI on their cell surface membranes
  • Mast cell activation
    • Occurs when allergen cross-links IgE-FcepsilonRI complexes on mast cells
    • Leads to degranulation of the mast cell and the release of preformed mediators including histamine, proteases and proteoglycans
    • Stimulates the mast cell to synthesize and generate newly generated mediators including...
      • Leukotrienes (LTC4, LTD4, and LTE4)
      • Prostanoids (PGD2, PGF2alpha, and TXA2)

8

Pathophysiology of asthma:
Role of mast cells

  • What has the ability to contract human bronchial smooth muscle
  • Mast cell also releases...
  • This latter stage of inflammation
  • The influx of eosinophils and T lymphocytes results in...

  • What has the ability to contract human bronchial smooth muscle
    • Histamine, PGD2 and leukotrienes
  • Mast cell also releases...
    • Cytokines, growth factors and other mediators that attract T cells and inflammatory cells, especially eosinophils, into the airway tissue
  • This latter stage of inflammation
    • Represents LAR
    • Occurs several hours after EAR
  • The influx of eosinophils and T lymphocytes results in...
    • The further release of mediators
    • Subsequent epithelial damage
    • The development of airway narrowing
    • Associated bronchial hyperresponsiveness

9

Pathophysiology of asthma

  • Combinations of cytokines and contact signals cause...
  • These different leukocyte subsets generate...

  • Combinations of cytokines and contact signals cause...
    • DCs and the thymic epithelium to conspire to drive the differentiation of an array of different leukocyte subsets that augment or protect the airways from inflammatory responses linked to asthma
  • These different leukocyte subsets generate...
    • Cytokines that influence different cell types
    • The attendant inflammatory response, driving allergic airway inflammation and airway hyperreactivity

10

Symptoms of asthma

  • The most common cause of asthmatic inflammation 
  • The relationship of allergens to the symptoms of asthma 
  • Intrinsic asthma
  • Asthma can also be linked to the workplace
  • Viral infections 

  • The most common cause of asthmatic inflammation
    • Inhalation of allergens
  • The relationship of allergens to the symptoms of asthma
    • May be obvious to the patient (immediate symptoms upon exposure to the cat)
    • Many patients who are allergic to dust mites are not aware of the association between exposure and their symptoms
  • Intrinsic asthma
    • Patients who do not have allergies that suffer from asthma
  • Asthma can also be linked to the workplace
    • Occupational exposure to sensitizing chemicals (e.g. isocyanates) is an important cause of asthma as the timely removal from exposure can cure the disease or at least prevent progression
  • Viral infections
    • One of the most common causes of asthma exacerbations

11

Symptoms of asthma

  • Symptoms of asthma occur due to...
  • Bronchocostriction results from a combination of...
  • Additionally, many patients with asthma develop symptoms to nonspecific stimuli such as...
  • Bronchial hyperresponsiveness
  • The cardinal symptoms of asthma 

  • Symptoms of asthma occur due to...
    • The narrowing of the airways or bronchconstriction
  • Bronchocostriction results from a combination of...
    • Bronchial smooth muscle contraction
    • Increased vascular permeability leading to edema
    • Increased airway mucus production
  • Additionally, many patients with asthma develop symptoms to nonspecific stimuli such as...
    • Exercise, cold air, or passive smoking
  • Bronchial hyperresponsiveness
    • The fact that the lungs of the patients with asthma can react to these kinds of stimuli
  • The cardinal symptoms of asthma
    • Wheezing, coughing, chest tightness, and shortness of breath

12

Symptoms of asthma

  • In all patients, the symptoms...
  • In the majority of patients, the symptoms...
  • Thus, most patients have...
  • Attacks may occur...
  • Careful questioning about factors that influence symptoms should distinguish between...
  • Questions about seasonal variations in symptoms are important; however, some patients...

  • In all patients, the symptoms...
    • Fluctuate in intensity
  • In the majority of patients, the symptoms...
    • Are intermittent
  • Thus, most patients have...
    • Normal or near-normal lung function and no symptoms between episodes
  • Attacks may occur...
    • Spontaneously (often at night or first thing in the morning)
    • After exercise
    • Shortly after exposure to a known trigger factor
  • Careful questioning about factors that influence symptoms should distinguish between...
    • Nonspecific triggers
    • Specific reactions that suggest that the patient is allergic
  • Questions about seasonal variations in symptoms are important; however, some patients...
    • Who are allergic to common indoor allergens do not describe seasonal variation
    • Whose attacks are triggered by viral infection report seasonal exacerbations in the autumn

13

Symptoms of asthma

  • The presence or absence of seasonality...
  • The attacks of asthma vary
  • Evidence of severity is based on...
    • The occurrence and the frequency of...
    • Treatment requirements, especially the use of...
    • Other

  • The presence or absence of seasonality...
    • Is not a basis for distinguishing between allergic and nonallergic causes
  • The attacks of asthma vary
    • Transient wheezing that recovers rapidly either spontaneously or after treatment with a bronchodilator
    • Episodes that develop over minutes, hours, or days into severe symptoms that are not responsive to any inhaled medicines
  • Evidence of severity is based on...
    • The occurrence and the frequency of...
      • Acute episodes
      • Emergency room visits
      • Hospitalizations
    • Treatment requirements, especially the use of...
      • Bronchodilators
      • Inhaled or oral steroids
    • Obstruction of lung function measured by spirometry

14

Diagnosis of asthma

  • Diagnosis of asthma is based on...
  • Further evaluation of patients with asthma involves establishing whether they are allergic with...
  • Evaluation of persistent or severe cases that are not responsive to treatment may also require...

  • Diagnosis of asthma is based on...
    • History
    • Spirometry before and after treatment with bronchodilators
    • Provocation tests to establish bronchial hyperresponsiveness
  • Further evaluation of patients with asthma involves establishing whether they are allergic with...
    • Routine blood count focusing on eosinophilia
    • Measurements of total serum IgE or specific IgE antibodies
    • Skin tests for immediate hypersensitivity
  • Evaluation of persistent or severe cases that are not responsive to treatment may also require...
    • Chest X ray
    • Sinus CT
    • Evaluation of the upper airway

15

Diagnosis of asthma

  • Clinical examination of the chest may identify...but...
  • Peak flow meter
    • General
    • Measures...
    • May establish...
    • The results...
  • Spirometry
    • Provides...
    • Most commonly expressed as...

  • Clinical examination of the chest may identify...but...
    • WheezingProlonged expiration
    • Poor air entry
    • But it is an unreliable method of estimating the extent of airway obstruction
  • Peak flow meter
    • The simplest technique for monitoring obstruction
    • Measures the maximum rate of expiratory flow in liters per minute
    • A chart showing repeated measurements over 2 weeks may establish...
      • Diurnal variation
      • Major changes from day to day
      • Consistently normal values
    • However, the results...
      • Are dependent on effort
      • Require consistent recording by the patient
      • Do not provide information about the pattern of flow
  • Spirometry
    • Provides a record of the forced expiratory volume (FEV) over time
    • Most commonly expressed as...
      • FVC- the forced vital capacity which is the forced volume over 6 seconds
      • FEV1- forced volume for the first second
      • FEV 25-75- the midflow forced expiratory flow

16

Diagnosis of asthma

  • Spirometry 
  • FEV1 and FVC in asthma and other obstructive diseases (COPD for example) 
  • In patients with severe disease, spirometry may demonstrate...
  • In patients with asthma that have normal lung function, hyperreactivity can be demonstrated by...

  • Spirometry
    • Can provide visual comparison of flow volume curves before and after treatment
    • Can yield clear evidence of obstruction
  • FEV1 and FVC in asthma and other obstructive diseases (COPD for example)
    • FEV1 is usually disproportionately decreased relative to FVC
    • FEV1/FVC ratio is decreased
  • In patients with severe disease, spirometry may demonstrate...
    • Minimal reversibility following bronchodilator therapy (i.e. <12 % increase in FEV1)
    • Reversibility (i.e. >12% increase) but still show marked obstruction
  • In patients with asthma that have normal lung function, hyperreactivity can be demonstrated by...
    • Several different provocation tests
    • Methacholine challenge test is widely used for routine clinical testing

17

Diagnosis of asthma

  • Methacholine
  • If methacholine challenge test is negative...
  • Vocal cord dysfunction
  • Biomarkers in asthma

  • Methacholine
    • Analogue of the cholinergic mediator for smooth muscle contraction in the lung
  • If methacholine challenge test is negative...
    • The patient does not have asthma
  • Vocal cord dysfunction
    • Common asthma mimicker
    • Should be suspected in all patients with atypical asthma symptoms
  • Biomarkers in asthma
    • Such as sputum eosinophils, periostin and exhaled nitric oxide
    • Might have an important role in predicting response to treatment and identifying asthma phenotypes

18

Treatment of asthma

  • Management of asthma is based on...
  • Periodic monitoring and assessment of patients with asthma 

  • Management of asthma is based on...
    • Frequency of attacks
    • Severity of attacks
    • Previous response to treatment
  • Periodic monitoring and assessment of patients with asthma
    • History, physical exam and measurement of lung function 
    • Crucial in optimal asthma care

19

Treatment of asthma:
The primary classification of drugs used in asthma

  • Short-acting bronchodilators
  • Anti-inflammatory drugs
  • Long acting bronchodilators (long-acting beta-2 agonist) 
  • Monoclonal antibodies 

  • Short-acting bronchodilators
    • Can relieve symptoms rapidly (relievers or rescue inhalers)
  • Anti-inflammatory drugs
    • Decrease the underlying inflammation in the lungs
    • Can control symptoms over a longer period of time (controllers)
    • The most important medications in this class include inhaled corticosteroids and leukotriene modifiers
  • Long acting bronchodilators (long-acting beta-2 agonist)
    • Relax airway smooth muscle
    • Provide long term bronchodilation
    • Beneficial to patients when added to inhaled corticosteroids for better control of symptoms
    • Long acting inhaled anticholinergic agents may also be beneficial.
  • Monoclonal antibodies
    • Omalizumab is currently the only FDA approved monoclonal antibody that binds free serum IgE that leads to decreased activation of mast cells
    • Additional benefit of omalizumab therapy is downregulation of IgE receptor FcepsilonRI on the surface of mast cells
    • Finally, it exerts an anti-inflammatory effect by decreasing eosinophils in the airways
    • Omalizumab has been shown to be effective in asthma by decreasing the rate of exacerbations and asthma symptoms
    • This therapy is reserved for patients with moderate to severe asthma

20

Treatment of asthma

  • Asthma severity and control should be assessed both in terms of...
  • If patient is not on any maintenance medications, the severity of asthma is classified by...
  • However, the majority of patients...
  • This approach presumes that the severity of asthma is related to...

  • Asthma severity and control should be assessed both in terms of...
    • The effect on patient quality of life from symptoms
    • The risk for future morbidity or impairment, such as risk of exacerbations and progressive loss of lung function
  • If patient is not on any maintenance medications, the severity of asthma is classified by...
    • Frequency and intensity of symptoms
    • The level of obstruction of lung function into following categories
      • Mild intermittent
      • Mild persistent
      • Moderate persistent and severe persistent
  • However, the majority of patients...
    • Are already on therapy when they present to specialist’s office
    • In these patients, the emphasis is changed to assessment of asthma control
  • This approach presumes that the severity of asthma is related to...
    • Its responsiveness to treatment

21

Treatment of asthma

  • The indicators of full asthma control include...
  • Uncontrolled can be further classified into...
  • Once the level of asthma control is determined,...
  • If patient’s asthma is not controlled,...
  • If asthma has been well controlled for at least three months,...

  • The indicators of full asthma control include...
    • No daytime or nighttime symptoms
    • No asthma exacerbations
    • No rescue inhaler use
    • Normal lung function
    • Normal activity levels
  • Uncontrolled can be further classified into...
    • Not well controlled
    • Very poorly controlled
  • Once the level of asthma control is determined,...
    • Treatment should be adjusted accordingly
  • If patient’s asthma is not controlled,...
    • Treatment should be stepped up until full or maximal control is achieved
  • If asthma has been well controlled for at least three months,...
    • Treatment can be stepped down

22

Treatment of asthma

  • What might be available to treat asthma in the future
  • What may have beneficial advantage
  • Suppressing the IL-4/IL-13 pathway 

  • What might be available to treat asthma in the future
    • New monoclonal antibodies
  • What may have beneficial advantage
    • Antagonising the eosinophilic mitogenic factor IL-5 with specific monoclonal antibodes, given that the eosinophil may also serve a pathogenetic role in the mixed Th2/Th1/Th17 endotype of asthma
  • Suppressing the IL-4/IL-13 pathway
    • Ablates Th2-mediated responses
    • Also modulates progression to more chronic severe form of the disease by preventing...
      • Mucus hypersecretion
      • Mucus metaplasia
      • Smooth muscle proliferation
      • Deposition of new matrix

23

Asthma phenotypes

  • A phenotype is defined as...
  • The concept of the phenotype has been suggested to be the prelude to that of the 'endotype'
  • TH2 asthma consists of both...
  • It is likely that the majority of early-onset allergic asthma is...but...
  • Later-onset eosinophilic asthma without traditional allergic elements 
  • Exercise induced asthma
  • Non-TH2 asthma

  • A phenotype is defined as...
    • The “observable properties of an organism that are produced by the interactions of the genotype and the environment”
  • The concept of the phenotype has been suggested to be the prelude to that of the 'endotype'
    • A specific biological pathway is identified that explains the observable properties of a phenotype
  • TH2 asthma consists of both...
    • Early- and later-onset disease over a range of severities
  • It is likely that the majority of early-onset allergic asthma is...but...
    • Mild but that an increasing complexity of immune processes leads to greater severity
  • Later-onset eosinophilic asthma without traditional allergic elements
    • More likely to be severe
  • Exercise induced asthma
    • Milder form of TH2 asthma
  • Non-TH2 asthma
    • Very late–onset asthma
    • Obesity-associated asthma
    • Smoking-related asthma
    • Neutrophilic asthma,
    • Asthma in which affected individuals show little inflammation

24

Asthma phenotypes:
Early-onset allergic

  • Natural history
  • Clinical and physiological features
  • Pathobiology and biomarkers
  • Genetics
  • Response to therapy

  • Natural history
    • Early onset
    • Mild to severe
  • Clinical and physiological features
    • Allergic symptoms and other disease
  • Pathobiology and biomarkers
    • Specific IgE
    • TH2 cytokines
    • Thick S3M
  • Genetics
    • 17q12
    • TH2-related genes
  • Response to therapy
    • Corticosteroid-responsive
    • TH2-targeted

25

Asthma phenotypes:
Late-onset eosinophilic

  • Natural history
  • Clinical and physiological features
  • Pathobiology and biomarkers
  • Response to therapy

  • Natural history
    • Adult onset
    • Often severe
  • Clinical and physiological features
    • Sinusitis
    • Less alergic
  • Pathobiology and biomarkers
    • Corticosteroid-refractory eosinophilia
    • IL-5
  • Response to therapy
    • Responseive to antibody to IL-5 and cysteinyl leukotriene modifiers
    • Corticosteroid-refractory

26

Asthma phenotypes:
Exercise-induced

  • Clinical and physiological features
  • Pathobiology and biomarkers
  • Response to therapy

  • Clinical and physiological features
    • Mild
    • Intermittent with exercise
  • Pathobiology and biomarkers
    • Mast-cell activation
    • TH2 cytokines
    • Cysteinyl leukotrienes
  • Response to therapy
    • Responsive to cysteinyl leukotriene modifiers, beta agonists, and antibody to IL-9

27

Asthma phenotypes:
Obesity-related

  • Natural history
  • Clinical and physiological features
  • Pathobiology and biomarkers
  • Response to therapy

  • Natural history
    • Adult onset
  • Clinical and physiological features
    • Women are primarily affected
    • Very symptomatic
    • Airway hyperresponsiveness less clear
  • Pathobiology and biomarkers
    • Lack of TH2 biomarkers
    • Oxidative stress
  • Response to therapy
    • Responsive to weight loss, antioxidants, and possibly to hormonal therapy

28

Asthma phenotypes:
Neutrophilic

  • Clinical and physiological features
  • Pathobiology and biomarkers
  • Response to therapy

  • Clinical and physiological features
    • Low FEV1
    • More air trapping
  • Pathobiology and biomarkers
    • Sputum neutrophilia
    • TH17 pathways
    • IL-8
  • Response to therapy
    • Possibly responsive to macrolide antibiotics

29

Asthma conclusions

  • The recognition that asthma is an inflammatory disorder of the airways in the early 1950s led to the discovery of the beneficial effect of...
  • Today, optimal control of the disease can be achieved in the vast majority of asthma patients by...
  • Yet, many asthma patients continue to have...
  • These patients are at risk of developing...
  • This is the indication of the complexity of a disease characterized by...

  • The recognition that asthma is an inflammatory disorder of the airways in the early 1950s led to the discovery of the beneficial effect of...
    • Corticosteroids
    • Inhaled formulations
  • Today, optimal control of the disease can be achieved in the vast majority of asthma patients by...
    • Inhaled formulations of corticosteroids and beta 2-adrenoceptor agonists
  • Yet, many asthma patients continue to have...
    • Uncontrolled disease that requires either improved adherence to medications or high intensity treatment
  • These patients are at risk of developing...
    • Significant side effects and account for about 60% of asthma-related healthcare costs
  • This is the indication of the complexity of a disease characterized by...
    • Marked heterogeneity in clinical phenotypes, inflammatory endotypes as well as therapeutic responses

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