24 Asthma Flashcards
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
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
- Who grow up in environments with a wide range of microbial exposures
- 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
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
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
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
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
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)
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
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
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
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
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
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
- The occurrence and the frequency of…
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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