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BRS2 - Cardiovascular & Respiratory Medicine > Asthma & Respiratory Immunology > Flashcards

Asthma & Respiratory Immunology Flashcards

1
Q

Discuss the epidemiology of asthma in the UK.

Why is this important?

A
  • 5.4 million people in UK currently receiving treatment for asthma
  • 1.1m children affected ( ~3 in every class)
  • On average, 3 people die of an asthma attack/day in UK
  • NHS spends ~ £1b/yr treating asthma

Epidemiology showing importance of asthma and how big of a problem it is

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2
Q

On average, how many people die of an asthma attack every day in the UK?

Why is this significant?

A

We know how to diagnose and treat asthma but people are still dying from asthma attacks

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3
Q

What are the cardinal features of asthma?

A
  1. Wheeze +/- dry cough
    - on exertion
    - worse with colds
    - with allergen exposure
    - breathlessness/dyspnoea
  2. Atopy/allergen sensitisation
  3. Reversible airflow obstruction
  4. Airway inflammation
    - Eosinophilia
    - Type 2 - lymphocytes
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4
Q

A wheeze is a whistling sound that comes from the airways.

What causes this sound?

A

Bronchoconstriction (narrowing) of the airway lumen

Narrowed airways —-> turbulent flow of air through airways —-> wheezing noise

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5
Q

What are the physiological abnormalities in asthma?

Pathophysiology

A

Reversible airflow obstruction

Airway inflammation

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6
Q

What 3 things must we test for in order to make a diagnosis of asthma?

A
  1. Atopy/allergen sensitisation
  2. Reversible airflow obstruction
  3. Airway inflammation
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7
Q

What feature is really important to test for when looking for evidence of asthma?

A

Airway inflammation

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8
Q

What are the two main cell types contributing to the airway inflammation that occurs in asthma?

A

Eosinophils

Type 2 - lymphocytes

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9
Q

What test would you use to look for reversible airway obstruction?

A

Lung function tests, e.g. spirometry (one of the most common tests done)

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10
Q

What loop is obtained during spirometry?

A

Flow volume loop

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11
Q

When considering airway obstruction, what part of a flow volume loop are they most concerned about: the expiratory part or the inspiratory part?

A

The expiratory part

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12
Q

What would show evidence of reversible airway obstruction?

A

Someone with untreated asthma would have demonstrate an obstructive flow volume loop

Following use of a bronchodilator, their flow volume loop would look normal

This shows evidence of reversibility

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13
Q

In asthma, there is reversible airway obstruction.

What is the significance of this?

A

Use of a bronchodilator can help reverse this airway obstruction

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14
Q

Compare the structure of a normal (healthy) airway vs an “asthmatic” airway.

A

Normal airway:

  • Patent airway lumen allowing laminar flow through airway
  • No noise with breathing (e.g. wheezing)
  • No difficulty in breathing

Asthmatic airway: (if not controlled with treatment)

  • Airway looks abnormal at baseline
  • Thickened airway wall due to inflammation (eosinophilic)
  • Baseline increase in airway smooth muscle (thickened wall)
  • Develop wheeze because airway lumen is narrowed (turbulent flow)
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15
Q

What kind of flow occurs through a patent airway lumen?

A

Turbulent flow

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16
Q
  1. Describe the structural abnormalities of the airways in a patient with asthma.
  2. How does this affect the flow of air through the lumen?
A
  1. Structural Abnormalities:
    - Thickened wall
    - Inflammation in walls

During attack

  • Tightened smooth muscles
  • Trapped air in alveoli
  1. Turbulent flow
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17
Q

What is a spirometry test?

A

A lung function test

  • Check how well lungs are working
  • Measure how much you inhale, exhale + how fast you exhale
  • Forced expiratory measure
  • Ask patient to take a deep breath out as hard + as fast as they can to empty their lungs
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18
Q

What does a spirometry test require of the patient?

A
  • Effort

- Co-operation from the patient

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19
Q

Why is spirometry not possible for very young children?

A

Requires both effort + co-operation from the patient

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20
Q

How might spirometry be adapted for children to ensure they exert maximum effort when carrying out this test?

A

Might use an incentive device on a computer

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21
Q

Patient A has asthma.

At their baseline, with proper treatment, their lumen is patent and normal.

However, following an injection of an allergen directly into their airways (in controlled situation) they are now exhibiting signs of an asthma attack.

What changes could be observed in the lumen 10 mins after injecting the allergen?

A

Increased swelling + inflammation

Both lumen = completely occluded

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22
Q

Describe the pathogenesis of allergic asthma.

A
  1. Usually h/v normal airway with bronchial epithelium sitting on a small amount of matrix and some smooth muscle
  2. In a patient that has susceptibility to asthma, if exposed to allergens and sensitised, might develop inflammation and remodelling (in parallel)
  3. Recruitment of inflammatory cells into airway - predominantly eosinophils

AND

Structural changes, inc. changes in epithelium:

  • develop increased goblet cells
  • increased amount of matrix
  • increased amount + size of muscle cells
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23
Q

What process occurs in a patient with pre-existing susceptibility to asthma who is exposed to an allergen?

A

Sensitisation

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24
Q

What two process will occur in parallel upon sensitisation to an allergen in a patient who is susceptible to asthma?

A
  1. Airway Inflammation

2. Air Remodelling

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25
Q

What is airway remodelling?

A

Changes in the structural cells of the airway

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26
Q

What structural changes will the airway undergo during remodelling in the pathogenesis of allergic asthma?

A

Changes in epithelium

  • develop increased goblet cells
  • increased amount of matrix
  • increased amount + size of muscle cells
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27
Q

What inflammatory cells are predominantly recruited to the airways in the pathogenesis of allergic asthma?

A

Eosinophils

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28
Q

What are the fundamental physiological abnormalities of asthma?

A

Recruitment of inflammatory cells into airway - predominantly eosinophils

AND

Structural changes, inc. changes in epithelium:

  • develop increased goblet cells
  • increased amount of matrix
  • increased amount + size of muscle cells
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29
Q

Why do only some people who are sensitised develop asthma?

A

There’s a definite underlying genetic susceptibility

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30
Q

Why do only some people who are sensitised develop asthma?

A

There’s a definite underlying genetic susceptibility (e.g. have allergy or allergic disease)

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31
Q

What are the events and stages required for development of asthma?

A
  1. Genetic susceptibility
    - Allergy
    - Allergic disease
  2. Environmental exposures, e.g.
    - Allergen
    - Infection, e.g. colds
    - Pollution
  3. Leading to
    - Allergy
    - Reversible airflow obstruction
    - Inflammation
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32
Q

What type of studies can be used to investigate genetic susceptibility in asthma?

A

Genome Wide Association Studies, GWAS

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33
Q

How could a GWAS be used to investigate genetic susceptibility in asthma?

A

Whole population level investigation of the genome in people

Comparison of genome (with asthma vs no asthma)

Look for variability in gene expression between 2 groups

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34
Q

What are some advantages to using GWAS to investigate genetic susceptibility in asthma?

A

Finding genes involved to help us find novel therapies

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35
Q

What kind of plot is used in GWAS?

A

Manhattan Plot

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36
Q

What do the P-values involved of genes in GWAS shown in Manhattan plots show?

A

How likely gene is to be increased normally

logP-values therefore has to be very high for it to be significant

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37
Q

What are some advantages to using GWAS to investigate genetic susceptibility in asthma?

A

Consistent results

Reproducible results

Identify genes that increase in expression in asthmatic patients

Finding genes involved to help us find novel therapies

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38
Q

Give an example of a known gene involved in genetic susceptibility to asthma.

A

IL33 - specific interleukin involved in asthma

GSDMB - very consistently comes up as increased in both children and adults with asthma

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39
Q

We know that patients with asthma have an underlying genetic susceptibility.

GWAS can be used to further investigate this.

However, this is not simple.

What kind of gene disorder is asthma?

A

Asthma is a multi-gene disorder and is polyfactorial –> asthma not caused by any 1 thing

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40
Q
  1. What type immunity reaction occurs in allergic asthma?

2. What does this determine?

A
  1. Type 2 immunity reaction

2. Determines the tests we do

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41
Q

Describe the type 2 immunity reaction that occurs in allergic asthma.

A
  1. Allergen (antigen) inhaled
  2. Presented to APC
  3. APC = dendritic cells in context of the lung

APC carries antigen via MHC class II to lymph nodes (mediastinal nodes because APC is in lung in case of asthma)

  1. Naive T cells (Th0) differentiate at mediastinal lymph nodes following APC arrival

Differentiate into Th1 & Th2

  1. Th2 subsequently secretes archetypal Th2 cytokines: IL-4, IL-5 & IL-13
  2. Cytokines have various actions:
  • VCAM-1 expression
  • Mast cell proliferation
  • IgE synthesis
  • Mucin secretion
  • Eosinophilic airway inflammation
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42
Q

Describe the type 2 immunity reaction that occurs in allergic asthma.

A
  1. Allergen (antigen) inhaled
  2. Presented to APC
  3. APC = dendritic cells in context of the lung

APC carries antigen via MHC class II to lymph nodes (mediastinal nodes because APC is in lung in case of asthma)

  1. Naive T cells (Th0) differentiate at mediastinal lymph nodes following APC arrival

Differentiate into Th1 & Th2

  1. Th2 subsequently secretes archetypal Th2 cytokines: IL-4, IL-5 & IL-13
  2. Cytokines have various actions:
  • VCAM-1 expression
  • Mast cell proliferation
  • IgE synthesis
  • Mucin secretion
  • Eosinophilic airway inflammation
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43
Q

What are the main class of Th cells involved in the pathogenesis of allergic asthma?

A

Th0 differentiates into Th1 & Th2

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44
Q

What are the 3 main interleukins involved in the pathogenesis of allergic asthma?

A

IL-4
IL-5
IL-13

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45
Q

Describe the type 2 immunity reaction that occurs in allergic asthma.

A
  1. Allergen (antigen) inhaled
  2. Presented to APC
  3. APC = dendritic cells in context of the lung

APC carries antigen via MHC class II to lymph nodes (mediastinal nodes because APC is in lung in case of asthma)

  1. Naive T cells (Th0) differentiate at mediastinal lymph nodes following APC arrival

Differentiate into Th1 & Th2

  1. Th2 subsequently secretes archetypal Th2 cytokines: IL-4, IL-5 & IL-13
  2. Cytokines have various actions:
  • VCAM-1 expression
  • Mast cell proliferation
  • IgE synthesis
  • Mucin secretion
  • Eosinophilic airway inflammation
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46
Q

What is the main role of IL-13 in allergic asthma?

A

Involved in mucus secretion

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47
Q

What is the main role of IL-5 in allergic asthma?

A

Recruits eosinophils into airways

Promotes eosinophil survival which contributes to eosinophilic airway inflammation in asthma

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48
Q

What is the main interleukin responsible for eosinophilic airway inflammation in allergic asthma?

A

IL-5

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49
Q

What are the main processes that occur due to Th2 cytokine action in the development of allergic asthma?

A
  • VCAM-1 expression
  • Mast cell proliferation
  • IgE synthesis
  • Mucin secretion
  • Eosinophilic airway inflammation
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50
Q

What are the 5 main stages involved in T2 immune reaction in the pathogenesis of allergic asthma?

[1 sentence per stage)

A
  1. Allergen presentation to airway epithelium
  2. Recognised by dendritic cells
  3. Presentation of antigen
  4. Th cell differentiation
  5. Th2 actions
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51
Q

In type 2 immune reaction, mast cells are degranulated following binding of IgE.

What substances might be released? (contributing to allergic asthma)

[6]

A
  1. Histamines
  2. Eicosanoids
  3. Cytokines
  4. Chemokines
  5. Enzymes
  6. Growth factors
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52
Q

Once sensitisation has occurred, what immunoglobulin will recognise the allergen in allergic asthma?

A

IgE

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53
Q

In a sensitised patient, what will IgE bind to in allergic asthma?

A

Mast cells

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54
Q
  1. In a sensitised patient, what process occurs upon IgE binding to mast cells in allergic asthma?
  2. What does this result in?
A
  1. Degranulation
  2. Mast cells will release various chemicals, inc.
  • Histamines
  • Eicosanoids
  • Cytokines
  • Chemokines
  • Enzymes
  • Growth factors

Results in allergic reaction and asthma

55
Q

What are the main 2 tests for detecting allergic sensitisation?

A
  1. Allergy skin tests

2. Blood tests

56
Q

In type 2 immune reaction, mast cells are degranulated following binding of IgE.

What chemicals might be released? (contributing to allergic asthma)

[6]

A
  1. Histamines
  2. Eicosanoids
  3. Cytokines
  4. Chemokines
  5. Enzymes
  6. Growth factors
57
Q

In order to detect allergy sensitisation, what can you test for in blood tests?

A

Can test for specific IgE antibodies to allergens of interest

Total IgE alone not sufficient to define atopy

58
Q

What do allergy skin tests involve?

A
  1. Intradermal injection of a positive control

HISTAMINE - because we all react to histamine

  1. Intradermal injection of a negative control - SALINE
  2. Compare with allergens, e.g. dust mite, grass, pollen, cat dander, dog dander etc.
59
Q
  1. What suggests a positive result to an allergen in allergy skin tests?
  2. How can we determine whether someone is sensitised to an allergen with a skin test?
A
  1. Develop wheal and flare as positive marker

AND

  1. Measure size of wheal to determine whether they are sensitised to that allergen
60
Q

There are several tests that can be conducted to test for eosinophilia.

What are the main 3?

A
  1. Blood eosinophil count when stable (not during asthma attack):

> /=300 cells/mcl is ABNORMAL

  1. Induced sputum eosinophil count: >/=2.5% eosinophils is ABNORMAL (see bilobar nucleus)
  2. Exhaled nitric oxide
    - Breath test
    - Being used more and more
    - Recommended as diagnostic test
61
Q

What significance does FeNO have in asthma?

A

A non-invasive biomarker of airway (type 2) inflammation

This reaction occurs in asthma

62
Q

Exhaled nitric oxide (FeNO) is routinely used for 3 main purposes concerning asthma.

What are these 3 purposes?

A
  1. Aid diagnosis
  2. Predicting steroid response
  3. Measuring adherence to ICS
63
Q

Exhaled nitric oxide (FeNO) is routinely used for 3 main purposes concerning asthma.

What supports an asthma diagnosis?

A

Elevated FeNO

Provided patient is not on treatment with steroids

64
Q

Exhaled nitric oxide (FeNO) is routinely used for diagnosis of asthma.

Why?

A

Fractional concentration of exhaled FeNO is a method for measuring airway inflammation

= an indirect marker of T2-high eosinophilic airway inflammation in asthma

Method =

  • Quantitative
  • Non-invasive
  • Safe
65
Q

What is FeNO an indirect marker of?

A

An indirect marker of T2-high eosinophilic airway inflammation in asthma

66
Q

Exhaled nitric oxide (FeNO) is routinely used for diagnosis of asthma.

What are the main advantages of this test?

A

Fractional concentration of exhaled FeNO:

  • Quantitative method
  • Non-invasive method
  • Safe method
  • Both children and adults can do test
  • Incentive device can be used to help them do measurement correctly
67
Q

Exhaled nitric oxide (FeNO) is routinely used in clinic.

What are the 3 main roles of exhaled nitric oxide concerning asthma?

A
  1. Aiding asthma diagnosis
  2. Predicting steroid responsiveness
  3. Assessing adherence to ICS
68
Q

FeNO is very sensitive to steroids.

What might a “sky-high” exhaled reading suggest?

A

Probably suggests that patient hasn’t been taking treatment

69
Q

A “sky-high” exhaled reading of FeNO might suggest that a patient has not been taking their treatment for asthma.

Why is this?

A

FeNO is very sensitive to steroids

70
Q

A single non-invasive biomarker does not reflect airway eosinophilic
inflammation.

What 3 requirement need to be met for a definite diagnosis of asthma?

A
  1. Symptoms
  2. Characteristic lung function of asthma
  3. Combination of blood or airway eosinophils AND exhaled nitric oxide (probably)
71
Q

What are the clinical guidelines for NICE asthma diagnosis concerning clinical assessment of asthma?

A
  • History & examination

- Assess/confirm wheeze when acutely unwell

72
Q

What are the clinical guidelines for NICE asthma diagnosis in regards to objective tests for asthma?

[3]

A
  • Airway obstruction on spirometry - FEV1/FVC ratio <0.7
  • Reversible airway obstruction - Bronchodilator reversibility >/= 12%
  • Exhaled nitric oxide (FeNO) >35ppb (children), >40ppb (adults)
73
Q

What is the suggested order of tests for diagnosis of asthma in children and young people outlined in the NICE clinical guidelines?

A
  1. Spirometry - if symptoms of asthma
  2. Consider BDR test if spirometry shows obstruction
  3. If diagnostic uncertainty remains after spirometry and BDR, consider FeNO
  4. If diagnosis uncertainty remains after FeNO, monitor peak flow variability for 2 to 4 weeks
74
Q

What is needed for diagnosis of asthma in children and young people (ages 5-16) according to NICE guidelines?

A
  1. Symptoms suggestive of asthma

AND

  1. FeNO level - 35ppb or more and positive peak flow variability

OR

  1. Obstructive spirometry + positive bronchodilator reversibility
75
Q

How many positive tests do NICE guidelines suggest are needed for a diagnosis of asthma?

A

At least 2

76
Q

What are the 3 main categories of treatment in asthma management?

A
  1. Reduce airway eosinophilic inflammation
  2. Acute symptomatic relief
  3. Treatment of severe asthma - steroid sparing therapies
77
Q

What maintenance therapy is prescribed for all asthma patients, regardless of the severity of their illness?

A

Inhaled corticosteroids (ICS)

Leukotriene receptor antagonists

78
Q

What is the target of the maintenance therapy prescribed for all asthma patients?

A

Maintenance therapy (involves preventer treatments)

79
Q

What therapies are used to reduce airway eosinophilic inflammation in asthma management?

A

Inhaled corticosteroids

80
Q

What purpose do inhaled corticosteroids have in asthma management?

A

Preventer treatment
- Target and reduce eosinophilic airway inflammation

  • Reduce baseline bronchoconstriction
81
Q

What purpose do leukotriene receptor antagonists have in asthma management?

A

Reduce type II inflammation

82
Q

What therapies are there for acute symptomatic relief in asthma management?

A
  • Beta-2 agonists

- Anticholinergic therapies

83
Q

When might a patient with asthma use a beta-2 agonist?

A

For acute symptomatic relief - if they suddenly develop symptoms

84
Q

When might a patient with asthma use anti-cholinergic therapy?

A

For acute symptomatic relief - if they suddenly develop symptoms

85
Q

What purpose do beta-2 agonists have in asthma management?

A

They are bronchodilators

Aid smooth muscle relaxation

For acute symptomatic relief - if they suddenly develop symptoms

86
Q

What purpose do anti-cholinergic therapies have in asthma management?

A

They are bronchodilators

Aid smooth muscle relaxation

For acute symptomatic relief - if they suddenly develop symptoms

87
Q

Beta-2 agonists and anti-cholinergic therapies can be used for acute symptomatic relief of asthma.

These therapies should not be used regularly.

Why?

A

This would be dangerous

To just have bronchodilators without an anti-inflammatory could result in asthma death

Therefore, must minimise background airway inflammation (with maintenance therapy) all the time

88
Q

What type of therapies are used in the management of severe asthma?

A

Steroid sparing therapies

89
Q

When might steroid sparing therapies be used to manage asthma?

A

To treat severe asthma - asthma that’s not responding to basic treatments

If not responding to ICS despite increasing dose + are adhering to treatment = severe asthma

Biologics (steroid sparing therapies) reduce exacerbations and reduce attacks; these things contribute to asthma mortality

90
Q

Give an example of steroid sparing therapies that might be prescribed to help manage severe asthma.

A

Biologic targeted to IgE
- Anti-IgE antibody

Biologics targeted to airway eosinophils

  • Anti-interleukin-5 antibody
  • Anti-interleukin-5 receptor antibody
91
Q

What interleukin can biologics target in order to help decrease airway eosinophils?

A

Il-5

92
Q

What is the mechanism of action of corticosteroids in asthma management?

A

Target and reduce type 2 inflammation

Primary function:
- reduce eosinophil number by promoting apoptosis

  • reduce Type 2 mediators released by Th2 cells (e.g. reduce IL-5)
  • reduce mast cell number
  • some evidence that steroids can also impact structural cells and can help deal with the airway remodelling that develops in asthma pathophysiology
93
Q

What are the most important aspects of asthma management?

A

Optimal device and technique - does patient know best technique?

Clear asthma management plan - what to do when feeling well and are taking daily treatments; what to do with symptom onset.

Adherence to ICS - preventer treatment

(Before escalating to biologics for treatment of severe asthma, important to make sure these bases are covered first)

94
Q

Why might patients with asthma not use their inhaler everyday?

A

Most days, they’ll feel completely fine

If not feeling symptoms, might not feel they need to take maintenance therapy (ICS)

95
Q

A patient with asthma seems to not be responding to the basic treatments.

What must you check before escalating to biologics (used in the treatment of severe asthma)?

A

Must check that they are adhering to their inhaled corticosteroids and taking as they should (maintenance therapy)

Check that they have optimal device and technique

Check understanding of asthma management plan

96
Q

What can be used to objectively assess adherence to asthma ICS therapy?

A

Electronic adherence monitoring device

97
Q

What is the purpose of electronic adherence monitoring in asthma management?

A

Attached to corticosteroid inhaler to help objectively assess adherence

(records date and number of doses)

98
Q

The British Thoracic Society have published guidelines containing an algorithm for asthma management.

What are the 4 main stages of asthma therapies?

A
  1. Regular preventer
  2. Initial add-on therapy
  3. Additional controller therapies
  4. Specialist therapies
99
Q

The British Thoracic Society have published guidelines containing an algorithm for asthma management.

What are the 6 aspects that are evaluated in a patient with diagnosed aspect?

A

1,2,3. Assess symptoms; Measure lung function; Check inhaler technique and adherence

  1. Adjust dose
  2. Update self-management plan
  3. Move up and down as appropriate
100
Q

The British Thoracic Society have published guidelines containing an algorithm for asthma management.

The clinician is instructed to move up and down the algorithm (in terms of strength of treatment) as needed.

Why might a clinical move up the algorithm?

A

To improve control as needed

If using 3+ doses of SABA a week

If not responding to basic treatments

101
Q

The British Thoracic Society have published guidelines containing an algorithm for asthma management.

The clinician is instructed to move up and down the algorithm (in terms of strength of treatment) as needed.

Why might a clinical move down the algorithm?

A

To find and maintain the lowest controlling therapy

102
Q

Asthma deaths still occur in the UK.

How might asthma mortality (death) relate to maintenance therapy adherence?

A

If not taking maintenance therapy and then get cold or sudden allergen exposure, could result in a severe attack which can be fatal

In asthma, death occurs due to asthma attacks

103
Q

What must we seek to prevent in order to reduce asthma mortality?

A

Asthma attacks

104
Q

Asthma attacks can also be called acute lung attacks.

“Exacerbation” is another term that has been used to mean asthma attacks.

Why are we now moving away from the term “exacerbation” to describe asthma attacks?

A

Moving away from term “exacerbation” to try and get people to understand the severity and seriousness of asthma “attacks”

105
Q

Describe the pathogenesis of an acute lung attack in asthma.

A

Background exposure to allergens (e.g. house dust)

On top of that, there are several other exacerbating factors (e.g. infection with a virus, bad day of pollution, tobacco smoke)

These factors can come together and culminate in a significant final event = asthma attack

Resulting in various responses:

  • eosinophilia –> eosinophilic airway inflammation
  • reduced anti-viral responses
  • reduced peak expiratory flow)
106
Q

People with asthma are affected by background exposure to allergens. There are also exposed to other factors that can contribute to acute lung attacks.

Name 3.

A

Pathogens (virus +/- bacteria)

Pollution

Tobacco smoke

107
Q

Describe the 3 main responses that occur as a result of an asthma attack.

A
  1. If infection is the predominant precipitant of an asthma attack:

INF-a, B + y reduce

Reduced anti-viral responses + increased viral replication results in a prolonged illness

  1. Eosinophilia

Increased airway eosinophilic inflammation (responsive to corticosteroids)

  1. Reduced peak expiratory flow rate + increased airway obstruction (background airway obstruction significantly exacerbated during an attack) resulting in acute wheeze

Responsive to bronchodilators

108
Q

Describe the 3 main responses that occur as a result of an asthma attack.

A
  1. If infection is the predominant precipitant of an asthma attack:

INF-a, B + y reduce

Reduced anti-viral responses + increased viral replication results in a prolonged illness

  1. Eosinophilia

Increased airway eosinophilic inflammation (responsive to corticosteroids)

  1. Reduced peak expiratory flow rate + increased airway obstruction (background airway obstruction significantly exacerbated during an attack) resulting in acute wheeze

Responsive to bronchodilators

109
Q
  1. How are anti-viral responses impacted during an asthma attack?
  2. How does this affect illness?
A
  1. Reduced anti-viral responses (reduced IFN-a,B+y)

2. As there’s a reduced anti-viral response and increased viral replication —-> prolonged illness

110
Q

How does eosinophil number change during an asthma attack?

A

Eosinophilia —-> increased airway eosinophilic inflammation

111
Q
  1. What happens to peak expiratory flow during an asthma attack?
  2. What does this result in?
A
  1. Reduced peak expiratory flow rate

2. Reduced PEFR + increased airway obstruction resulting in acute wheeze

112
Q
  1. How do the corticosteroids used in asthma attacks differ to those used routinely as maintenance therapy in asthma?
  2. What is the reason for this difference?
A

1.

113
Q
  1. How do the corticosteroids used in asthma attacks differ to those used routinely as maintenance therapy in asthma?
  2. What is the reason for this difference?
A
  1. Treat acute attacks with systemic high dose steroids, usually prednisolone
  2. ICS used as maintenance therapy in asthma isn’t enough to dampen inflammatory airways in an acute attack
114
Q

Humanised anti-IgE monoclonal antibody is a biologic used in the treatment of severe asthma.

What is its mechanism of action?

A

Binds and captures circulating IgE

To prevent interaction with mast cells and basophils to stop allergic cascade during acute allergen exposure

115
Q

Humanised anti-IgE monoclonal antibody is a biologic used in the treatment of severe asthma.

IgE production can decrease with time when patients are given anti-IgE Ab.

What is the implication of this?

A

Reduction in serum IgE over time means the therapy may not need to be used indefinitely

However, no evidence yet (Nov ‘21) that stopping anti-IgE Ab after some time is a long-term solution

Studies have shown that symptoms return a few months after stopping treatment

116
Q

The treatments that currently exist for asthma manage/control symptoms. They’re not disease-modifying treatments.

True or False?

A

True

117
Q

What type of drug is Omalizumab?

A

Monoclonal antibody

Anti-IgE antibody

118
Q

What can Omalizumab be used to treat?

A

Severe (allergic) asthma

Nasal polyps

Urticaria (hives)

119
Q

What is the criteria for prescribing Omalizumab to a patient who has severe asthma?

A

Severe, persistent allergic (IgE-mediated) asthma in patients >/= 6yo who need continuous or frequent treatment with oral corticosteroids

4+ courses of oral corticosteroids in previous year

Optimised standard therapy

Documental compliance (and still not responding to treatment despite good adherence)

120
Q

What is the total serum IgE level for which Omalizumab can be prescribed in the treatment of severe asthma?

A

30-15000

121
Q

For Omalizumab to prescribed in the treatment of severe asthma, total serum IgE levels must be between 30-1500.

What is the implication of this?

[Disadvantage of Omalizumab]

A

Very fixed and tight serum IgE level for which Omalizumab can be prescribed

Problem because many patients have IgE level that’s outside of this specified range —-> ~2/3 patients not eligible for it

122
Q

Omalizumab can be used in the treatment of severe asthma.

What is its dosing based on?

A

Weight and serum

123
Q

Omalizumab can be used in the treatment of severe asthma.

How is it administered?

A

2-4 weekly s/c injections

124
Q

Compare the cost of Omalizumab: Min 75mg 4 weekly s/c injections vs Max 600mg 2 weekly s/c injections.

A

Min 75mg 4 weekly s/c injections = £1,655/patient /year

Max 600mg 2 weekly s/c injections = £26,640/patient/year

125
Q

Omalizumab can be used in the treatment of severe asthma.

How is improvement of asthma management tracked?

A

Main output/improvement is in reduction of asthma attacks

126
Q

What type of drug is Mepolizumab?

A

Monoclonal antibody

Anti-IL5-antibody

Licensed for adults and children >/= 6yo

127
Q

What is Mepolizumab used to treat?

A

Severe eosinophilic asthma

128
Q

Mepolizumab can be used in the treatment of severe asthma.

What is its mechanism of action?

A

Binds IL-5

Prevents IL-5 binding IL-5Ra receptor

IL-5 regulates growth, recruitment, activation and eosinophil survival

129
Q

What are the current UK for recommendations for prescribing Mepolizumab to treat severe asthma?

A

Severe eosinophilic asthma

Blood eosinophils >/= 300 cells/mcl in the last 12 months (with previous asthma diagnosis)

Min. 4 exacerbations requiring oral steroids in the last 12 months

Trial for 23 months - 50% reduction in attacks, then continue

130
Q

What is an RDBPC trial?

A

Randomised Double Blind Placebo Controlled Trial

131
Q

What is the biggest set of data that we have for the efficacy of Mepolizumab?

A

The DREAM trial

A multi-centre RDBPC trial held across 81 centes in 13 countries

132
Q

The “DREAM trial” is the biggest set of data that we have for the efficacy of Mepolizumab.

What were the criteria for patient admittance into this trial?

A

Patients aged 12-74yo

Diagnosis of severe/refractory asthma (high dose ICS)

> /= 2 exacerbations in previous year

Sputum eosinophils >3% or FeNO >50ppb or blood eosinophils >/= 0.3x10^9/ml

133
Q

Mepolizumab can be used in the treatment of severe asthma.

How is improvement of asthma management tracked?

A

Reduction in asthma attacks (exacerbations)

134
Q

The lowest dose of Mepolizumab is used in the treatment of severe asthma.

Why is this?

A

Study shows clinically significant exacerbations reduced with Mepolizumab in asthma.

Not really dependent on dose so use lowest dose (75mg)

BRS2 - Cardiovascular & Respiratory Medicine (4 decks)

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