5.5 - Asthma and respiratory immunology Flashcards
1
Q
What are some epidemiology facts about asthma?
A
- 5.4 million people in the UK currently receiving asthma treatment
- 1.1 million children affected (approx 3 in every class)
- on average, 3 people die of an asthma attack every day in the UK
- NHS spends approx £1.5 billion annually treating asthma
2
Q
What are the cardinal features of asthma? (5)
A
- wheeze +/- dry cough +/- dyspnoea
- persistent symptoms + episodes (attacks) - precipitated by exertion, colds, allergen exposure
- atopy / allergen sensitisation
- reversible airflow obstruction
- airway inflammation
3
Q
What atopic triad is seen in asthma?
A
HAEfever - Hayfever, Asthma, Eczema
4
Q
Why do asthma patients have a wheeze?
A
Narrowed airway lumen in asthmatic patients causes turbulent flow –> wheezing noise
5
Q
What does atopy / allergen sensitisation cause?
A
Narrowing of airway - seen with local allergen challenge where you introduce an allergen down bronchoscope, red inflamed erythematous
6
Q
What is the airway like in normal vs asthma patients?
A
- normal airway is patent allowing laminar flow through it
- asthma airway even when well and not on treatment = abnormal airways with inflamed (eosinophilic) and thickened walls
7
Q
How do we look for reversible airflow obstruction in asthma?
A
- flow volume loop obtained through spirometry
- scooping inwards of top part of curve (expiratory breath)
- but it can go to normal with bronchodilation (hence reversible)
8
Q
What is the FEV1/FVC ratio for airflow obstruction in adults and children?
A
- <0.7 - adults
- <0.8 - children
9
Q
What immune cells are involved in airway inflammation?
A
- eosinophilia
- type 2 lymphocytes (Th2 lymphocytes - CD4+ cells)
10
Q
Describe the pathogenesis of allergic asthma.
A
- starts with healthy airway wall with bronchial epithelium, matrix and smooth muscle (top to bottom)
- an allergen is introduced which sensitises airway –> inflammation and airway remodelling
- recruitment of inflammatory cells into airway (most eosinophils) and structural changes in airway –> increase in goblet cells which produce mucus
- amount of matrix increases, as well as amount and size of smooth muscle –> thickened airway wall
11
Q
Why are only some people who are sensitised develop asthma?
A
- due to genetic susceptibility of asthma - polygenic and environmental
- some people may have allergies but not asthma
12
Q
What do GWAS for asthma susceptibility show about the genetic cause of asthma?
A
Multigene disorder and polyfactorial - some people with asthma may have increased levels of GSDMB, but not IL33 and vice versa
13
Q
How does type 2 immunity in asthma work?
A
- patients with asthma have exposure to inhaled allergen (antigen)
- this allergen is presented to and binds lung dendritic cells (APC)
- carried via MHC class II to mediastinal lymph nodes
- naive T cells in nodes differentiate into Th2 cell which secretes IL4, IL5 and IL13
14
Q
What does IL-4 do?
A
Helps conversion B plasma cells secrete IgE
15
Q
What does IL-5 do?
A
Recruits eosinophils into airways and promotes their survival causing eosinophilia
16
Q
What does IL-13 do?
A
Involved in mucus secretion
17
Q
Once sensitised to allergen, what happens if re-exposed?
A
- allergic immune response
- IgE recognises circulating antigen and binds to mast cells
- mast cells degranulate and release histamines, cytokines, chemokines, growth factors, enzymes, eicosanoids
18
Q
How do we test for allergic sensitisation? (2)
A
- blood tests - for specific IgE antibodies to allergens of interest (total IgE alone not sufficient to tell you about sensitisation - atopy)
- allergy skin prick tests - wheal and flare reaction in response to allergic reaction
19
Q
How do we test for eosinophilia?
A
- blood eosinophil count when stable: >300cells/mcl is abnormal (present in asthma)
- induced sputum eosinophil count: >3% eosinophils is abnormal
- exhaled nitric oxide
20
Q
What is fraction of exhaled nitric oxide (FeNO) - eosinophilia test?
A
- quantitative, non-invasive and safe method of measuring airway inflammation and is an indirect marker of T2-high eosinophilic airway inflammation in asthma
- has a role in aiding asthma diagnosis, predicting steroid responsiveness and assessing adherence to inhaled corticosteroids
21
Q
Are nitric oxide levels high or low in asthma?
A
During airway inflammation, activated epithelial cells increase production of NO
22
Q
What is involved in the clinical assessment to diagnose asthma? (2)
A
- history and examination
- assess/confirm wheeze when acutely unwell (doctor diagnosed wheeze)
23
Q
What objective tests are done to diagnose asthma? (3)
A
- airway obstruction on spirometry - FEV1/FVC ratio <0.7 / 0.8 if child
- reversible airway obstruction - bronchodilator reversibility >12%
- exhaled nitric oxide (FeNO) > 35ppb (children), >40ppb (adults) - in a treatment naive patient
24
Q
How do we confirm asthma diagnosis in children and young people (aged 5-16)?
A
- if they have symptoms suggestive of asthma AND
- obstructive spirometry and positive bronchodilator reversibility (do this test first) OR
- FeNO level of >35ppb and positive peak flow variability
25
What are the three areas of asthma management?
- reduce airway eosinophilic inflammation
- acute symptomatic relief
- severe asthma - steroid sparing therapies
26
How do we reduce airway eosinophilic inflammation? (3)
- inhaled corticosteroids (ICS)
- leukotriene receptor antagonists
- (maintenance therapy all asthma patients should be on - regular preventer)
27
How do we provide acute symptomatic relief of asthma? (2)
- beta-2 agonists (smooth muscle relaxation)
- anticholinergic therapies (smooth muscle relaxation)
28
How do we treat severe asthma with steroid sparing therapies? (2)
- biologics targeted to IgE e.g. anti-IgE antibody
- biologics targeted to airway eosinophils e.g. anti-IL5 antibody, anti-IL5 receptor antibody
29
Why do we use corticosteroids? (6)
- reduce eosinophil numbers through apoptosis
- reduce mast cell numbers
- reduce Th2 cells, macrophages, DCs
- reduce mucus secretion
- reduce cytokines and mediators
- reduce endothelial cell leakage
30
What are the most important aspects of asthma management to consider before prescribing further medication? (3)
- optimal device and technique
- clear asthma management plan
- adherence to inhaled corticosteroids
31
What is the order of treatment for adult asthma patients?
- regular preventer - low dose ICS
- initial add-on therapy - add inhaled LABA
- additional controller therapies - consider increasing ICS to medium dose or adding LTRA (stop LABA if no response to it)
- specialist therapies - refer patient for specialist care
32
What is the order of treatment for paediatric asthma patients?
- regular preventer - very low dose ICS / LTRA <5y
- initial add-on therapy - add inhaled LABA or LTRA / add LTRA <5y
- additional controller therapies - consider increasing ICS to low dose or adding LTRA/LABA if >5y (stop LABA if no response to it)
- specialist therapies - refer patient for specialist care
33
What is the SMART approach to improve adherence to asthma therapy?
- Single inhaler Maintenance And Reliever Therapy
- uses a single combination inhaler to deliver an ICS and quick-acting LABA to patients
- although a fixed maintenance dose may be required, SMART can also be used as needed
- use of SMART improves some asthma outcomes while potentially reducing the total delivered dose of ICS
34
Why is UK the 3rd highest country in deaths from asthma in 10-24yo and 2nd highest for 10-14?
When feeling well, adults do not want to take maintenance therapy and when they get a cold/sudden allergen exposure they have a sudden attack
35
What is the pathogenesis of an acute asthma attack? (School-age children)
- exposure to allergens e.g. house dustmites, pathogens (virus/bacteria), pollution, tobacco smoke
- if there is an infection predominantly, asthma patients have reduced IFN and anti-viral responses = viral replication increases = prolonged illness
- reduced peak expiratory flow rate and increased airway obstruction --> acute wheeze, responsive to bronchodilators
- increased airway eosinophilic inflammation, responsive to corticosteroids
36
How does anti-IgE antibody therapy work?
- humanised anti-IgE monoclonal antibody
- binds and captures circulating IgE - prevents its interaction with mast cells and basophils to stop allergic cascade
- IgE production can decrease with time if given anti-IgE AB
- reduction in serum IgE over time means therapy may not need to be used indefinitely
37
What is the downside of anti-IgE antibody therapy?
No evidence yet that stopping anti-IgE AB after some time is a long-term solution
38
Why do we use biologics?
They reduce exacerbations/asthma attacks which cause death
39
What is Omalizumab?
Commonly used anti-IgE antibody given as subcutaneous injections, effective at reducing exacerbations compared to placebo
40
When is Omalizumab used?
- severe, persistent allergic (IgE mediated) asthma in patients >6 years who need continuous or frequent treatment with oral corticosteroids
- have to have optimised standard therapy with good adherence with no response
- very expensive
41
What serum IgE level is Omalizumab prescribed for?
Total serum IgE between 30-1500 iU/ml
42
What is mepolizumab?
- anti-IL5 antibody for severe eosinophilic asthma
- IL-5 regulates growth, recruitment, activation and eosinophil survival
- licensed for adults and children >6y
43
When is mepolizumab trialled?
- severe eosinophilic asthma
- blood eosinophils >300 cells/mcl in last 12 months
- at least 4 exacerbations requiring oral steroids in last 12 months
- trial for 12 months and continue if 50% reduction in attacks
44
Does mepolizumab seem to have a greater effect in adults or children with asthma?
Adults - clinically significant exacerbations reduced in adults 50% vs 27% in children
45
What is dupilumab?
- anti-IL4Ralpha antibody
- IL4 receptor alpha is a shared receptor for IL4 and IL13
- fewer asthma attacks AND improved lung function
