1B asthma and respiratory immunology Flashcards
How common is asthma?
- 5.4 mil people in UK currently receiving asthma treatment
- 1.1 mil children affected (approx 3 in every class)
- On average 3 people die of asthma attack every day in UK
- NHS spends £1 bil annually treating asthma
What are the cardinal features of asthma?
- Wheeze +/- dry cough- on exertion, worse with colds and allergen exposure
- Persistent symptoms + episodes (attacks)
- Atopy/allergen sensitisation: causes narrowing of airway
- Reversible airflow obstruction
- Airway inflammation
- Type 2: TH2 lymphocytes - CD4+ cells
- Eosinophilia
Why is asthma worse with colds and allergen exposure?
Narrowed airway lumen in asthmatic patients causes turbulent flow and makes wheezing noise
What is reversible airflow obsctruction?
- In normal airway, it’s patent allowing laminar flow through it
- In asthmatic, even when well and not on treatment, they have abnormal airways with inflamed (eosinophilic) and thickened walls
- The inflammation + thickened walls are reversible
How do we look for reversible airflow obstruction (wheeze)?
We look at flow volume loop obtained through spirometry
Scooping inwards of top part of curve (black line)- but it can go to normal (red line) with bronchodilation which is why it’s reversible
FEV1/FVC ratio:
< 0.7 (adults)
< 0.8 (children)
What immune cells are involved in airway inflammation?
- Eosinophilia- image of asthmatic airway with eosinophilia
- Type 2 lymphocytes
Describe the pathogenesis of allergic asthma
1) We start with normal airway with bronchial epithelium, some matrix and some smooth muscle under it
2) An allergen is introduced which sensitises airway which causes inflammation and airway remodelling
3) Recruitment of inflammatory cells into airway (mostly eosinophils) and structural changes in airway is increase in goblet cells which produce mucus
4) Amount of matrix increases too and amount + size of smooth muscle cells increase
Why are only some people who are sensitised develop the disease of asthma?
- Due to genetic susceptibility to asthma
- Some people may have allergies but don’t have asthma
Which genes are more expressed in asthma patients?
IL33, GSDMB
This means that asthma is a multigene disorder and is polyfactorial- some people with asthma may have increased levels of 1 gene but not of another which others may do
How does type 2 immunity reaction come about in allergic asthma?
- Patients with asthma have exposure to inhaled allergen
- This allergen binds to lung dendritic cells and are carried via MHC class II to mediastinal lymph nodes
- Naive T cells in nodes differentiate into Th2 cell which secretes IL4, 5 and 13
What does IL-4 do?
Helps conversion of B plasma cells to secrete IgE
What does IL-5 do?
IL-5 recruits eosinophils into airways and promotes their survival- causing eosinophilia
What does IL-13 do?
Involved in mucus secretion
Now the patient is sensitised to allergen- what happens if they’re exposed to it again?
- There’s an allergic immune response
- IgE recognises circulating antigen and binds to mast cells
- Mast cells degranulate and release histamines, cytokines, chemokines, growth factors, enzymes, eicosanoids
How do we test for allergic sensitisation?
- Blood tests- for specific IgE antibodies to allergens of interest- total IgE alone doesn’t tell you about sensitisation (atopy)
- Allergy skin prick tests- wheal and flare reaction in response to allergic reaction
How do we test for eosinophilia?
- Blood eosinophil count when stable → ≥300 cells/mcl is abnormal
- Induced sputum eosinophil count: ≥2.5% eosinophils is abnormal
- Exhaled Nitric Oxide
How is fraction of exhaled nitric oxide (FeNO) related to the diagnosis of eosinophilia?
- Quantitative, non-invasive and safe method of measuring airway inflammation and is an indirect marker of T2-high eosinophilic airway inflammation in asthma
- It also has a role in aiding asthma diagnosis and seeing if patients are adhering to their steroid treatment since it’s a very sensitive test and NO levels drop when patients are taking treatment
What clinical assessment is done to diagnose asthma?
- History and exam
- Assess/confirm wheeze when acutely unwell
What objective tests are done to diagnose asthma?
- Airway obstruction on spirometry- FEV1/FVC ratio <0.7
- Reversible airway obstruction- bronchodilator reversibility ≥12%
- Exhaled NO (FeNO) >35ppb (children), >40ppb (adults)
What do we need to confirm asthma diagnosis in children and young people (5-16)?
If they have symptoms suggestive of asthma and:
- FeNO level of 35ppb or more and positive peak flow variability
or
- Obstructive spirometry and positive bronchodilator reversibility
What are the 3 areas of asthma management?
- Reduce airway eosinophilic inflammation
- Acute symptomatic relief
- Severe asthma treatment
How is eosinophilic inflammation reduced?
- Inhaled corticosteroids- target and reduce eosinophilic inflammation
- Leukotriene receptor antagonists- can reduce type 2 inflammation
- This is maintenance therapy which all asthma patients should be on- a regular preventer
How is acute symptomatic relief of asthma provided?
- Beta-2 agonists (smooth muscle relaxation)
- Anticholinergic therapies (smooth muscle relaxation)
How is severe asthma managed?
Steroid sparing therapies
- Biologics targeted to IgE e.g. anti-IgE antibody
- Biologics targeted to airway eosinophils e.g. anti-interleukin-5 antibody and anti-interleukin-5 receptor antibody
Why are corticosteroids used for asthma (what things do they do?)
- Reduce eosinophil numbers through apoptosis
- Reduce mast cell numbers
What is the most important aspect of asthma management?
- That patient has optimal device and technique
- Clear asthma management plan- what to do when well and when not well
- Adherence to inhaled corticosteroids
How do we measure adherence objectively?
Electronic adherence monitoring
Why is it that UK is 3rd highest country in deaths from asthma in 10-24 year olds and 2nd highest for children 10-14?
When feeling well, adults don’t want to take their maintenance therapy and when they get a cold or sudden allergen exposure they have a sudden attack
What happens in acute asthma attacks?
- There’s a lot of exposure to many allergens like house dust, pathogens (virus +/- bacteria), pollution, tobacco smoke
- These all come together to do an asthma attack
- If there’s an infection predominantly, asthma patients have reduced IFN so viral replication increases resulting in prolonged illness
- Reduced peak expiratory flow rate and increased airway obstruction resulting in acute wheeze, responsive to bronchodilators
- Increased airway eosinophilic inflammation, responsive to corticosteroids
How do we treat acute asthma attacks?
- With systemic high dose steroids like prednisolone
- Inhaled steroids in maintenance therapy isn’t good enough
How does anti-IgE antibody therapy work?
- Binds and captures circulating IgE- prevents its interaction with mast cells and basophils to stop allergic cascade
- IgE production can decrease with time when patients given anti-IgE Ab
- Reduction in serum IgE over time means the therapy may not need be used indefinitely
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
Why do we use biologics in asthma?
They reduce exacerbations/asthma attacks which are what cause death
What is Omalizumab?
- The commonly used anti-IgE antibody given as subcutaneous injections
- Is very expensive
- Is effective at reducing exacerbations compared to placebo
When is Omalizumab used?
Severe, persistent allergies (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
What serum IgE level is Omalizumab prescribed for and what are the approx costs?
Total serum IgE between 30-1500
Min 75mg 4 weekly = £1,665 /patient/year
Max 600mg 2 weekly = £26,640 /patient/year
What is Mepolizumab?
- Anti-IL5-antibody for severe eosinophilic asthma
- Reduces IL-5 effect, reducing eosinophilic inflammation in severe eosinophilic asthma
- Licensed for adults and children ≥6
When is Mepolizumab trialled?
Blood eosinophils ≥300 cells/mcl in the last 12 months
At least 4 exacerbations requiring oral steroids in the last 12 months
For 12 months- 50% reduction in attacks, then continue
Describe the pathway of treatment for adult asthma
Describe the pathway of treatment for paediatric asthma
What are approaches to improve adherence in asthma management?
SMART
Single inhaler Maintenance And Reliever Therapy
What is SMART?
- Uses a single combination inhaler to deliver an ICS and a quick-acting LABA to patients
- Although a fixed maintenance dose may be required, SMART can also be used for as needed, symptom-driven delivery of ICS
- Use of SMART improves some asthma outcomes while potentially reducing the total delivered dose of ICS
