5.5 - Asthma and respiratory immunology Flashcards
What are some epidemiology facts about asthma?
- 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
What are the cardinal features of asthma? (5)
- wheeze +/- dry cough +/- dyspnoea
- persistent symptoms + episodes (attacks) - precipitated by exertion, colds, allergen exposure
- atopy / allergen sensitisation
- reversible airflow obstruction
- airway inflammation
What atopic triad is seen in asthma?
HAEfever - Hayfever, Asthma, Eczema
Why do asthma patients have a wheeze?
Narrowed airway lumen in asthmatic patients causes turbulent flow –> wheezing noise
What does atopy / allergen sensitisation cause?
Narrowing of airway - seen with local allergen challenge where you introduce an allergen down bronchoscope, red inflamed erythematous
What is the airway like in normal vs asthma patients?
- 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
How do we look for reversible airflow obstruction in asthma?
- 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)
What is the FEV1/FVC ratio for airflow obstruction in adults and children?
- <0.7 - adults
- <0.8 - children
What immune cells are involved in airway inflammation?
- eosinophilia
- type 2 lymphocytes (Th2 lymphocytes - CD4+ cells)
Describe the pathogenesis of allergic asthma.
- 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
Why are only some people who are sensitised develop asthma?
- due to genetic susceptibility of asthma - polygenic and environmental
- some people may have allergies but not asthma
What do GWAS for asthma susceptibility show about the genetic cause of asthma?
Multigene disorder and polyfactorial - some people with asthma may have increased levels of GSDMB, but not IL33 and vice versa
How does type 2 immunity in asthma work?
- 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
What does IL-4 do?
Helps conversion B plasma cells secrete IgE
What does IL-5 do?
Recruits eosinophils into airways and promotes their survival causing eosinophilia
What does IL-13 do?
Involved in mucus secretion
Once sensitised to allergen, what happens if re-exposed?
- 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? (2)
- 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
How do we test for eosinophilia?
- blood eosinophil count when stable: >300cells/mcl is abnormal (present in asthma)
- induced sputum eosinophil count: >3% eosinophils is abnormal
- exhaled nitric oxide
What is fraction of exhaled nitric oxide (FeNO) - eosinophilia test?
- 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
Are nitric oxide levels high or low in asthma?
During airway inflammation, activated epithelial cells increase production of NO
What is involved in the clinical assessment to diagnose asthma? (2)
- history and examination
- assess/confirm wheeze when acutely unwell (doctor diagnosed wheeze)
What objective tests are done to diagnose asthma? (3)
- 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
How do we confirm asthma diagnosis in children and young people (aged 5-16)?
- 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
What are the three areas of asthma management?
- reduce airway eosinophilic inflammation
- acute symptomatic relief
- severe asthma - steroid sparing therapies
How do we reduce airway eosinophilic inflammation? (3)
- inhaled corticosteroids (ICS)
- leukotriene receptor antagonists
- (maintenance therapy all asthma patients should be on - regular preventer)
How do we provide acute symptomatic relief of asthma? (2)
- beta-2 agonists (smooth muscle relaxation)
- anticholinergic therapies (smooth muscle relaxation)
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
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
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
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
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
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
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
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
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
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?
They reduce exacerbations/asthma attacks which cause death
What is Omalizumab?
Commonly used anti-IgE antibody given as subcutaneous injections, effective at reducing exacerbations compared to placebo
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
What serum IgE level is Omalizumab prescribed for?
Total serum IgE between 30-1500 iU/ml
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
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
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
What is dupilumab?
- anti-IL4Ralpha antibody
- IL4 receptor alpha is a shared receptor for IL4 and IL13
- fewer asthma attacks AND improved lung function
