Asthma and Respiratory Immunology Flashcards
What is the epidemiology of asthma in the UK?
5.4 million of which 1.1 million children
3 people die of asthma every day
NHS spends over a billion pounds each year on asthma treatment
What are the clinical features of asthma?
Wheeze +/- dry cough = worse on exertion, respiratory infections (colds), allergen exposure etc.
Allergen sensitisation / atopy
Reversible airflow obstruction
Airway inflammation - eosinophilia, type 2 lymphocytes
Which of the 3 clinical features can be tested for to confirm a diagnosis of asthma?
Allergen sensitisation / atopy
Reversible airflow obstruction
Airway inflammation - eosinophilia, type 2 lymphocytes
What is the pathophysiology of asthma?
Normal airway - allows for laminal flow
In an asthmatic, even when they are well but not on treatment, their airway looks abnormal at baseline - thickened airway wall
What causes the thickened airway wall in a well, but untreated asthmatic patient?
Caused by eosinophilic inflammation and baseline increase in airway smooth muscle
This thickening is reversed in patients receiving treatment
Why do asthmatics develop a wheeze?
Due to narrowed airway = turbulent airflow
How can reversible airflow obstruction be tested for?
Lung function tests e.g. spirometry
Take a deep breath in, and exhale as hard and quickly as possible
Flow volume graph shows scooped line for expiration (like a mirrored exponential increase)
This is reversed upon treatment, flow volume graph shows straight line (instead of scoop)
How can airway wall inflammation be tested for?
e.g. airway wall biopsy = shows eosinophilia
What happens in allergic asthma? (pathogenesis)
Healthy airway wall = bronchial epithelium sitting on matrix and small amount of smooth muscle
In a patient with allergen sensitisation, exposure to antigen results in inflammation and airway remodelling = changes in structural cells in the airway
Inflammation = inflammatory cells = eosinophils
Structural changes = increased goblet cells (mucus secreting), increased matrix, increased thickness and amount of smooth muscle
Why do only some of the people who have the allergy, develop the disease (asthma)?
Patient with underlying genetic susceptibility to asthma, will develop asthma from environmental exposures e.g. allergen, infection, pollution
Patients without genetic susceptibility may have allergies, but not asthma
Genome wide association studies confirm this - polygenic and polyfactorial
What are the features of asthma?
Allergy
Reversible airflow obstruction
Wheeze
Inflammation
Why is gene therapy not a solution for asthma?
Due to polygenic and polyfactorial characterists of asthma
Why is type 2 immunity important in allergic asthma?
What is the immune response in allergic asthma when first encountering the allergen?
Determines the tests conducted in practice
Patient exposed to allegen (inhaled)
Antigens on allergen presented to antigen presenting cells (APC), i.e. dendritic cells in the lungs, on MHC-II receptors
APC carries antigens to mediastinal lymph nodes where naive T helper cells(Th0) differentiate into T helper 2 (Th2) cells
The Th2 cells produce IL-4, IL-5 and IL-13
IL-5 recruits eosinophils into the airways to promote eosinophil survival = leads to eosinophilic inflammation
IL-4 helps the conversion of B cells to secrete IgE
IL-13 involved in mucus secretion
What is the immune response after the intial encounter with the allergen (i.e. person is now sensitised to this allergen)?
Sensitised allergen = allergen that has already induced an immune response before
Re-exposure to allergen induces an allergic immune response
Allergen is recognised by IgE that has been made and is circulating
IgE binds to mast cells - leads to release of growthfactors, chemokines and cytokines when they degranulate
Leads to allergic reaction - histamines, eicosanoides, and type 2 mediators released
Even more constricted airway
What are the tests for allergic sensitisation?
- Skin-prick test = intradermal injection of positive control (histamine) compared to negative control (saline), compared to allergens
Positive reaction = wheel and flare reaction, size of wheel determines sensitivity - Blood tests - look for specific IgE antibodies to allergens of interest
What are the tests for eosinophilia?
- Blood tests - during stable disease, elevated blood eosinophil count = supportive of asthma
- Induced sputum eosinophil coint: >2.5% eosinophils is abnormal
- Exhaled nitric oxide - reccommended to be used as a diagnostic test
What is the exhaled nitric oxide test?
What is it used for?
Exhaled nitric oxide is a non-invasive biomarker of type 2 inflammation
Fractional concentration of exhaled nitric oxide (FeNO) = quantitative and safe measure of airway inflammation as it is an indirect marker of T2-high eosinophilic airway inflammation
Elevated nitric oxide (provided they are not on treatment with steroids) = very supportive of asthma
Can be used to diagnose asthma and for progress checks (i.e. to check if medications are improving their asthma)
What biomarkers are required to make a certain asthma diagnosis?
Symptoms
Lung function tests
Blood tests - increased eosinophil count
What do the NICE guidelines suggest to making an asthma diagnosis?
Clinical assessment:
History and examination
Assess / confirm wheeze when patient is acutely unwell
Objective tests:
Airway obstruction on spirometry - FEV1/FVC ration <0.7
Reversible airway obstruction - Bronchodilator reversibility >12%
Exhaled nitric oxide (FeNO) >35ppb (children), >40ppb (adults)
Require 2 objective tests to confirm diagnosis
Or do peak expiratory flow test over 2 weeks to demonstrate variability
How is asthma managed in 3 steps?
- All patients on anti-eosinophilic treatment - to reduce airway eosinophiilic inflammation:
- inhaled corticosteroids (ICS)
- leukotrine receptor antagonists - Acute symptomatic relief treatment - for sudden symptom onset:
- beta-2-agonists (smooth muscle relaxation)
- antichocholinergic therapies (smooth muscle relaxation) - Severe asthma (not responding to basic treatments) - steroid sparing therapies
- biologic targeted to IgE (anti-IgE antibody)
- biologics targeted to airway eosinophils (anti-IL5 antibody / anti-IL5 receptor antibody)
Why are acute symptom relief bronchodialators not used often / on their own?
Dangerous to use bronchodialators without an antiinflammatory = can result in asthma death
Therefore all patients must minimise inflammation in the background in the meantime (i.e. that’s why all patients take anti-eosinophilic treatment daily as a baseline)
What is the aim of the baseline anti-eosinophilic treatment for asthma?
Reduce airway inflammation, tightening and mucus
How do inhaled corticosteroids (ICS) achieve reduced airway inflammation?
Reduce eosinophil count by promoting apoptosis
Also reduces type 2 mediators produced by T helper 2 cells (Th2)
Reduce mast cell numbers
Some evidence that the steroids help the structural remodelling
Why might there be low compliance by the patient to take their inhalers daily?
Most days they feel fine - feel it is pointless to take their inhaler daily
Do not understand it is baseline preventative treatment
What is most important for the maximum efficacy of asthma management?
Optimal device and technique
Clear asthma management plan
Adherance to ICS
How can adherence be measured clinically?
Objective measurement via electronic monitoring device attached to ICS inhaler
Should patients with only mild asthma be prescribed anything?
YES - must be precribed a regular preventer no matter how mild
Why does the UK have the 3rd highest death rate from asthma between 10-24 year olds?
Adolescents and young adults do not like to adhere to baseline ICS treatment because they feel ‘fine’
Then they get a cold or exposure to allergen - severe attack can be fatal
What occurs during an acute lung attack?
Coming together of multiple triggers e.g. allergens, pathogens, pollution, tobacco smoke, leading to a severe reaction
Asthmatics have reduced antiviral responses due to decreased interferons, so increased viral replication results in prolonged and more severe illness
Background airway obstruction exacerbated during an attack, increased eosinophilic inflammation (responsive to ICS - e.g. prednisolone)
Leads to reduced peak expiratory flow rate and increased airway obstruction = acute wheeze (responsive to bronchodilators)
Why are steroid-sparing treatments required in patients with severe asthma?
Due to lack of response to baseline steroid treatment despite increased dosage and currect usage in patients with severe asthma
Therefore, biologics e.g. anti-IgE antibody therapy help reduce exacerbations and asthma attacks
Biologics are only most effective on treating attacks, not as much for baseline treatment
How do anti-IgE antibodies work?
Treatment to manage symptoms - not a cure, stopping this treatment means symptoms reappear after a few months
Humanised anti-IgE monoclonal antibody
Binds and captures circulating IgE – to prevent 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 to be used indefinitely
No evidence yet that stopping anti-IgE Ab after some time is a long-term solution
Name an anti-IgE antibody medication?
Omalizumab
What is the criteria to prescribing Omalizumab?
How much does Omalizumb cost yearly?
6yrs +
Must have had frequent allergic asthma attacks
Lack of response to standard treatment despite increased dosages
Documented compliance with optimised standard therapy
Total serum IgE between 30-1500 [two thirds of patients lie outside this range]
Dosing based on weight and serum IgE 2-4 weekly s/c injections
Min 75mg 4 weekly = £1,665 /patient/year
Max 600mg 2 weekly = £26,640 /patient/year
Name an anti-IL5 antibody medication:
When and why is it prescribed?
Mepolizumab
Suitable for severe eosinophilic asthma
IL-5 regulates growth, recruitment, activation and eosinophil survival
Licenced for adults and children >6 years
What are the current reccomendations / guidelines for prescribing Mepolizumab?
Severe eosinophilic asthma
Blood eosinophils >300 cells/mcl in the last 12 months
At least 4 exacerbations requiring oral steroids in the last 12 months
Trial for 12 months – 50% reduction in attacks, then continue
