Asthma and Respiratory Immunology Flashcards
How many people are currently receiving treatment for asthma?
5.4 million people in the UK
How many children are affected by asthma?
1.1 million children affected (approx. 3 in every class)
How many people die of an asthma attack every day in UK?
On average, 3 people die of an asthma attack every day in the UK
How much does the NHS spend on asthma?
NHS spends approx. £1billion annually treating asthma
What are the cardinal features of asthma?
- Wheeze +/- Dry cough – on exertion, worse with colds, with allergen exposure: most important
- Atopy / allergen sensitisation
- Reversible airflow obstruction
- Airway inflammation
What causes airway inflammation?
- Eosinophilia
* Type 2 - lymphocytes
Why do only some people who are sensitized develop disease (asthma)? What are these manifestations of asthma?
- genetic susceptibility and environmental exposures:
1. Allergy
2. Reversible airflow obstruction
3. Inflammation
What can genetic susceptibility lead to?
- Allergy
- Allergic disease
- Need genetic susceptibility for asthma not guaranteed with just an allergy
What are some environmental exposures?
- Allergen
- Infection that causes colds
- Pollution
What is the test for allergic sensitisation?
- Blood tests – for specific IgE antibodies to allergens of interest
- Total IgE alone not sufficient to define atopy - need specific IgE
What are the tests for eosinophilia?
- Blood eosinophil count when stable: >300 cells /mcl is abnormal during stable disease
- Induced sputum eosinophil count: >2.5% eosinophils is abnormal
- Exhaled nitric oxide
How is fractional concentration of exhaled nitric oxide (FeNO) used?
- quantitative
- non-invasive
- safe
- method of measuring airway inflammation
- an indirect marker of T2-high eosinophilic airway inflammation in asthma
- So high NO then supportive of asthma provided not on treatment with steroids
How else is FeNO used?
- aiding asthma diagnosis
- predicting steroid responsiveness and assessing adherence to inhaled corticosteroids
- So if started treatment but NO still sky high suggests not taking as NO very sensitive to steroids
What parts of clinical assessment is needed for asthma diagnosis?
- History & examination
2. Assess / confirm wheeze when acutely unwell
What are the objective tests for asthma diagnosis?
- Airway obstruction on spirometry - FEV1/FVC ration <0.7
- Reversible airway obstruction - Bronchodilator reversibility >12%
- Exhaled nitric oxide (FeNO) >35ppb (children), >40ppb (adults) - not on any treatment
What other condition other than symptoms suggestive of asthma to diagnose asthma in children and young people (aged 5to16)?
- FeNO level of 35ppb or more and positive peak flow variabilityor
- Obstructive spirometry and positive bronchodilator reversibility
- need two tests!
How do you reduce airway eosinophilic inflammation in the management of asthma?
- Inhaled corticosteroids (ICS)
2. Leukotriene receptor antagonists - reduce T2 inflammation
How do you manage acute symptomatic relief in management of asthma?
- Beta-2 agonists (smooth muscle relaxation)
2. Anticholinergic therapies (smooth muscle relaxation)
How do you manage severe asthma (steroid sparring therapies) in the management of asthma?
- Biologic targeted to IgE
- Anti-IgE antibody - Biologics targeted to airway eosinophils
- Anti-interleukin-5 antibody
- Anti-interleukin-5 receptor antibody
Which structural cells do corticosteroids affect?
- Epithelial cell
- Endothelial cell
- Airway smooth muscle
- Mucus gland
Which inflammatory cells do corticosteroids affect?
- Eosinophil
- T-lymphocyte
- Mast-cell
- Macrophage
- Dendritic cell
What is the airway like in asthmatics?
- Laminar flow in normal person and with asthmatic even when well but not on treatment airway looks abnormal
- thickened airway wall (caused by inflammation) and baseline increase in airway smooth muscle, but if treated should look all normal
Why do asthmatic wheeze?
due to narrowed airway lumen resulting in turbulent flow through airways
What lung function test is carried out to see reversible airway obstruction?
Spirometry lung function test
What is the pathogenesis of asthma?
If exposed to allergens and sensitised then will develop inflammation and airway remodelling
What is examples of airway remodelling in pathogenesis of asthma?
- recruitment of inflammatory cells into airway (predominantly eosinophils)
- structural changes include changes in epithelium
- increased goblet cells
- amount of matrix increases
- amount and size of smooth muscle increase
How do we know about genetic susceptibility for asthma?
- GWAS studies e.g. iL-33 gene increased in asthma and GSDMB
- Manhattan plot looks at chromosome where gene is and p value tells how likely it is that gene increased normally and then look at disease
- Log P value so has to be very high P value to be significant
Is asthma a single gene disorder?
No - multigene and polyfactorial (so gene therapy can’t really be used, but looking for genes for novel therpaies)
How does asthma manifest?
- In asthma exposed to inhaled allergen (antigen) which is presented to antigen presenting cells (APC) (dendritic cells for lungs)
- Which carry the antigen via MHC class II to lymph nodes in mediastinum where naive T helper cells (Th0) differentiate into Th2 cells
What does the Th2 cells secrete?
Il-4, Il-5 and Il-13
What does Il-4 do?
helps conversion of plasma cells (B cells0 to secrete Ig-E
What does Il-5 do?
recruits eosnphil into airway and promotes eosinophil survival
What does Il-13 do?
mucus secretion
What happens when you are exposed to the same allergen again?
build an allergic immune response which means that allergen is recognised by IgE
What does the IgE do?
binds to mast cells which release various growth factors, cytokines, chemokine when they degranulate which results in allergic reaction e.g. histamines and type 2 mediators are released so final allergic reaction
What is a skin prick test for allergies?
- Intradermal injection of positive control (histamine) which we all react to compared
- to saline which is a negative control
- compare that to allergens e.g. pollen, grass
What will the skin prick show if the patient is sensitised?
develop and wheel and flare reaction (like stinging nettle reaction) and measure size of wheel to determine other they are sensitised to that allergen
How do corticosteroids affect eosinophils?
Decrease numbers by apoptosis
How do corticosteroids affect T-lymphocytes?
Decrease cytokines
How do corticosteroids affect mast cells?
Decreased numbers
How do corticosteroids affect macrophages?
Decrease cytokines
How do corticosteroids affect dendritic cells?
Decrease numbers
How do corticosteroids affect epithelial cells?
Decrease cytokines + mediators
How do corticosteroids affect endothelial cells?
Decrease leak
How do corticosteroids affect airway smooth muscle?
Increase Beta 2 receptors
Decrease cytokines
How do corticosteroids affect mucus glands?
Decrease mucus secretion
What is the main aim of using corticosteroids?
Target T2 inflammation and reduce that
What is the most important aspect of asthma management?
- Optimal device and technique
- Clear asthma management plan
- Adherence to inhaled corticosteroids
