Asthma and respiratory immunology Flashcards
What are the main features of asthma?
- wheeze +/- dry cough on exertion, worse w/ colds and allergen exposure
- atopy/allergen sensitisation
- reversible airflow obstruction
- airway inflammation: eosinophilia, type 2- lymphocytes
What is an airway of an untreated asthma patient like?
thickened airway wall caused by inflammation (eosinophilic) and an increase in airway smooth muscle–> narrowed airway lumen
What causes wheeze?
turbulent flow of air through narrowed airways
What occurs during airway remodelling in asthma?
- recruitment of inflammatory cells (eosinophils)
- increased goblet cells in epithelium (secrete mucus)
- inc. amount of matrix
- inc. size and amount of smooth muscle
Why do only some people who are sensitised develop asthma?
genetic susceptibility
What genes are linked to asthma?
- IL33
- GSDMB
- RAD50
- CDHR3
- IL1R1
How does the underlying immunology (type 2 immunity) cause the manifestations of asthma?
- exposed to inhaled allergen (antigen)
- presented to APC (dendritic cells in lung)–> carry antigen via MHC class II to mediastinal lymph nodes
- naive Th0 cells differentiate into Th2 cells–> secrete IL-4, IL-13, and IL-5
- IL-5 recruits eosinophils into airways, promoting their survival
- IL-4 promotes B cells to secrete an IgE
- IL-13 involved in mucus secretion
How do we test for allergic sensitisation?
- skin prick test: intradermal injection of +ve control (histamine), -ve control (saline), and allergens –> wheal and flare reaction if sensitised- measure size of wheal
- blood test for specific IgE antibodies for allergens of interest (total IgE alone not sufficient)
How do we test for eosinophilia?
- blood eosinophil count when stable (>300cells/mcl is abnormal)
- look in airway for eosinophils (sputum eosinophil count >2.5%= abnormal)
- exhaled nitric oxide (if elevated= abnormal) - helpful in diagnosis and determining adherence
How do we manage asthma?
- reduce airway eosinophilic inflammation–> inhaled corticosteroids or leukotriene receptor antagonists
^v. important in background the whole time - acute symptomatic relief–> beta-2 agonists (smooth muscle relaxation) or anticholinergic therapies (smooth muscle relaxation)
- severe asthma- steroid sparing therapies–> biologic targeted to IgE (anti-IgE antibody) or targeted to airway eosinophils (anti-IL-5 antibody, anti-IL-5 receptor antibody )
What are the mechanisms of action of corticosteroids?
- promote apoptosis of eosinophils
- reduce type-2 mediators released by Th2 cells
- reduce mast cell numbers
- impact structural cells
What are the most important aspects of asthma management?
- optimal device and technique
- clear asthma management plan
- adherence to inhaled corticosteroids !!!
What occurs during an acute asthma attack?
- background exposure to allergens e.g. house dust
- infection–> reduced antiviral responses (interferons) in asthma
- pollution
- tobacco smoke
^all come together to result in asthma attack
How do we treat an acute asthma attack?
high dose systemic inhaled steroids- prednisolone
Why do we give biologics?
in severe asthma, reduce exacerbations/attacks, which cause mortality
How does anti-IgE antibody therapy work?
- humanised anti-IgE monoclonal antibody
- binds and captures circulating IgE to present its interaction w/ mast cells and basophils to stop allergic cascade
- IgE production can decrease w/ time, but when you stop treatment, symptoms return after a few months
^not disease-modifying, but manages and controls symptoms
What are the criteria for omalizumab?
(anti-IgE antibody)
- severe, persistent IgE-mediated asthma
- > =6years old
- frequent exacerbations
- not responding to optimised standard therapy despite good adherence
- total serum IgE between 30-1500 (a lot of patients not eligible)
What is mepolizumab and the criteria for use?
- anti-IL-5 antibody biologic–> causes apoptosis of eosinophils
- for severe eosinophilic asthma
- > =6year olds
- blood eosinophils >=300cells/mcl in last 12 months
- at least 4 attacks in last 12 months requiring oral steroids
- 12 month trial- continue if 50% reduction in attacks