🫀🫁Cardio & Resp🫀🫁 - Asthma & Respiratory Immunology Flashcards
Outline the epidemiology of asthma in the UK
5.4 million people in the UK receiving treatment for asthma
1.1 million children
3 people die of an asthma attack every day in the UK
£1billion annual cost to the NHS
What are the cardinal features of presenting asthma?
Wheeze +/- dry cough +/- dyspnoea
Episodes of worsening (+/- persistent symptoms) - precipitated by exertion, viral colds, allergen exposure, “high pollution days”
Atopy/allergen sensitisation
Airway inflammation
Which cardinal feature of asthma immediately distinguishes it from COPD?
Reversible airflow obstruction - immediate symptomatic relief upon application of a vasodilator
What is the first thing you are looking for if you suspect a diagnosis of asthma?
A recurring wheeze
What is the most common form of asthma?
Allergic asthma
85-90% of cases
How can you hear a wheeze in asthma?
Not always immediately apparent
May only be immediately noticeable in severe cases/during an episode
Baseline may only be detectable with a stethoscope - sometimes not even then
What type of airway inflammation is characteristic of asthma?
Type 2 immune reaction - Th2 lymphocytes
Eosinophilia
What is the vague pathogenesis of allergic asthma?
Presence of allergen causes airway remodelling (poorly understood, no existing treatments) and inflammation (target of existing treatments)
What produces the wheeze in asthma?
Turbulent air flow through constricted airways
What is the difference between a wheeze and stridor?
Turbulent airflow from narrowing in lower airways = wheeze
Turbulent airflow from narrowing in upper airways (i.e. an upper airway obstruction above the carina) = stridor
How do asthmatic airways compare to normal airways?
Narrower and more inflamed, even at baseline
What is the predominant inflammatory infiltrate in asthma?
Eosinophilia
What practical examination can be used to asses airflow obstruction?
Spirometry test
What should be looked at in a spirometry test?
FEV1/FVC ratio (0.8> in children, 0.7> in adults)
SHAPE of curve
How do people develop asthma?
Genetic susceptibility
Polygenic - so is unpredictable, but cannot arise without genetic susceptibility
Why is immunotherapy not a viable treatment for asthma?
Too much variety between cases - patients are sensitised to different and often multiple allergens
Outline the immunological cascade that occurs in allergic asthma
APCs (dendritic cells in this case) present antigen to Th0 cells
Th0 cells differentiate into Th2 cells (type 2 immunity), with produce lots of IL-4,-5 and -13
Leads to eosinophilia, IgE synthesis and mucus secretion
What are the interleukins produced by Th2 responsible for?
IL-13 stimulates mucin secretion
IL-4 stimulates B cells to produce IgE - allergen sensitisation of mast cells and basophils, stimulation of mast cells upon re-exposure
IL-5 - most significant IL - stimulate eosinophilia
What is the result of eosinophilia, in the context of allergic asthma?
Release of histamines, cytokines, chemokines, enzymes, growth factors…
Leads to inflammation, bronchoconstriction, airway remodelling etc…
How can allergic sensitization be tested?
Skin prick tests
How can eosinophilia be tested?
Blood eosinophil count easiest - >300 cells/mcl is abnormal (in a patient with suspected/confirmed asthma)
Induced sputum eosinophil count: >3% eosinophils is abnormal - can be difficult to obtain
Combine blood eosinophil count with spirometry and skin prick test to come to a diagnosis
What exhaled substance can be used as a biomarker of airway (type-2) inflammation?
Fraction of exhaled Nitric Oxide (FeNO)
Indirect marker of T2-high eosinophilic airway inflammation in asthma
Why is nitric oxide useful for measuring inflammation?
Nitric oxide is release by epithelial cells with allergen exposure
Briefly outline the asthma diagnosis guideline
What is the criteria for diagnosis of asthma in children?
Symptoms suggestive of asthma
AND
FeNO >35 and positive peak flow variability
OR
Obstructive spirometry and positive bronchodilator reversibility
What are the 3 ways of treating asthma?
Reduce airway eosinophilic inflammation
Acute symptomatic relief
Severe asthma – steroid sparing therapies
What is the main aim of current treatments of asthma?
Reduce airway eosinophilic inflammation
What is the current treatment for patients with asthma?
2 inhalers
Inhaled corticosteroids (extremely effective at reducing eosinophilic inflammation) - baseline treatment taken twice a day
“Blue inhaler” - acute symptomatic relief - Beta-2 agonists (smooth muscle relaxation)
Anticholinergic therapies (smooth muscle relaxation)
Fast acting bronchodilator
Currently, what is the biggest problem facing treatment for asthma?
Patients not reliably taking their inhaled corticosteroids
Why do patients sometimes not take their inhaled corticosteroids?
Doesn’t provide immediate symptomatic relief - benefits not immediately felt
Therefore don’t always see the point of taking it every day
What issue arises from patients not taking their baseline inhaled corticosteroids?
Eosinophilia build up over time, leads to more primed airway to allergen and more severe episodes
What are the actions of corticosteroids?
Help with nearly every aspect
Main and most potent action is reduced numbers of eosinophils
What is the first step for a patient who present with asthma?
Immediately prescribe inhaled corticosteroids - regardless of severity
What are the most important aspects of asthma managements?
Optimal device and technique
Clear asthma management plan - every patient needs their own individual plan
Adherence to inhaled corticosteroids
How is the problem of patients not taking their inhaled ICS being solved?
Production of a single, combined inhaler
SMART - Single inhaler Maintenance And Reliever Therapy
Same inhaler for maintenance and symptomatic relief during an episode
Outline the pathogenesis for an acute asthma attack?
Allergens with a combination of pathogens, pollution, tobacco smoke etc…
Triggers immune response
Previous increase of type 2 immunity causes a reduction in type 1 immunity (incl. anti-viral immunity)
Unable to fight cold, marked reduction in lung function, type 2 then gets even more pronounced, eosinophil population skyrockets
What is the significance of IgE in allergic asthma?
Fundamental allergic immunoglobulin associated with allergic disease/responses
Outline anti-IgE antibody therapy
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
No evidence yet that stopping anti-IgE Ab after some time is a long-term solution
What is the main example of anti-IgE antibody therapy?
Omalizumab
What are the drawbacks of omalizumab?
Serum IgE must be between 30-1500 IU/ml - 40% of patients ineligible
Of the remaining 60%, only 50-60% respond to treatment
What is mepolizumab?
Anti IL-5 antibody - for severe eosinophilic asthma
IL-5 regulates growth, recruitment, activation and survival of eosinophils
Licenced for adults and children >6 years
How efficacious is mepolizumab?
Clinically significant exacerbations in adults reduced by 50%
Lower efficacy in children - only 25%
Which groups of patients respond best to mepolizumab?
Patients with elevated blood eosinophils
Higher number of previous exacerbations
Higher dose of inhaled steroids
i.e. more severe asthma
What are the current UK recommendations for criteria to use 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
Why are asthma medications referred to as treatments?
NO CURE
Patients will return to baseline immediately upon withdrawal of treatment
