🫀🫁Cardio & Resp🫀🫁 - Asthma & Respiratory Immunology

Question 1

Outline the epidemiology of asthma in the UK

Answer 1

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

Question 2

What are the cardinal features of presenting asthma?

Answer 2

Wheeze +/- dry cough +/- dyspnoea
Episodes of worsening (+/- persistent symptoms) - precipitated by exertion, viral colds, allergen exposure, “high pollution days”
Atopy/allergen sensitisation
Airway inflammation

Question 3

Which cardinal feature of asthma immediately distinguishes it from COPD?

Answer 3

Reversible airflow obstruction - immediate symptomatic relief upon application of a vasodilator

Question 4

What is the first thing you are looking for if you suspect a diagnosis of asthma?

Answer 4

A recurring wheeze

Question 5

What is the most common form of asthma?

Answer 5

Allergic asthma
85-90% of cases

Question 6

How can you hear a wheeze in asthma?

Answer 6

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

Question 7

What type of airway inflammation is characteristic of asthma?

Answer 7

Type 2 immune reaction - Th2 lymphocytes
Eosinophilia

Question 8

What is the vague pathogenesis of allergic asthma?

Answer 8

Presence of allergen causes airway remodelling (poorly understood, no existing treatments) and inflammation (target of existing treatments)

Question 9

What produces the wheeze in asthma?

Answer 9

Turbulent air flow through constricted airways

Question 10

What is the difference between a wheeze and stridor?

Answer 10

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

Question 11

How do asthmatic airways compare to normal airways?

Answer 11

Narrower and more inflamed, even at baseline

Question 12

What is the predominant inflammatory infiltrate in asthma?

Answer 12

Eosinophilia

Question 13

What practical examination can be used to asses airflow obstruction?

Answer 13

Spirometry test

Question 14

What should be looked at in a spirometry test?

Answer 14

FEV1/FVC ratio (0.8> in children, 0.7> in adults)
SHAPE of curve

Question 15

How do people develop asthma?

Answer 15

Genetic susceptibility
Polygenic - so is unpredictable, but cannot arise without genetic susceptibility

Question 16

Why is immunotherapy not a viable treatment for asthma?

Answer 16

Too much variety between cases - patients are sensitised to different and often multiple allergens

Question 17

Outline the immunological cascade that occurs in allergic asthma

Answer 17

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

Question 18

What are the interleukins produced by Th2 responsible for?

Answer 18

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

Question 19

What is the result of eosinophilia, in the context of allergic asthma?

Answer 19

Release of histamines, cytokines, chemokines, enzymes, growth factors…
Leads to inflammation, bronchoconstriction, airway remodelling etc…

Question 20

How can allergic sensitization be tested?

Answer 20

Skin prick tests

Question 21

How can eosinophilia be tested?

Answer 21

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

Question 22

What exhaled substance can be used as a biomarker of airway (type-2) inflammation?

Answer 22

Fraction of exhaled Nitric Oxide (FeNO)
Indirect marker of T2-high eosinophilic airway inflammation in asthma

Question 23

Why is nitric oxide useful for measuring inflammation?

Answer 23

Nitric oxide is release by epithelial cells with allergen exposure

Question 24

Briefly outline the asthma diagnosis guideline

Answer 24

Question 25

What is the criteria for diagnosis of asthma in children?

Answer 25

Symptoms suggestive of asthma
AND
FeNO >35 and positive peak flow variability
OR
Obstructive spirometry and positive bronchodilator reversibility

Question 26

What are the 3 ways of treating asthma?

Answer 26

Reduce airway eosinophilic inflammation
Acute symptomatic relief
Severe asthma – steroid sparing therapies

Question 27

What is the main aim of current treatments of asthma?

Answer 27

Reduce airway eosinophilic inflammation

Question 28

What is the current treatment for patients with asthma?

Answer 28

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

Question 29

Currently, what is the biggest problem facing treatment for asthma?

Answer 29

Patients not reliably taking their inhaled corticosteroids

Question 30

Why do patients sometimes not take their inhaled corticosteroids?

Answer 30

Doesn’t provide immediate symptomatic relief - benefits not immediately felt
Therefore don’t always see the point of taking it every day

Question 31

What issue arises from patients not taking their baseline inhaled corticosteroids?

Answer 31

Eosinophilia build up over time, leads to more primed airway to allergen and more severe episodes

Question 32

What are the actions of corticosteroids?

Answer 32

Help with nearly every aspect
Main and most potent action is reduced numbers of eosinophils

Question 33

What is the first step for a patient who present with asthma?

Answer 33

Immediately prescribe inhaled corticosteroids - regardless of severity

Question 34

What are the most important aspects of asthma managements?

Answer 34

Optimal device and technique
Clear asthma management plan - every patient needs their own individual plan
Adherence to inhaled corticosteroids

Question 35

How is the problem of patients not taking their inhaled ICS being solved?

Answer 35

Production of a single, combined inhaler
SMART - Single inhaler Maintenance And Reliever Therapy
Same inhaler for maintenance and symptomatic relief during an episode

Question 36

Outline the pathogenesis for an acute asthma attack?

Answer 36

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

Question 37

What is the significance of IgE in allergic asthma?

Answer 37

Fundamental allergic immunoglobulin associated with allergic disease/responses

Question 38

Outline anti-IgE antibody therapy

Answer 38

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

Question 39

What is the main example of anti-IgE antibody therapy?

Answer 39

Omalizumab

Question 40

What are the drawbacks of omalizumab?

Answer 40

Serum IgE must be between 30-1500 IU/ml - 40% of patients ineligible
Of the remaining 60%, only 50-60% respond to treatment

Question 41

What is mepolizumab?

Answer 41

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

Question 42

How efficacious is mepolizumab?

Answer 42

Clinically significant exacerbations in adults reduced by 50%
Lower efficacy in children - only 25%

Question 43

Which groups of patients respond best to mepolizumab?

Answer 43

Patients with elevated blood eosinophils
Higher number of previous exacerbations
Higher dose of inhaled steroids
i.e. more severe asthma

Question 44

What are the current UK recommendations for criteria to use mepolizumab?

Answer 44

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

Question 45

Why are asthma medications referred to as treatments?

Answer 45

NO CURE
Patients will return to baseline immediately upon withdrawal of treatment