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Y2 - BRS - CVR > Asthma and Respiratory Immunology > Flashcards

Asthma and Respiratory Immunology Flashcards

1
Q

What is the epidemiology of asthma in the UK?

A

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

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2
Q

What are the clinical features of asthma?

A

Wheeze +/- dry cough = worse on exertion, respiratory infections (colds), allergen exposure etc.

Allergen sensitisation / atopy

Reversible airflow obstruction

Airway inflammation - eosinophilia, type 2 lymphocytes

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3
Q

Which of the 3 clinical features can be tested for to confirm a diagnosis of asthma?

A

Allergen sensitisation / atopy

Reversible airflow obstruction

Airway inflammation - eosinophilia, type 2 lymphocytes

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4
Q

What is the pathophysiology of asthma?

A

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

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5
Q

What causes the thickened airway wall in a well, but untreated asthmatic patient?

A

Caused by eosinophilic inflammation and baseline increase in airway smooth muscle

This thickening is reversed in patients receiving treatment

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6
Q

Why do asthmatics develop a wheeze?

A

Due to narrowed airway = turbulent airflow

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7
Q

How can reversible airflow obstruction be tested for?

A

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)

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8
Q

How can airway wall inflammation be tested for?

A

e.g. airway wall biopsy = shows eosinophilia

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9
Q

What happens in allergic asthma? (pathogenesis)

A

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

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10
Q

Why do only some of the people who have the allergy, develop the disease (asthma)?

A

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

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11
Q

What are the features of asthma?

A

Allergy
Reversible airflow obstruction
Wheeze
Inflammation

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12
Q

Why is gene therapy not a solution for asthma?

A

Due to polygenic and polyfactorial characterists of asthma

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13
Q

Why is type 2 immunity important in allergic asthma?

What is the immune response in allergic asthma when first encountering the allergen?

A

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

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14
Q

What is the immune response after the intial encounter with the allergen (i.e. person is now sensitised to this allergen)?

A

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

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15
Q

What are the tests for allergic sensitisation?

A
  1. 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
  2. Blood tests - look for specific IgE antibodies to allergens of interest
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16
Q

What are the tests for eosinophilia?

A
  1. Blood tests - during stable disease, elevated blood eosinophil count = supportive of asthma
  2. Induced sputum eosinophil coint: >2.5% eosinophils is abnormal
  3. Exhaled nitric oxide - reccommended to be used as a diagnostic test
17
Q

What is the exhaled nitric oxide test?

What is it used for?

A

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)

18
Q

What biomarkers are required to make a certain asthma diagnosis?

A

Symptoms
Lung function tests
Blood tests - increased eosinophil count

19
Q

What do the NICE guidelines suggest to making an asthma diagnosis?

A

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

20
Q

How is asthma managed in 3 steps?

A
  1. All patients on anti-eosinophilic treatment - to reduce airway eosinophiilic inflammation:
    - inhaled corticosteroids (ICS)
    - leukotrine receptor antagonists
  2. Acute symptomatic relief treatment - for sudden symptom onset:
    - beta-2-agonists (smooth muscle relaxation)
    - antichocholinergic therapies (smooth muscle relaxation)
  3. 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)
21
Q

Why are acute symptom relief bronchodialators not used often / on their own?

A

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)

22
Q

What is the aim of the baseline anti-eosinophilic treatment for asthma?

A

Reduce airway inflammation, tightening and mucus

23
Q

How do inhaled corticosteroids (ICS) achieve reduced airway inflammation?

A

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

24
Q

Why might there be low compliance by the patient to take their inhalers daily?

A

Most days they feel fine - feel it is pointless to take their inhaler daily

Do not understand it is baseline preventative treatment

25
Q

What is most important for the maximum efficacy of asthma management?

A

Optimal device and technique

Clear asthma management plan

Adherance to ICS

26
Q

How can adherence be measured clinically?

A

Objective measurement via electronic monitoring device attached to ICS inhaler

27
Q

Should patients with only mild asthma be prescribed anything?

A

YES - must be precribed a regular preventer no matter how mild

28
Q

Why does the UK have the 3rd highest death rate from asthma between 10-24 year olds?

A

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

29
Q

What occurs during an acute lung attack?

A

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)

30
Q

Why are steroid-sparing treatments required in patients with severe asthma?

A

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

31
Q

How do anti-IgE antibodies work?

A

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

32
Q

Name an anti-IgE antibody medication?

A

Omalizumab

33
Q

What is the criteria to prescribing Omalizumab?

How much does Omalizumb cost yearly?

A

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

34
Q

Name an anti-IL5 antibody medication:

When and why is it prescribed?

A

Mepolizumab

Suitable for severe eosinophilic asthma

IL-5 regulates growth, recruitment, activation and eosinophil survival

Licenced for adults and children >6 years

35
Q

What are the current reccomendations / guidelines for prescribing Mepolizumab?

A

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

Y2 - BRS - CVR (21 decks)

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