Asthma and respiratory immunology

Question 1

What are the cardinal features of asthma?

Answer 1

Wheeze +/- Dry cough +/- Dyspnoea
Persistent symptoms + episodes (attacks) – precipitated by exertion, colds, allergen exposure
Atopy / allergen sensitisation
Reversible airflow obstruction
Airway inflammation
Eosinophilia
Type 2 - lymphocytes

Question 2

How is reversible air flow obstruction shown on a graph?

Answer 2

Above the x axis, it is closer to the y axis

Below the axis is inspiration and this is not affected

Only expiratory part of flow volume loop is affected

Question 3

How is an asthmatic airway wall different to a healthy airway wall?

Answer 3

There is inflammation (eosinophilia) and airway remodelling - the number of smooth muscle cells and bronchial epithelium increase

Question 4

What genes are commonly associated with asthma?

Answer 4

IL33 , GSDMB

Question 5

What is type 2 immunity in asthma?

Answer 5

The antigen, e.g. pollen/allergen, goes through epithelium and is detected by the Antigen presenting cell (specifically dendritic cells in lungs)
Takes the antigen to cd4 cells in the local mediastinal lymph node for the lung, where naive t cells will be preferentially differentiating to th2 cells
TH2 cells is what determines type 2 immunity as they secrete th2 type 2 cytokines - IL4 (tells plasma cells to secrete IGE and this exacerbates the allergen cycle) , IL5 (central to allergic asthma, which attracts eosinophils from the bone marrow into the blood and into the airways), IL13 (this will be produced the next time the allergen is recognised, also produces mucous)

Question 6

What tests do you do for asthma?

Answer 6

Tests for allergic sensitisation - skin prick test and blood test (for specific IgE antibodies to allergens of interest; Total IgE alone not sufficient to define atopy)
for specific IgE antibodies to allergens of interest

Tests for Eosinophilia - Blood eosinophil count when stable: >300 cells/mcl is abnormal (in a patient with suspected/confirmed asthma)
Induced sputum eosinophil count: >3% eosinophils is abnormal
Exhaled nitric oxide

Question 7

How does Fraction of exhaled nitric oxide (FeNO) lead to a diagnosis?

Answer 7

Fractional concentration of exhaled nitric oxide (FeNO) is a quantitative, non-invasive and safe method of measuring airway inflammation and is an indirect marker of T2-high eosinophilic airway inflammation in asthma

FeNO has a role in aiding asthma diagnosis, predicting steroid responsiveness and assessing adherence to inhaled corticosteroids

Question 8

What do the NICE 2017 guidelines say is required to diagnose asthma?

Answer 8

Clinical assessment
—–History & examination
—–Assess / confirm wheeze when acutely unwell (doctor diagnosed wheeze)
Objective tests
——Airway obstruction on spirometry - FEV1/FVC ratio <0.7 (adults), <0.8 (children)
——-Reversible airway obstruction - Bronchodilator reversibility >12%
——-Exhaled nitric oxide (FeNO) >35ppb (children), >40ppb (adults) – in a treatment naïve patient

Question 9

How do you manage asthma?

Answer 9

Reduce airway eosinophilic inflammation
—Inhaled corticosteroids (ICS)
—Leukotriene receptor antagonists

Question 10

How do you get acute symptomatic relief from asthma?

Answer 10

Beta-2 agonists (smooth muscle relaxation)
Anticholinergic therapies (smooth muscle relaxation)

Question 11

How do you treat severe asthma – steroid sparing therapies

Answer 11

Biologic targeted to IgE
—-Anti-IgE antibody
Biologics targeted to airway eosinophils
—–Anti-interleukin-5 antibody
—–Anti-interleukin-5 receptor antibody

Question 12

Why do we use corticosteroids

Answer 12

Dampen airway eosinophilia
Steroids stop and reduce the recruitment of eosinophils from the bone marrow to the blood to the airways
If they get into the airways, the steroids will induce apoptosis of the eosinophils - therefore reduced recruitment and survival

Question 13

Why do we specifically use inhaled corticosteroids?

Answer 13

As they go directly to the tissue and therefore avoid the systemic side effects to the rest of the body (such as dampening adrenal function)

Question 14

What is the most important aspect of asthma management

Answer 14

Optimal device and technique
Clear asthma management plan
Adherence to inhaled corticosteroids

Question 15

How do you decide treatment does for asthma?

Answer 15

Start with regular dose and then keep increasing if it is not effective
If you go beyond the high dose treatment, you need specialist treatment

Question 16

Describe the pathogenesis of an acute lung attack

Answer 16

Allergens + virus + pollution + tobacco

IFN -a, b, l. Reduced anti-viral responses and increased viral replication result in a prolonged illness

Reduced peak expiratory flow rate and increased airway obstruction resulting in acute wheeze, responsive to bronchodilators

Increased airway eosinophilic inflammation, responsive to corticosteroids

Question 17

How does Anti-IgE antibody therapy work?

Answer 17

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

Question 18

When should Omalizumab be given?

Answer 18

Severe, persistent allergic (IgE mediated) asthma in patients >6 years who need continuous or frequent treatment with oral corticosteroids
4 or more courses in the previous year

Optimised standard therapy

Documented compliance

ALSO
Total serum IgE between 30-1500 IU/ml

Dosing based on weight and serum IgE 2-4 weekly s/c injections

Question 19

How does Mepolizumab work?

Answer 19

Anti-IL5 antibody for severe eosinophilic asthma

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

Licenced for adults and children >6 years

Question 20

What are the current UK recommendations for mepolizumab

Answer 20

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