Asthma and Respiratory Immunology

Question 1

What are the cardinal features of asthma?

Answer 1

Wheeze +/- Dry cough – on exertion, worse with colds, with allergen exposure
Atopy / allergen sensitisation
Reversible airflow obstruction
Airway inflammation - Eosinophilia, Type 2 has lymphocyte involvement

Question 2

Describe the pathogenesis of asthma

Answer 2

In a patient susceptible to asthma, if they are exposed to allergens and are sensitised, will develop parallel inflammation and remodelling. Remodelling is changes in structural cells of the airway – recruitment of inflammatory cells (eosinophils) + changes in epithelium (more goblet cells, more matrix, amount and size of smooth muscle cells increase)

Question 3

Describe the pathophysiology of asthma

Answer 3

Thickened airway wall where thickening is caused by eosinophilic inflammation and baseline increase in airway smooth muscle.
Narrow airway lumen results in turbulent flow of air causing wheezing sound.

Question 4

Why do only some people who are sensitized develop disease (asthma)?

Answer 4

Genetic susceptibility to allergy and allergic disease plays a role. Secondly, environmental exposures to allergens, infection and pollution also plays a role.

Question 5

Describe role of type 2 immunity in asthma

Answer 5

Inhaled antigen presented to APC in context of MHC class 2 by dendritic cells which carry it to lymph nodes. Th0 cells differentiate into Th2 cells, which secretes IL-4, IL-5 and IL-13. IL-5 recruits eosinophils into airways plus promotes longer survival times which is what results in eosinophilic airway inflammation in asthma. IL-4 causes B-cells to secrete IgE and IL-13 causes mucus secretion.

Question 6

What is the role of IgE in asthma?

Answer 6

IgE binds to mast cells which then release various growth factors, cytokines, chemokines when they degranulate. Histamines, eicosanoids and type 2 mediators are released which result in final manifestation of allergic reaction. Eicosanoids are made from oxidation of arachidonic acid.

Question 7

What test can check for allergic sensitisation?

Answer 7

Skin test can be done where allergen introduced to skin. Histamine used as positive control, saline used as negative control. Level of reaction measured against other antigens - if allergic, wheal and flare reaction observed.

Question 8

What are 3 tests for eosinophilia?

Answer 8

1. Blood eosinophil count when patient is stable: >300 cells /mcl is abnormal
2. Induced sputum eosinophil count: >2.5% eosinophils is abnormal
3. Exhaled nitric oxide can be used to check for eosinophil levels

Question 9

What is FeNO?

Answer 9

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.

Question 10

How can FeNO reflect adherence?

Answer 10

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

Question 11

Can a single non-invasive biomarker reflect airway eosinophilic inflammation?

Answer 11

Multiple used to confirm diagnosis such as serum IgE and blood eosinophil levels.

Question 12

What is the NICE asthma diagnosis clinical guidelines?

Answer 12

Clinical assessment involves history & examination. Assess / confirm wheeze when 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)

Question 13

When is asthma diagnosed in young people?

Answer 13

Diagnose asthma in children and young people (aged 5to16) if they have symptoms suggestive of asthma and:

FeNO level of 35ppb or more and positive peak flow variabilityor

obstructive spirometry and positive bronchodilator reversibility.

Question 14

How is asthma managed?

Answer 14

1. Reduce airway eosinophilic inflammation - Inhaled corticosteroids (ICS) and Leukotriene receptor antagonists
2. Acute symptomatic relief
   Beta-2 agonists (smooth muscle relaxation)
   Anticholinergic therapies (smooth muscle relaxation)
3. Severe asthma – steroid sparing therapies
   Biologic targeted to IgE: Anti-IgE antibody
   Biologics targeted to airway eosinophils:
   Anti-interleukin-5 antibody
   Anti-interleukin-5 receptor antibody

Question 15

Why are anti-inflammatories important?

Answer 15

Acute relief bronchodilators in absence of background reduction of inflammation can result in asthma death as these should not be used regularly. Hence, some anti-inflammatories must be prescribed to prevent flare-ups.

Question 16

How do corticosteroids have an effect on inflammatory cells?

Answer 16

1. Reduce T-lymphocyte numbers hence reducing cytokine numbers, eosinophil numbers by apoptosis and mast cell numbers.
2. Reduce cytokines released from activated macrophages
3. Reduce dendritic cell numbers

Question 17

How do corticosteroids have an effect on structural cells?

Answer 17

1. Reduce cytokines and mediators produced by epithelial cells
2. Reduce leakiness of endothelial cells
3. Increase b2 receptors and reduce cytokines produced by airway smooth muscle
4. Reduce mucus secretion by mucus glands

Question 18

What are 3 important aspects of asthma management?

Answer 18

1. Optimal device and technique
2. Clear asthma management plan
3. Adherence to inhaled corticosteroids

Question 19

Describe pathogenesis of acute lung attack in school age children

Answer 19

Multiple factors can come together resulting in an asthma attack (pathogen, allergens, pollution, tobacco smoke). If infection is predominant precipitant:

1. Antiviral response is reduced causing more severe illness as there is reduced IFN-alpha, beta gamma so increased viral replication results in prolonged illness. 2. Reduced peak expiratory flow rate observed and increased airway obstruction resulting in acute wheeze, responsive to bronchodilators. May not be reversible if very serious.
2. Increased airway eosinophilic inflammation, responsive to corticosteroids.

Question 20

What is anti-IgE antibody therapy?

Answer 20

Humanised anti-IgE monoclonal antibody administered.

Binds and captures circulating IgE to prevent interaction with mast cells and basophils to stop allergic cascade

Question 21

Why is anti-IgE antibody therapy potentially effective?

Answer 21

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 22

Who is omalizumab prescribed to?

Answer 22

Prescribed in case of severe, persistent allergic (IgE mediated) asthma in patients >6 years who need continuous or frequent treatment with oral corticosteroids. Have already completed 4 or more courses in last year.

Question 23

What is mepolizumab?

Answer 23

Anti-IL5 antibody for severe eosinophilic asthma. IL-5 regulates growth, recruitment, activation and eosinophil survival. Licenced for adults and children >6 years.

Question 24

What are current UK recommendations for mepolizumab?

Answer 24

Prescribed in case of severe eosinophilic asthma. If:

1. Blood eosinophils >300 cells/mcl in the last 12 months
2. At least 4 exacerbations requiring oral steroids in the last 12 months
3. Trial for 12 months – 50% reduction in attacks, then continue