Cardio - Asthma + Resp Immunology

Question 1

What is the epidemiology of asthma in the UK?

Answer 1

→ 5.4 mil suffer from it
→ 1.1 mil are children
→ 3 per day die of asthma attack

Question 2

What are the cardinal features of asthma?

Answer 2

→ Wheeze
→ Dry cough ( on exertion, worse w colds and allergen exposure)
→ Atopy / Allergen Sensitisation
→ Reversible airflow obstruction
→ Airway inflammation (with eosinophilia or lymphocytic Type2)

Question 3

What are the airways like in someone with asthma?

Answer 3

→ In asthmatic airways:
→ Thickened walls due to eosinophilic inflammation
→ Relaxed smooth muscle

Question 4

What happens to the airways during an asthma attack?

Answer 4

→ Tightened smooth muscle
→ Walls further thickened and inflamed
→ Air trapped in alveoli

Question 5

How is reversible airflow obstruction proven?

Answer 5

→ BDR test (bronchodilator reversibility test)
→ administer bronchodilator and check
→ Change is seen between the flow volume loop before + after

Question 6

What is the pathogenesis of allergic asthma?

Answer 6

→ allergens (e.g. pollen, dust mites, mold) irritate the bronchial epithelium
→ inflammation occurs + airway remodelling starts

Question 7

What does airway remodelling in asthma consist of?

Answer 7

→ higher recruitment of inflammatory cells (especially eosinophils)
→ increase in goblet cells for increased mucus production
→ increase in matrix + amount and size of smooth airway muscle
→ creates a thicker airway wall

Question 8

Why do only some people who are sensitised to allergens develop asthma?

Answer 8

→ genetic susceptibility to allergies and allergic diseases

→ environmental exposures except for allergens (e.g. infection, pollution)

Question 9

What have GWA studies for asthma shown?

Answer 9

→ polygenic causes (ILL33, GSDMB)
→ multi-factorial regardless of genetics
→ gene therapy is not really a cure but can help with novel therapies

Question 10

What are the cascade of reactions in Type 2 immunity is asthma?

Answer 10

→ allergen / antigen triggers dendritic cells int he lungs to become APCs with MHC class II
→ these recruit Th0 cells that differentiate into Th1 and Th2
→ Th2 cells release IL-4, IL-5, IL-13

Question 11

What are the different interleukins responsible for in the Type 2 immune response?

Answer 11

→ IL-4 helps convert plasma cells (B-cells) + encourages production of IgE
→ IL-5 recruits eosinophils + promotes their survival
→ IL-13 involved in mucus secretion

Question 12

How do clinics test for asthma allergy sensitisation?

Answer 12

→ allergy skin tests (wheel + flare)
→ blood tests for specific IgE antibodies to allergens of interest
→ total IgE alone however is not sufficient to define atopy

Question 13

How do asthma clinics test for eosinophilia?

Answer 13

→ blood eosinophil count ( >300 cells/mcl is abnormal)
→ induced sputum eosinophil count ( >2.5% eosinophils is abnormal)
→ exhaled nitric oxide breath test

Question 14

How is exhaled nitric oxide used for diagnosis of asthma?

Answer 14

→ fractional conc. of exhaled FeNO is quantitative + non-invasive
→ measures airway inflammation
→ indirect marker of T2-high eosinophilic airway inflammation in asthma

Question 15

How is exhaled nitric oxide used to test for adherence to medication for asthmatic patients?

Answer 15

conc. of exhaled FeNO should decrease if patient is adhering to steroids (very sensitive to steroids)

Question 16

What are the disadvantages of FeNO?

Answer 16

a single non-invasive biomarker does not reflect airway eosinophilic inflammation

Question 17

What clinical assessments need to be done for asthma according to the NICE guidelines?

Answer 17

→ history + examination

→ assess/ confirm wheeze when acutely unwell

Question 18

What are the order of diagnostic tests that need to be done for asthma according to the NICE guidelines?

Answer 18

→ airway obstruction through spirometry
→ BDR test is spirometry shows obstruction
→ if diagnostics are still uncertain, do FeNO
→ if diagnostics are still uncertain, do peak flow variability

Question 19

How are children tested for asthma if they’re unable to perform objective tests?

Answer 19

→ treat based on observation + clinical judgement

→ try doing tests agains every 6 months

Question 20

What test results are needed for a diagnosis of asthma objectively?

Answer 20

→ airway obstruction on spirometry (FEV1/FVC ratio < 0.7)
→ reversible airway obstruction - (BDR > 12%)
→ exhaled nitric oxide > 35 ppb in children or 40 ppb in adults

Question 21

What test results are needed for a diagnosis of asthma objectively in children and young people (5-16 yrs)?

Answer 21

→ FeNO level of 35 ppb or more + positive peak flow variability OR
→ obstructive spirometry + positive BDR

Question 22

What are the 3 main aspects of asthma management?

Answer 22

→ reduce airway eosinophilic inflammation
→ acute symptomatic relief
→ severe asthma prevention

Question 23

How is airway eosinophilic inflammation reduced?

Answer 23

→ inhaled corticosteroids (ICS)

→ leukotriene receptor agonists

Question 24

How is acute symptomatic relief given to asthmatic patients?

Answer 24

→ beta-2-agonists (smooth muscle relaxation)

→ anticholinergic therapies (smooth muscle relaxation)

Question 25

What are some steroid sparing therapies? (Biological)

Answer 25

→ Anti-IgE antibodies (biological targeting of IgE) | → Anti-IL-5 antibodies or Anti-IL-5 receptor antibodies (biological targeting of airway eosinophils)

Question 26

What is the mechanism of action of corticosteroids on inflammatory cells?

Answer 26

→ reduces no. of eosinophils through apoptosis → reduces T-lymphocyte cytokine production → reduces no. of mast cells → reduces macrophage cytokine production → reduces no. of dendritic cells

Question 27

What is the mechanism of action of corticosteroids on structural cells?

Answer 27

→ reduces no. of cytokines + mediators produced by epithelial cells → reduces leakage from endothelial cells → increases beta-2 receptors but reduces cytokines from airway smooth muscle → reduces mucus secretion from mucus glands

Question 28

What is the most important factor in asthma management?

Answer 28

adherence to inhaled corticosteroids

Question 29

What is the regular starting treatment for asthma?

Answer 29

low dose ICS (inhaled corticosteroid)

Question 30

What is the initial add-on therapy for asthma?

Answer 30

addition of LABA to low-dose ICS (fixed dose or MART)

Question 31

What are additional controller therapies?

Answer 31

→ increasing ICS to medium dose OR → adding LTRA → if no response to LABA, scrap it

Question 32

When are biological therapies offered to asthmatic patients?

Answer 32

→ when they don't respond to baseline steroids | → when they have severe asthma

Question 33

What is the pathogenesis of an acute lung attack?

Answer 33

→ reduced anti-viral responses (due to infection) + increased viral replication = prolonged illness → reduced peak expiratory flow rate + increased airway obstruction resulting in acute wheeze, responsive to bronchodilators → increased airway eosinophilic inflammation, responsive corticosteroids

Question 34

What can trigger an asthma attack?

Answer 34

``` accumulation of: → allergens → pathogens (viral/bacterial) → pollution → tobacco smoke ```

Question 35

What is anti-IgE antibody therapy?

Answer 35

→ humanised anti-IgE MAB → binds + captures circulating IgE → prevents interaction with mast cells + basophils to stop allergic cascade → IgE production decreases over time

Question 36

What is the anti-IgE antibody therapy commonly prescribed in the UK?

Answer 36

omalizumab

Question 37

What is the criteria for anti-IgE antibody therapy?

Answer 37

``` → severe, persistant allergic IgE mediated asthma in patients >6 years who need continuous or frequent treatment w oral corticosteroids → optimised standard therapy → documented compliance → total serum IgE between 30-1500 → dosing based on weight and serum IgE ```

Question 38

What are the advantages + disadvantages to anti-IgE antibody therapies?

Answer 38

→ definite reduction in exacerbations → very expensive → many people don't fit into the criteria for it

Question 39

When is anti-IL5-antibody therapy prescribed?

Answer 39

→ for severe eosinophilic asthma → licensed for adults + children over 6 → blood eosinophils > 300 cells/mcl in the last 12 months → a least 4 exacerbations requiring oral steroids in the last 12 months