Asthma And Respiratory Immunology Flashcards
What are the cardinal features of asthma?
Wheeze (turbulent airflow due to contracted airways)+/- 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
At baseline, describe the airway of a person with asthma?
Abnormal airway
Airway inflammation and some narrowing at baseline
Does asthma affect inspiration, expiration or both?
Expiration
Black line - patient with asthma
Red dotted line - after bronchodilator therapy (reversible airway obstruction)
What does this image show?
Airway eosinophilia
Can spirometry be done with children?
Yes, aged 5+ with computer-aided incentive devices
What does this image show?
Local allergen challenge
Describe the pathogenesis of allergic asthma
Exposure to allergen (they are sensitised to)
Inflammation - eosinophilia
Airway remodelling - changes in airway wall (epithelium, matrix and smooth muscle increased in asthma, even at baseline - thickened airway wall)
Are there treatments for airway remodelling in asthma?
No, only for eosinophilia currently
Does everyone who has allergy have allergic disease (asthma) and why?
No, genetic susceptibility may play a role
Genetic susceptibility + allergy + environmental exposure -> allergic disease (reversible airway obstruction + eosinophilia)
Why isn’t gene therapy used for asthma?
Not a single gene defect, complex, multifactorial and polygenic
IL33, GSDMB - may play a role
Describe the inflammatory pathway in allergic asthma
Antigen/allergen recognised by APC (dendritic cell in lungs)
APC takes antigen to local mediastinal lymph node where naive t-cells are differentiated into Th2 cells
Th2 cells secrete IL-4, Il-5 and IL-13
What does IL-13 contribute to?
Mucin secretion
What does IL-4 do?
Locates plasma cells and signals them to produce IgE antibodies which exacerbates the allergic cycle (mast cell proliferation etc)
What does IL-5 do?
Central to allergic asthma
Attracts eosinophils from bone marrow, into blood, into the airways
Drives inflammation
Is there a singular gold standard test for asthma?
No
What are some tests for allergic sensitisation?
Allergy skin tests (skin prick test)
Blood tests for specific IgE antibodies to allergens of interests (total IgE alone is not sufficient)
What are some tests for eosinophilia?
Blood eosinophil count (when patient is stable) - >/= 300 cells/mcl is abnormal in a patient with suspected/confirmed asthma
Induced sputum eosinophil count - >/= 3% eosinophils is abnormal
Exhale nitric oxide (routinely used)
(Together with spirometry used to make a diagnosis of asthma)
Identify the cells on this image
What is fraction of exhaled nitric oxide (FeNO)?
Non-invasive (indirect) biomarker of type 2 eosinophilic airway inflammation
What role does exhaled nitric oxide play in adherence and steroid response?
Plays a role in asthma diagnosis, predicting steroid responsiveness and assessing adherence to inhaled corticosteroids (sensitive to steroids)
What are the NICE 2017 asthma diagnosis clinical guidelines for clinical assessment?
History & examination
Assess/confirm wheeze when acutely unwell (doctor diagnosed wheeze)
What are the objective tests required for asthma diagnosis according to the NICE 2017 guidelines?
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 naive patient
What is the first step in asthma management?
Reduce airway eosinophilic inflammation:
- Inhaled corticosteroids (ICS)
- Leukotriene receptor antagonists
What is the second step in asthma management?
Acute symptomatic relief:
- Beta-2 agonists (smooth muscle relaxation)
- Anticholinergic therapies (smooth muscle relaxation)
How is severe asthma managed?
Steroid sparing therapies:
Biologic targeted to IgE
- Anti-IgE antibody
Biologics targeted to airway eosinophils
- Anti-interleukin-5 antibody
- Anti-interleukin-5 receptor antibody
What is the mechanism of corticosteroids?
Dampen eosinophilia inflammation
Reduce the recruitment of eosinophils from bone marrow to blood to airways
Steroids induce apoptosis of eosinophils in airways (reduced recruitment and survival)
Why are inhaled corticosteroids used?
Go directly to the tissue - avoiding side effects of systemic steroids on the rest of body (e.g. dampening adrenal function)
How long must corticosteroids be taken for to see benefit?
At least six weeks
Need to be taken long term to maintain effect of dampening inflammation
What basic steps are important for asthma management?
Optimal device and technique
Clear asthma management plan
Adherence to inhaled corticosteroids
Describe treatment progression for adults with asthma
Describe treatment progression for children with asthma
What is the pathogenesis of acute lung attack (school age children)?
Exposure to sensitised allergen/pathogen/pollution/tobacco smoke
Reduced anti-viral responses (interferons) and increased viral replication result in a prolonged illness
Increased airway eosinophilic inflammation, responsive to corticosteroids (may require systemic - oral/IV)
Reduced peak expiratory flow rate and increased airway obstruction (wheeze, responsive to bronchodilators)
What is anti-IgE antibody therapy and how does it work?
Humanised anti-IgE monoclonal antibody
Binds and captures circulating IgE - prevents interaction with mast cells and basophils to stop allergic cascade
IgE production can decrease with time when patients are given anti-IgE Ab
Does anti-IgE antibody therapy need to be used indefinitely?
Reduction in serum IgE over time means the therapy may not need to be used indefinitely
However, no evidence yet that stopping treatment after some time is a long-term solution
Give an example of anti-IgE antibody
Omalizumab
What are the requirements for a patient to be started on Omalizumab?
Severe, persistent allergic (IgE mediated) asthma in patient aged 6 and above who require continuous or frequent treatment with oral corticosteroids (4 or more courses in the previous year)
Optimised standard therapy + documented compliance
Total serum IgE between 30-1500 IU/mL
What is the dosing of Omalizumab based on?
Weight and serum IgE
2-4 weekly subcutaneous injections
What is a negative of Anti-IgE antibody therapy?
Expensive
Is Omalizumab given to all patients with severe asthma?
No, only 60% eligible due to serum IgE range and only 50-60% of these patients actually respond
What is Mepolizumab and how does it work?
Anti-IL5-antibody licensed for adults and children aged 6 and above
Used for severe eosinophilic asthma
IL-5 regulates growth, recruitment, activation and eosinophil survival - prevents this
What are the UK recommendations for mepolizumab?
Severe eosinophilic asthma
Blood eosinophils >/= 300 cells/mcl in the last 12 months
At least 4 attacks requiring oral steroids in last 12 months
12 month trial - 50% reduction in attacks, then continue
