Asthma and Respiratory Immunology Flashcards
What are the cardinal features of asthma?
- wheeze (on exertion, worse with colds and allergen exposures
- (possible) dry cough and dyspnoea
- Atopy/allergen sensitisations
- reversible airflow obstruction
- airway inflammation (Eosinophilia and T2-Lymphocytes, CD4+ cells)
What does an untreated asthma airway look like?
- abnormal even at baseline
- thickened wall caused by inflammation
- increase in airway smooth muscle
- reduced lumen causes turbulent airflow, leading to wheeze
How is a reversible airflow obstruction diagnosed?
- lung function test (spirology)
- flow volume loop with scooped black line (red is normal)
- changes to normal with treatment
What must be tested in the diagnosis of asthma?
- evidence of inflammation, eosinophilia (biopsy)
What causes asthma?
- gentic suspetibility to asthma
- exposure and sensitisation to pathogens
- inflammation and airway remodelling (changes in the structure)
- changes in epithelial (increased goblet cells)
- increased matrix
- increased sized and number of smooth muscle cells
Why do only some people that are sensitized develop disease?
need the underlying genetic susceptibly to develop it.
What genes have been consistently shown to cause an increased susceptibility to asthma?
- IL33
- GSDMB
Is one gene enough to cause a susceptibility to asthma?
no - multifactorial cause
Why is type II immunity important in allergic asthma?
- determines the tests done
What is the pathway of an antigen causing eosinophilic airway inflammation?
- antigen
- antigen presenting cell (MHC class II)
- Th0
- Th2
- release of IL-4, -5, -13
What does IL-5 do?
recruitment and survival of eosinophils
What does IL-4 do?
conversion of B cells to secrete IgE
What does IL-13 do?
involved in mucus secretion
What happens when a patient is sensitised to an allergen and is the exposed to allergen again?
- build an allergic immune response
- IgE binds to mast cells that release growth factors, cytokines, and chemokines
- causing the allergic reactions: histamines, elcosanoids
How do you test for allergic sensitization?
- skin prink tests
- blood tests
What tested in the blood tests for allergic sensitisation?
- specific to IgE antibodies to allergens of interest
- total IgE alone is not sufficient to define atropy.
What tests are done for eosinophilia?
- blood test (when stable)
- induced sputum test
- exhaled nitric oxide.
What blood eosinophil count (when stable) is indicative of asthma?
> 300 cells/mcl is abnormal
What induced sputum eosinophil count if abnormal?
> /= 3%
What is exhaled nitric oxide?
a non-invasive biomarker of airway (type-2) inflammstion
How is exhaled nitric oxide used to diagnosis asthma?
Fractional concentration of exhaled nitric oxide
- quantitative
- non-invasive
- safe
- indirect marker of T2-high eosinophilic airway inflammation in asthma
When should exhaled nitric oxide not be used in the diagnosis of asthma?
when steroids have been use
What can exhaled nitric oxide also do?
- prediction of steroid responsiveness
- assessing adherence to inhaled corticosteroids
What is involved in the clinical assessment for asthma confirmation?
- history and examination
- confirm the presence of a wheeze when acutely unwell
What are the objective tests done when looking to confirm a diagnosis of asthma?
- airway obstruction on spirometry - <0.7 in adults
<0.8 in children - reversible airway obstruction - bronchodilator reversibility >= 12%
- exhaled nitric oxide >35ppb in children and >40ppb in adults
When should asthma be diagnosed in those aged 5-16?
symptoms of asthma and:
- FeNO level of >35 and positive peak flow variability
OR
- obstructive spirometry and positive bronchodilator reversibility
In what order should be the tests be performed?
- spirometry if obstruction: - BDR if uncertainty remains: - FeNO if uncertainty remains: - peak flow variability
How is asthma managed?
- reduce airway eosinophilic inflammation
- acute symptomatic relief
- severe asthma - steroid sparing therapies
How do you reduce airway eosinophilic inflammation?
- inhaled corticosteroids
(target and reduce eosinophilic inflammation) - leukotriene receptor antagonists
What is the maintenance therapy given to all patients with asthma (irrelevant of severity)?
- inhaled corticosteroids
(target and reduce eosinophilic inflammation) - leukotriene receptor antagonists
What is used for acute symptomatic relief?
- Beta-2 agonists
- anticholinergic therapies
(smooth muscle relaxation)
Why is reducing eosinophilic inflammation necessary?
needed to prevent asthmatic death
How often is acute symptomatic relief used?
- as and when needed during an attack
- NOT used regularly
What is used for those with severe asthma that are not responding to the other treatments?
Steroid Sparing Therapies
- Biologic targeting IgE
- Biologics targeted to airway eosinophils (anti-IL5 antibody and anti-IL5 receptor antibody)
Why are corticosteroids used?
- reduce the number of eosinophils by promoting apoptosis
- reduce the type 2 mediators released by the TH2 cells
- Reduce mast cell numbers
- some impact and prevent remodelling
What are the most important aspects of asthma management?
- optimal device and techniques
- clear asthma management plan
- ensure adherence to inhaled corticosteroids
How can adherence be monitored?
electric adherence monitoring - attached to inhaler
What can be prescribed if ICS are not being effective?
Leukotriene receptor agonists FIRST before considering escalation
What is the pathogenesis of an acute lung attack in children?
Multifactorial exposure
- reduced antiviral response and increased viral replication results in a prolonged illness
- reduced peak expiratory flow (acute wheeze)
- increased eosinophilic inflammation
What happens when an infection is the primary cause of an asthma attack?
- reduced IFN-alpha, IFN-beta, IFN-lambda
- reduced antiviral responses
- increased viral replication leading to prolonged illness
What can cause an acute lung attack?
allergens
pathogens
pollution
tobacco smoke
Is obstructive reduced flow reversible during an attack?
no
How are acute lung attacks managed?
high dose systemic steroids (usually with prednisolone)
What is anti-IgE antibody therapy?
humanised anti-IgE monoclonal antibody
What does anti-IgE antibody therapy do?
binds and captures circulating IgE to prevent interaction with mast cells and basophils to stop and allergic cascade
What are the impacts of long term use of anti-IgE antibody therapy?
- IgE production decreases
- therefore, therapy may not be needed indefinitely
- No evidence yet that stopping anti-IgE Ab after some time is a long-term solution
What is the criteria for the use of Omalizumab (anti-IgE antibody therapy)?
- severe, persistent allergic (IgE mediated) asthma
- > /= 6 years old
- currently use continuous and frequent treatment with oral corticosteroids (4 or more over 1 year)
- optimised standard therapy
- documented compliance
How is Omalizumab administered?
- based on weight and serum IgE
- 2/4 weekly subcutaneous injections
- Min 75mg 4 weekly = £1,665 /patient/year
- Max 600mg 2 weekly = £26,640 /patient/year
When is Mepolizumab (Anti-IL5 antibody therapy) used?
- Only in severe eosinophilic asthma
- Blood eosinophils >/= 300cells/mcl (12 months)
- > /= 6 years old
- at least 4 excacerbations requiring oral steroids in the last 12 months
What is Omalizumab?
anti-IgE antibody therapy
What is Mepolizumab?
Anti-IL5 antibody therapy
What does Mepolizumab do?
reduced regulation of growth, recruitment and survival of eosinophils
What is the process of administering Mepolizumab?
Trial for 12 months
if 50% reduction in attacks, continue
What is Dipulimab?
Anti-IL4RA
- target IL4 and IL13
- prevents IgE and mucus secretion
What is Tezepelumab?
Anti-TSLP
- prevents eosinophilia
- upstream of all immune responses
- could target the initiation of disease and attacks
What is the epidemiology of asthma?
- 5.4 million people in the UK currently receiving treatment for asthma
- 1.1 million children affected (approx. 3 in every class)
- On average, 3 people die of an asthma attack every day in the UK
- NHS spends approx. £1billion annually treating asthma
What percentage pf patients are responsive to omalizumab and what percentage respond to the treatment?
- Only approx. 60% of patients are eligible
- Of those, only approx. 50-60% respond
