asthma Flashcards
what is the epidemiology of asthma?
- 4 million people in the UK currently receiving treatment for asthma
- 1 million children affected (approx. 3 in every class) (1/10)
On average, 3 people die of an asthma attack every day in the UK
NHS spends approx. £1billion annually treating asthma
what are the main features of asthma?
Wheeze +/- Dry cough – on exertion, worse with colds, with allergen exposure
Atopy / allergen sensitisation
physiological: Reversible airflow obstruction Airway inflammation Eosinophilia Type 2 - lymphocytes
atopy, reversible airflow obstruction and airway inflammation are the thing we test for for asthma
what is the pathophysiology of asthma?
reversible airflow obstruction:
normally airway is round and patent
people with asthma have eosinophilic inflammation that causes a thickened airway wall and obstructed air flow. there is also increased airway smooth muscle.
we do spirometry to test this.
gives a flow volume loop
expiration line shows obstruction (scooped)
but there should also be the possibility after bronchodilator for the loop to be normal.
(spirometry requires effort, so is not usable in very young children)
they will also have airway eosinophilia. (show up red)
what is the pathogenesis of allergic asthma?
in normal people: there is bronchial epithelium with a thin amount of matrix underneath, and some smooth muscle
people who have a susceptibility to asthma, when sensitised by an allergen:
their airway undergoes simultaneous inflammation and airway remodelling
airway remodelling:
recruitment if inflammatory cells (eosinophils)
increased goblet cells on epithelium
increased amount of matrix
increased amount and size of smooth muscle
(airway wall is much thicker)
why do only some people who are sensitised develop disease (asthma)?
only people with an underlying genetic susceptibly will develop the disease. (not everyone will develop asthma)
these people have an environmental exposure (allergen, infection, pollution)
this leads to asthma:
allergy, reversible airflow, inflammation
how do we know about the genetic cause for asthma susceptibility?
GWAs
genome wide association studies
gives a manhatten ploy
shows specific genes that occur more often in people with asthma
eg. IL33, GSDMB
but it is a multi gene disease, polyfactorial
so gene therapy is not a solution at the moment
wha tare the cardinal features of asthma?
must have:
wheezing
reversible airflow obstruction
eosinophilic inflammation
why is type 2 immunity important in asthma, what is the immune process?
allergic antigens are presented to antigen presenting Cells in the lungs (dendritic cells) these axpress antigen via MHC class II
these then activate naive t cells in the lymph nodes
causing them to differentiate into Th2
the Th2 cell secretes cytokines, IL-4, IL-5, IL-13
IL-5 recruits eosinophils into the airways and keeps them alive. causes eosinophilic inflammation
IL-4 helps the conversion of plasma cells to secrete IgE
IL-13 is involved in mucous secretion
when exposed to the same allergen again, it will invoke an allergic immune response. as it is recognised by IgE
this binds to mast cells, which degranulate, releasing cytokines and chemokines. this results in the allergic reactions. eg. histamine release.
how do we test for evidence of allergic asthma?
skin prick tests:
intradermal injection of positive control (histamine), negative control (saline), compared to allergens
if they are sensitised they will develop a weal and flare reaction. size of weal determines extent of allergy
Blood tests:
for specific IgE antibodies to allergens of interest
Total IgE alone not sufficient to define atopy (allergen sensitisation), need to look for specific IgE
how do we test for eosinophilia?
Blood eosinophil count when stable (not during an acute attack):
>300 cells /mcl is abnormal
Induced sputum eosinophil count: >2.5% eosinophils is abnormal
Exhaled nitric oxide (recommended diagnostic test)
what is the exhaled nitric oxide test (FeNO)?
a non-invasive biomarker of airway (type-2) inflammation
diagnosis:
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
adherence and steroid response:
FeNO has a role in aiding asthma diagnosis, predicting steroid responsiveness and assessing adherence to inhaled corticosteroids.
as it is very sensitive to steroids, it comes down to normal levels when you are taking treatment
(but you cant just rely one one biomarker, you should look at symptoms and blood too)
what are the NICE asthma diagnosis clinical guidelines?
Clinical assessment:
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)
how is asthma managed?
- Reduce airway eosinophilic inflammation:
Inhaled corticosteroids (ICS)
Leukotriene receptor antagonists
all should be on this - Acute symptomatic relief:
Beta-2 agonists (smooth muscle relaxation)
Anticholinergic therapies (smooth muscle relaxation) (ipatropium brominde)
these arent used regularly as it is dangerous
3. Severe asthma – steroid sparing therapies: Biologics targeted to IgE Anti-IgE antibody Biologics targeted to airway eosinophils Anti-interleukin-5 antibody Anti-interleukin-5 receptor antibody
why do we used inhaled corticosteroids?
they reduce eosinophil number by promoting apoptosis
they also reduce mast cell numbers
reduce type II mediators released by Th2 cells
they also impact structural cells, helps with remodelling
but main target is to reduce type II inflammation
what is the most important aspect of asthma management?
Optimal device and technique
Clear asthma management plan
Adherence to inhaled corticosteroids
these should be ensured before moving onto more advanced treatments
you can get electronic monitors that measure usage in inhalers
what is the pathogenesis of an acute asthma attack?
allergens + pathogens (virus/bacteria) + pollution + tobacco stoke
these multiple events can all come together to result in an acute attack
people with asthma have reduced antivirals, so their infections are longer and more severe
during an attack, airway obstruction is significantly worse
eosinophilia is much much worse
to treat these we have to use high dose systemic steroids
why do we need additional treatments that are steroid sparing?
for patients with severe asthma, who arent responding to inhaled corticosteroids
they aim to reduce exacerbations
what are the biologics used for asthma at the moment?
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
but not disease modigying, only manages symptoms
Anti IL-5
Anti IL-5 receptor
what is omalizumab?
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
Total serum IgE between 30-1500
very specific, 2/3 of patients are outside this range
Dosing based on weight and serum IgE 2-4 weekly s/c injections
expensive but it is effective
what is mepolizumab?
anti-IL5-antibody
for severe eosinophilic asthma
IL-5 regulates growth, recruitment, activation and eosinophil survival
Licenced for adults and children >6 years
At least 4 exacerbations requiring oral steroids in the last 12 months
Trial for 12 months – 50% reduction in attacks, then continue
