asthma and respiratory immunology Flashcards
can you die of asthma?
YES asthma attack, approx 3/ day in uk
core symptoms of asthma
1) wheeze (remember sounds from lecture), dry cough, dyspnoea
2) persistend symptoms AND attacks
what are asthma attacks percipitated by
cold, exertion, allergen exposure
what are the pathophysiology core asthma features
1) atopy: allergen sensitisation
2) reversible airway obstruction
3) inflammation with a) type 2 t helper cell recruitment and b) eosinophelia
other than airway inflammation, what other pathophysiological procedure takes place in airways in asthma?
airway remodelling
Why do only some people who are sensitized develop disease (asthma)?
1) GENETICS may determine is someone has just allergy or develops allergic diseaseee
2) environmental exposures: how much are u exposed to allergens, infections, pollution
what is the name of the type of graph for genome wide associationstudies presentation
manhattan plot bc it looks likel manhattan skyline
what is type 2 immunity and type 2 t helper cell
immunity where antigen is an allergen and t2 thelper cell (cd4) is a subtype of cd4 only for allergy
what describe how type 2 immunity is triggered in asthma (how th2 cell is activated)
1) APC (dendritic cell: specific apc of lungs) binds allergen and presents it to
2) naive T cell (undifferentiated to helper or killer yet)
3) naive t cell differentiates to helper, and particularly Type 2 helper (allergic)
what does the th2 cell release and what does it trigger?
IL4: B CELL - IgE production
IL5: eosinophils
IL13: MUCUS
final step of immune pathway in inflammation in allergic asthma?
1) mast cell activated by igE and 2) eosinophils produce: histamines, eicosanoids, cytokines, chemokines, enzymes, growth factors
what is one inappropriate and one appropriate measurement of allergic sesitization?
blood test screening for:
for specific igE antibodies to relevant allergens
TOTAL igE NOT SUFFICIENT to define atopy
what are the tests doen for eosinophil count?
blood eosinophil count, sputum eosinophil count and exhaled nitric oxide
abnormal levels of blood eosinophil and sputum and in who do they apply
> /=300 cells/mcL abnormal in patient with SUSPECTED or CONFIRMED asthma
> /=3%
what units are nitric oxide levels counted in and where from?
fractional concentration of EXHALED nitric oxide
what is nitric oxide a marker of? (primarily)
INDIRECT marker of th2-high eosinophilic airway inflammation
what is nitric oxide also a marker of?
steroid responsiveness (if anything changes when they take short acting dose) and assessing adherence to inhaled corticosteroids (if theyve been taking their long term dose i think)
why is nitric oxide present in asthmatic inflammation?
increased production of it from inflammed: activated epithelial cells
normal levels NO in adults and children
<20-25 adult
<15-20 child
NO levels to contribute to asthma diagnosis in adult and child
> /=40 adult ppb
/=35 child ppb
when do you diagnose child / young operson with asthma
1) if they have symptoms: a) history and examination b) confirmed by doctor wheeze when acutely unwell
2) and one of the following :
a)obstructive spirometry (FEV1/FVC ratio <0.7 (adults), <0.8 (children) )
AND
bronchodilator reversibility positive. (reversibility>/= 12%)
or
NO >35 and positive peak flow variability
order of objective tests
if they have sympotms
1) spirometry
2) BDR if spirometry shows obstruction (bronchodilator reversibility- checking if its reversible airway obstruction as it should be in asthma)
3) if diagnostic uncertainty remains after these consider FeNO
4) if uncertainty remains monitor peak flow variability for 2-4 weeks
what do you do if child cant perform objective tests for some reason?
treat based on observation and clinical judgement
and try doing tests again every 6-12 months
what are the 3 management types of asthma and in what case is each used?
1) every asthmatic is given this: reduce eosinophelic inflammation: inhaled corticosteroids or leukotriene receptor antagonist
2) for acute sympotmatic relief:
beta 2 agonist and anticholinergic therapies (smooth muscle relaxation)
3) severe asthma therapies:
biologics:
Anti-IgE antibody
Biologics targeted to airway eosinophils
Anti-interleukin-5 antibody
Anti-interleukin-5 receptor antibody
through what mechanism do corticosteroids target macrophages and T lymphocytes
reduce cytokines
through what mechanism do corticosteroids target dendritic cell and mast cell and eosinophils
decreasing numbers through apoptosis
through what mechanism do corticosteroids target smooth muscle in aiway
incr b2 receptors
decr cytokines
through what mechanism do corticosteroids target endothelial cells
decr leak
through what mechanism do corticosteroids target epithelial cells
decr cytokines and mediators
what are the 3 most critical elements for asthjma management to be effective
1) using machine right
2) adhering to treatment
3) HAVING CLEAR ASTHMA MANAGEMENT PLAN: its mandatory to have this plan written somewhere for patient
what are the typical triggers in pathogenesis of acute lung attack in school age children
allergens + viruses/ bacteria: pathogens + pollution + tobaco smoke
what is the pathogenesis of acute lung attack in school children- cellular level
the combination of the triggers leads to
1) reduced IFN a, beta and lamda leading to decreased antivrial responses and increased viral replication
2) increased airway inflammation by eosinophils (responsive to corticosteroids)
what is the pathogenesis of acute lung attack in school children- the result seen clinically
reduced peak expiratory flow rate and
increased airway obstruction
resulting in acute wheeze
responsive to bronchodilators
what are IgE antibody’s full name?
humanised anti-IgE monoclonal antibody
what are the observed effects of IgE ab
1) BINDS IgE and prevents it from activating mast cells and basophils to stop allergic cascade
2) may lead to IgE production reduction
what is an indicator that you could stop IgE ab therapy? is stopping it an upholding long term solution?
IgE production level drop. we dont know - no evidenc ethat it is
name of anti IgE antibody drug
omalizulab
criteria for eligibility for omalizulab? what proportion is that? what proportion repsonds
1) severe persistent asthma, has had to take 4 or more oral corticosteroids over last few years
2) 6 yrs old or older
3) optimised standard therapy
4) has DOCUMENTED COMPLIANCE to therapy
60% eligible
50-60 % respond
goals of IgE levels with omalizulab, dosing and price?
30-1500 IU/ml (International Units/ ml)
dosing based on weight and serum ige 2-4 weeks s/c injections
Min 75mg 4 weekly = £1,665 /patient/year
Max 600mg 2 weekly = £26,640 /patient/year
name of anti IL-5 anitbody drug
mepolizumab
who is mepolizumab for?
severe eosinophilic asthma
adilts and children 6 and overBlood eosinophils >300 cells/mcl in the last 12 months
At least 4 exacerbations requiring oral steroids in the last 12 months
Trial for 12 months – 50% reduction in attacks, then continue
characteristics of those who respond best to mepolizumab
elevated blood eosinophils
number of previous exacerbations
dose of inhaled steroids
is mepolizumab more effective in children or adults?
adults, more trials need to be done specific for children
what is dupilumab?
anti-IL4Ra Ab, shared receptor for IL-4 AND IL13
WHAT is unique and very clinically important about dupilumab?
fewer asthma attacks AND improved lung function (has never been succeded before by other drug)
what does IL-5 and 13 do?
recruit b cells
what is the order in which you perscribe drugs for asthma in adults from suspected asthma to severe asthma
1) start low dose ICS and monitor
if infrequent short lived wheeze
2) regular preventer: low dose ICS
3) INITIAL ADD ON: add inhaled LABA (long acting …) - (fixed dose SMART)
4) ADDItional controlled therapies: increase ICS to medium or add LTRA
+ consider stopping LABA if not effective
5) specialist referal
differences of treatment doses for children
1) low dose replaced by very low dose/ paediatric dose
2) medium dose replaced by low dose
3) children <5 cant take LABA ONLY LTRA
SOLUTION FOR BETTER ADHERANCE TO ICS THERAPIES
SMART: single inhaler maintenance reliever therapy.
