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brs (phase 1b) > (cardioresp) asthma & respiratory immunology > Flashcards

(cardioresp) asthma & respiratory immunology Flashcards

1
Q

how many people in the UK currently receive treatment for asthma?

A

around 5.4 million people

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2
Q

how many children in the UK are affected by asthma approximately?

A

approx 1.1 million children (= 3 in every class)

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3
Q

how many people on average die of an asthma attack everyday in the UK?

A

approx 3 people a day

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4
Q

how much does the NHS annually spend on treating asthma?

A

approx £1 billion

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5
Q

what are the cardinal features of asthma?

A

wheeze +/- dry cough – on exertion, worse with colds, with allergen exposure

atopy/allergen sensitisation

reversible airflow obstruction

airway inflammation (eosinophilia, type 2 lymphocytes)

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6
Q

what causes the wheezing in asthma?

A

airway lumen become narrower due to mucus build-up or inflammation

turbulent flow of air through lumen = have to work harder to get air in and out

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7
Q

when is wheezing most commonly seen in asthmatic patients?

A

1) on exertion
2) worse with colds
3) with allergen exposure

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8
Q

define atopy

A

familial tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment

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9
Q

what is reversible airflow obstruction?

A

a hallmark of asthma that differentiates it from COPD and other conditions that have similar presenting symptoms

i.e. when the obstruction in the airways can either resolve spontaneously or with treatment

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10
Q

what three key features must you look for on a tests to diagnose asthma?

A

atopy/allergen sensitisation

reversible airflow obstruction

airway inflammation (eosinophilia
type 2 - lymphocytes)
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11
Q

describe how and why airflow differs between an asthmatic and a non-asthmatic patient

A

in a normal, non-asthmatic patient = normal lumen so uninterrupted, laminar flow with no obstruction to breathing

in an asthmatic patient = eosinophilic inflammation causes airway smooth muscle thickening so turbulent airflow

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12
Q

how do we diagnose asthma?

A

peak flow test
spirometry
blood tests
FeNO (exhaled nitric oxide)

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13
Q

how is a peak flow test carried out on children?

A

nose clips to ensure air only leaves via the mouth

visual stimulation to ensure maximal effort

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14
Q

can spirometry/peak flow tests be done on very young children?

A

no - as they require cooperation from patient (harder to obtain)

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15
Q

describe the structure of a healthy airway wall

A

epithelial cells positioned on extracellular matrix positioned on airway smooth muscle

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16
Q

describe how the airway wall changes following exposure to an allergen

A

becomes sensitised and subsequent inflammatory response causes airway remodelling

1) eosinophils recruited to the airway
2) changes in the epithelium w increase in mucus-secreting goblet cells, increase in matrix amount and amount and size of airway smooth muscle

= bronchiole thickening

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17
Q

what changes in epithelium occur as a result of allergen exposure?

A

increase in mucus-secreting goblet cells

increase in extracellular matrix amount

increase in size and amount of airway smooth muscle

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18
Q

which type of leukocytes will respond to allergens in the airways and how?

A

eosinophils but causing eosinophilic inflammation

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19
Q

why do only some people who are sensitised to an allergen develop asthma?

A

as there is a definitive underlying genetic susceptibility that patients must have before an allergen can cause an exaggerated effect

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20
Q

what two components are required for asthma to manifest as symptoms in an individual?

A

genetic susceptibility AND exposure to an allergen

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21
Q

what are some environmental exposures that people with a genetic susceptibility to asthma can react to?

A

environmental allergens, infections, air pollution

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22
Q

describe how the genetic susceptibility in asthmatic patients was discovered

A

population level genome wide association study (GWAS)

to assess the variability in gene expression bw asthmatic and non-asthmatic patients

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23
Q

what did the GWAS for asthma susceptibility tell us?

A

asthmatics have increased gene expression for IL33 and GSDMB

so asthma is a polyfactorial, multi-gene disorder

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24
Q

describe how a type 2 immunity response occurs in allergic asthma

A

allergen inhaled

comes across antigen-presenting dendritic cells

carry antigen via MHC class II to lymph nodes

in lymph nodes, naive TH cells (TH0) differentiate into TH2 cells

TH2 cells secrete cytokines IL4, IL5 and IL13

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25
Q

what effects do the cytokines released by TH2 cells have?

A

IL4 = stimulates plasma B cell class switching to IgE

IL5 = stimulates eosinophil recruitment and promotes eosinophil survival

IL13 = stimulates mucus secretion

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26
Q

which cytokines are released by TH2 cells?

A

IL4, IL5 and IL13

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27
Q

what happens during the second exposure to an allergen (post sensitisation)?

A

the mast cells have IgE bound to their cell surface as a result of the primary sensitisation

the allergen binds to the IgE receptor and causes mast cell degranulation

= release of histamine, cytokines, chemokines, eicosanoids and growth factors = asthma/allergic reaction symptoms

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28
Q

what tests are carried out to assess allergic sensitisation?

A

blood test for serum IgE

skin prick test

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29
Q

how is a skin prick test carried out?

A

intradermal injection of a positive control (histamine)

intradermal injection of a negative control (saline)

injection/touch with different allergens

compare the resulting wheal and flare shapes and sizes

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30
Q

what does a blood test for allergic sensitisation require?

A

should test for the presence of specific IgE antibodies against the allergen of interest

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31
Q

what tests are carried out to assess eosinophilia?

A

blood eosinophil count

induced sputum eosinophil count

exhaled nitric oxide

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32
Q

what is an abnormal blood eosinophil count?

A

greater than or equal to 300 cells/mcl

33
Q

what is an abnormal induced sputum eosinophil count?

A

greater than or equal to 2.5% eosinophils

34
Q

what is FeNO?

A

fraction of exhaled nitric oxide

35
Q

what does FeNO indicate?

A

a non-invasive bio-marker of airway (type-2) inflammation

36
Q

what are two reasons that FeNO is carried out?

A

to diagnose asthma as elevated FeNO is indicative of increased T2 eosinophilic airway inflammation

to predict steroid responsiveness AND assess adherence to inhaled corticosteroids

37
Q

a patient is steroid naive and they have an elevated FeNO - what does this suggest?

A

diagnosis of asthma

38
Q

a patient is on steroid teratment and they have an elevated FeNO - what does this suggest?

A

poor adherence/compliance w steroid treatment

39
Q

what does an elevated FeNO mean?

A

there is inflammation in the lining of the airways (either due to diagnosis of allergic asthma OR reduced compliance w ICS or reduced predicted responsiveness to steroid treatment)

40
Q

how do we effectively reflect eosinophilic inflammation?

A

need multiple biomarkers to reflect eosinophilic inflammation (not just one)

(e.g. FeNO, blood eosinophils, serum IgE, sputum eosinophils, symptoms lung function tests)

41
Q

what is the clinical assessment for asthma?

A
  • history and physical examination

- assess/confirm wheeze when acutely unwell

42
Q

what is the most important, indicative symptom for asthma?

A

wheeze

43
Q

what results are expected on the objective tests carried out to diagnose asthma?

A

1) airway obstruction on spirometry - FEV1/FVC ratio < 0.7
2) reversible airway obstruction - bronchodilator reversibility > 12%
3) exhaled nitric oxide (FeNO) > 35ppb (children) OR > 40ppb (adults)

44
Q

what spirometry results are required to diagnose asthma?

A

FEV1/FVC ratio < 0.7

45
Q

what bronchodilator reversibility results are required to diagnose asthma?

A

bronchodilator reversibility > 12%

46
Q

what FeNo results are required to diagnose asthma?

A

> 35 ppb (children) OR > 40 ppb (adults)

47
Q

what are the NICE guidelines for asthma diagnosis in children (5-16)?

A

symptoms suggestive of asthma + either

1) FeNO > 35 ppb AND positive peak flow variability

OR

2) obstructive spirometry AND positive bronchodilator reversibility

48
Q

what is the order of tests to diagnose asthma in children?

A

spirometry + BDR (bronchodilator reversibility)

then FeNO

then monitor peak flow variability

49
Q

how is asthma managed?

A

maintenance (baseline) treatment
- inhaled corticosteroids OR leukotriene receptor antagonists

THEN EITHER
1) acute symptomatic relief 
- beta-2 agonists
- anticholinergic therapies
(both promote smooth muscle releaxation)

2) severe asthma steroid sparing therapies
- biologics targeted to IgE (anti IgE antibody) or airway eosinophil cytokine IL5 (anti IL5 or anti IL5 receptor antibody)

50
Q

what is the baseline treatment that all asthma patients must be on and why?

A

inhaled corticosteroids OR leukotriene receptor antagonists

= reduce eosinophilic airway inflammation

51
Q

how is an acute asthmatic attack managed?

A

patient should be on maintenance therapy already (ICS/leukotriene receptor antagonist)

+ THEN
either beta-2 agonists (salbutamol) OR anticholinergic (ipatropium bromide) therapies = both relax ASM

52
Q

what MUST you ensure before giving an asthmatic patient an acute relief bronchodilator?

A

they MUST already be on anti-inflammatory ‘maintenance’ therapy (i.e. already must take ICS or leukotriene receptor antagonist)

= otherwise can be fatal (!!!)

53
Q

how can severe asthma that does not respond to anti-inflammatory or bronchodilators be managed?

A

using biologics that target IgE or cytokines that stimulate eosinophils

e.g. anti IgE antibody, anti IL5 antibody, anti IL5 receptor antibody

54
Q

what is the mechanism of action of corticosteroids?

A

inflammatory cells
- stimulate apoptosis of eosinophils

  • reduce cytokine release by T lymphocytes and macrophages
  • reduce mast cell and dendritic cell number

structural cells
- reduce cytokine release by ASM and epithelial cells

  • reduce mucus secretion
55
Q

how do corticosteroids affect inflammatory cells?

A

stimulate apoptosis of eosinophils

reduce cytokine release by T lymphocytes and macrophages

reduce numbers of dendritic and mast cells

56
Q

how do corticosteroids affect structural cells?

A

reduce epithelial cell and ASM release of cytokines

reduce mucus secretion

57
Q

what are the most important aspect of asthma management?

A

optimal device and technique

clear asthma management plan

adherence to inhales corticosteroids

58
Q

what must you ensure before escalating an asthmatic patient to biologics?

A

ensure they are already engaging with their ICS treatment and have optimal device and technique

59
Q

how is adult asthma managed?

A

must take ICS as a regular preventer and if symptoms worsen with continued engagement w treatment, can give bronchodilators or even biologics as needed

60
Q

how is child asthma managed?

A

must take low-dose ICS as a regular preventer and if symptoms worsen with continued engagement w treatment, can give bronchodilators or even biologics as needed

61
Q

why do 10-24 year olds in the UK have the 3rd highest death rate from asthma worldwide?

A

unless patients experience severe symptoms = do not take maintenance therapy (should be take regardless) so if there is a sudden exposure to an allergen = severe attack results

62
Q

what factors can precipitate an acute lung attack?

A

sudden exposure to an allergen

infection w a virus

air pollution

tobacco smoke

63
Q

describe what happens in an acute lung attack if an infection is the predominant precipitant

A

reduces anti-viral responses/interferons + increased viral replication = result in a prolonged illness (greater duration and severity)

64
Q

describe what happens to the peak expiratory flow rate in an acute lung attack

A

peak expiratory flow rate reduces significantly due to an worsening obstruction of the airways = ACUTE WHEEZE

65
Q

what is an acute wheeze responsive to in an acute lung attack?

A

bronchodilators (will normalise the reduced peak expiratory flow rate)

66
Q

describe what happens to eosinophils in an acute lung attack

A

increase eosinophilic inflammation in the airways

67
Q

what is the airway eosinophilic inflammation responsive to in an acute lung attack?

A

high dose systemic steroids + prednisolone (not just ICS as they are not strong enough)

68
Q

why are inhaled corticoseroids not given to treat an acute lung attack?

A

not strong enough to reduce extent of eosinophilic inflammation in the airways - give high dose steroids and prednisolone instead

69
Q

describe how anti-IgE antibody therapy works

A

binds to circulating IgE antibodies and prevents interaction of these IgE with mast cells and basophils during an acute allergic reaction = preventing degranulation

70
Q

what are the long term effects of anti-IgE antibody therapy?

A

reduction IgE production and therefore reduction in serum IgE

BUT no evidence to suggest this treatment is disease-modifying (i.e. can’t stop anti-IgE therapy once levels have fallen as they can go back up)

71
Q

give two examples of biological treatment used for severe asthma

A

omalizumab (anti-IgE antibody) and mepolizumab (anti-IL5 antibody)

72
Q

what are the indications for treatment with omalizumab?

A

for severe, persistent IgE-mediated asthma in patients at/above the age of 6 who are on oral corticosteroid maintenance therapy

(four or more courses in the previous year + documented compliance)

AND total serum IgE between 30-1500

73
Q

how is the dose of omalizumab determined?

A

based on weight and serum IgE 2-4 weekly subcutaneous injections

74
Q

what serum IgE level is required for a patient to qualify for omalizumab treatment?

A

total serum IgE between 30-1500

75
Q

explain the mechanism of action of mepolizumab

A

anti-IL5 antibody that binds to circulating IL5, preventing its action

= preventing eosinophilic recruitment and survival = promoting eosinophilic apoptosis (reducing eosinophilic inflammation)

76
Q

explain the mechanism of action of omalizumab

A

anti-IgE antibodies that bind to circulating IgE preventing binding and interaction with mast cells and basophils to prevent degranulation and the progression of the allergic cascade

77
Q

what are the indications for treatment with mepolizumab?

A

adults and children > or = 6 years

severe eosinophilic asthma

blood 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

78
Q

what must occur for a patient to be classified as a responder to meoplizumab?

A

trial for 12 months and if attacks reduce by 50% = responser + can continue w treatment

brs (phase 1b) (71 decks)

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