Asthma

Question 1

what is oxygen saturation level (sats)?

Answer 1

normal is above 95%
in asthma, can be 85%

Question 2

what are the two types of respiratory failure?

Answer 2

type 1: oxygen level drops and carbon dioxide levels stay low
- early phase of respiratory failure

type 2 is worse: carbon dioxide goes up and oxygen drops

Question 3

is mild asthma common?

Answer 3

90% of asthma cases are mild-moderate
- well controlled and managed

rare that patients die from asthma attack - can be serious if not monitored

Question 4

where can clinical management of asthma go wrong?

Answer 4

Short comings in patient management:
- Discharge too soon
- No personalised management plan
- Inhaler technique not checked
- GP follow up not arranged
- Patient discharged after DNA nurse clinic (despite experiencing life threatening attack)
- The most important cause of this preventable death is the lack of regular preventer therapy use
- Non-adherence to ICS (inhaled corticosteroid)

Question 5

how many people may die from different asthma severities?

Answer 5

in 2014:
- 39% severe (steps 4/5)

likely undertreated uncontrolled asthma: 60% of patients die don’t have severe asthma
- 49% moderate (steps 2/3)
- 9% mild (step 1)
- 3% first attack
- this highlights that there is a problem with asthma management, where even mild patients can die

60000 admissions of asthma every year in UK - many
- 3/4 of those are preventable if patient has optimised treatment

Question 6

how are mild-moderate and severe patients treated?

Answer 6

severity is measured by the treatment patients are on

steps 1-3 - treatment inhaler - short-acting b2-agonist (SAMA), ICS and preventative inhaler - steroids (ICS) and long-acting b2-agonist (LABA) to open airways

steps 4/5: preventative treatment to stop attacks - ICS, LABA, long-acting muscarinic agents (LAMA)

aims to cause bronchodilator

Question 7

how does uncontrolled asthma impact patients?

Answer 7

Uncontrolled asthma has a significant impact on quality of life and cost of treatment
- Uncontrolled symptoms of wheezing, shortness of breath, and cough, result in a high burden of symptoms and attacks, often leading to admission to hospital and even death.
- Asthma outcomes have improved over the last few years. However, many people with severe or difficult asthma still do not receive the support and treatment they need.
- There are effective treatment and management options for people with difficult and severe asthma; it is vital that they receive the specialist care they need to access them.

Question 8

how common is asthma and how does it vary amongst patients?

Answer 8

• ~1 in 10 people have asthma, 5.4 million in UK receive treatment
• 10% of asthma patients/200,000 have severe/refractory asthma - varies
• despite advances in therapy, there has been a 33% increase in asthma mortality over last 10 years in England and Wales
• asthma should be a benign, controlled disease, but many patients suffer unnecessarily
• 90% have preventative disease

Question 9

what are the guidelines on asthma?

Answer 9

national and global

GINA = global initiative for asthma
- physicians around the world

countries then have their own added guidelines
in UK
- three guidelines: NICE/BTS/SIGN along with GINA

GINA is most up to date:
- step 1-2 (mild)
- step 4-5 (severe)
- preferred track 1: reliever is a low dose ICS-formoterol to reduce risk of exacerbations instead of SABA - use reliever and controller together. Low dose ICS maintenance used as controller
- alternative track 2: if track 1 can’t be done, use SABA as reliever if patient has good adherence and no exacerbations in last 12 months, and continue with low dose ICS for maintenance

Question 10

why is salbutamol limited?

Answer 10

heavy reliance on salbutamol (SABA) (inhaler) - instant relief, but over-reliance and doesn’t fix the problem
- only hides the problem
- reduces airway inflammation and relaxes smooth muscle
- but can happen again and doesn’t reduce risk of exacerbations
- now is used as an alternative therapy, ICS is main

Question 11

how are severe patients treated?

Answer 11

Track 1
- medium dose maintenance ICS at step 4
- add on LAMA at step 5, maybe with anti-IgE, anti-IL-5, high dose ICS

Track 2:
- step 4: medium/high ICS-LABA for maintenance
- step 5: add LAMA and high dose ICS-LABA

Question 12

why are steroids limited in asthma?

Answer 12

long-term use can cause complications:
- weight gain
- osteoporosis
- CVD
- metabolic syndrome
- diabetes
- cushing syndrome
- muscle weakness
- shorter life expectancy

need to change steroid tactic in asthma

Question 13

how are the airways altered in asthma?

Answer 13

bronchoscopy biopsy of the airways
- epithelium is broken
- smooth muscle hyperplasia/hypertrophy
- infiltration of lymphocytes, neutrophils, mast cells
- inflamed mucus glands
- similar to broken skin of ezcema but in airways
- airways look red, swollen - no longer an effective barrier for breathing - can’t protect from pollutants and pathogens
- airways are inflamed
- smooth muscles are exaggerated - more spasms
- mucus from goblet cells is highly secreted to block airway
- airways have increased sensitivity

Question 14

how can asthma patient breathing capacity be measured?

Answer 14

spirometry:
- measures lung function
- can see before and after salbutamol treatment
- blows out as hard as possible for as long as possible
- this flow of air goes up and plateaus
- asthmatic person has reduced forceful expiration and reduced speed of airflow compared to healthy person - low peak flow
- FEV1 = forced expiratory volume in 1 second
- FVC = forced vital capacity = overall expiratory output

Question 15

how can asthma be diagnosed by spirometry?

Answer 15

• can calculate FEV1/FVC ratio for diagnosis, where below 70% indicates obstructive lung disease. normal lungs is 80%
• GINA: if bronchodilator improves FEV1 by 12%, this is enough to diagnose asthma
• obstruction and reversibility indicates asthma

Question 16

what are the key asthma measures/biomarkers?

Answer 16

Total IgE in serum
- normal is <100, patient has 1035

House dust mites (HDM) IgE
- IgE in serum specific to HDM
- high total in blood of asthma patient - grade 4

FeNO - fractional exhaled nitric oxide
- high in asthma patients - indicates airway inflammation
- NO produced by inflamed epithelium
- normal = <25, this patient has 36

PBE - peripheral blood eosinophils
- high in asthma patients
- important cells in asthma - induce inflammation
- normal = <0.15, this patient has 0.76

Asthma control questionnaire (ACQ) - 0-6 scale, 6 being poorest symptoms

Question 17

why aren’t the corticosteroids effective in this patient?

Answer 17

patient is taking oral prednisolone, along with salbutamol and symbicort
- high doses, but still not controlled
- patient isn’t taking the prednisolone - assay of it in blood <20nmol/L - too low
- cortisol level is too high, around 200nmol/L, indicating that it is suppressed
- taking prednisolone would be cortisol levels would reduce, but the patient isn’t taking it properly

Question 18

how common is non-adherence in chronic respiratory diseases including asthma?

Answer 18

very common - non-adherence rate is in up to 50% of patients, tending to be higher in milder cases

Question 19

why may asthma become severe or difficult to treat?

Answer 19

range of reasons
- oral corticosteroids (OCS) can cause many side effects that complicate symptoms
- psychology - asthma can cause psychological issues, stress
- obesity
- immunodeficiency
- adrenal insufficiency
- gastro-oesophageal responses
- breathing pattern disorder
- inducible laryngeal obstruction (ILO) - can be confused or consistent with asthma

Question 20

how is difficult to treat asthma defined?

Answer 20

Asthma severity model:
Difficult to treat asthma
(uncontrolled despite treatment at steps4/5 of guidelines)
- not necessarily all severe asthma, mild-moderate patients can be difficult to treat

Misdiagnosis
Poor adherence
Psychology, ILO, BPD, EDAC
Triggers, occupational
Unresolved co-morbidities
- GORD, Sleep apnoea
- Infection, bronchiectasis
-Obesity

Question 21

what is the asthma severity model?

Answer 21

17% patients have difficult asthma
3.7% (varies) have severe asthma
- Severe asthma: uncontrolled asthma despite treatment at step 4/5 of guidelines, or requires high level treatment to control

Question 22

what are the phenotypes of severe asthma?

Answer 22

one size fits all model does not work - very heterogeneous disease
- step-wise asthma isn’t fully accurate, and patients are treated in the same way despite different phenotypes
- atopic asthma
- allergic asthma
- severe
- need to move away from one size fits all model

Question 23

how do allergens enter the airway epithelium?

Answer 23

epithelium is broken, where tight junctions are leaky, and enables dysregulated entry of allergens
- allergens e.g. HDM, is in the air and we breathe it in
- HDM pellets dry up and is inhaled, pass through tight junctions and can access APCs

Question 24

what happens when the allergen interacts with APCs?

Answer 24

• DCs internalise allergen and present on MHCII to naive T cell TCR
• drives Th2 differentiation upon the correct cytokine environment - IL-33, IL-25, TSLP (thymic stromal lymphopoietin) - alarmins produced by airway epithelium in response to damage
• alarmins induce switch of T cell to Th2
• Th2 produce cytokines IL-4, IL-13, which drive B cell isotype switch to IgE, as well as IL-5, IL-9

Question 25

what are the outcomes of IgE class switch in allergic asthma?

Answer 25

- IgE can bind to second exposure of HDM allergen and rapidly cross-link FceR on mast cells, leading to degranulation and release of histamine, prostaglandins into the mucosa and submucosa to drive swelling, oedema, coughing, bronchospasm - this is what drives the early-onset allergic inflammation in asthma

Question 26

what are the other effects of Th2-released cytokines in allergic asthma?

Answer 26

- Th2 also release IL-9 which drives mast cell activity - IL-5 is important as it drives production of eosinophils in the bone marrow and drives their activation and migration to inflammatory site of the airways - IL-13 can drive smooth muscle constriction, and can activate the epithelium to express adhesion receptors to enable eosinophil access

Question 27

what is ICS sensitive and ICS resistant asthma?

Answer 27

ICS sensitive: early-onset allergic eosinophilic airway inflammation (extrinsic asthma) - within 15 mins, acute ICS resistant: late-onset nonallergic eosinophilic airway inflammation (intrinsic asthma) - occurs in 6-12 hours, more chronic - this is classical chronic asthma

Question 28

how does ICS resistant intrinsic asthma occur?

Answer 28

driven by pollutants, microbes, glycolipids passing through the epithelium - leads to release of the same alarmins, but these act on naive innate lymphocytes, leading to their switch to ILC2 - these drive type 2 inflammation associated with intrinsic asthma - ILC2s release IL-5 to activate eosinophils - also release IL-13 to activate epithelium and smooth muscle contraction

Question 29

what is omalizumab?

Answer 29

anti-IgE - binds constant chain of IgE to block its binding to FceR on mast cells - used for many years

Question 30

what is mepolizumab?

Answer 30

anti-IL-5 - stops circulating IL-5 binding to IL-5R and mops it up - prevents eosinophil mobilisation and activation, so reduces eosinophilic inflammation - reduces no. eosinophils in circulation

Question 31

what is benralizumab?

Answer 31

anti-IL-5R - binds to the receptor to prevent IL-5 binding - competitive inhibitor - causes death of eosinophils - depletion from circulation to reduce inflammation - blood count shows wipe out of eosinophils following treatment

Question 32

can the biologics be injected by patients themselves?

Answer 32

yes, they can self-inject at home following guidance

Question 33

what is type 2 immune inflammation?

Answer 33

Type 2 immune inflammation manifests as eosinophilic inflammation, airway hyper-responsiveness, IgE production, and goblet cell hyperplasia. These pathological features develop as a consequence of enhanced production of key cytokines during inflammation: interleukin (IL)-4, IL-5, and IL-13, secreted by a range of immune and stromal cells in the lung, but primarily T helper 2 (Th2) cells and innate lymphoid type 2 cells (ILC2s).

Question 34

what is dupilumab?

Answer 34

anti-IL-4Ra which is shared for both IL-4 and L-13 - stops IL-4 and IL-13 binding to their receptor - these cytokines are important in IgE class switch in allergic disease, eczema, dermatitis, nasal polyps - in a patient treated with dupilumab and their blood eosinophils are measured, the eosinophil count is unaffected, but their migration into the airway is reduced, as the IL-4/13 can't induce chemoattractant release

Question 35

what is tezepelumab?

Answer 35

anti-TLSP - human monoclonal IgG2 - anti-alarmin - blocks TSLP from interacting with its receptor - early driver of inflammatory cascade - reduces eosinophils, IgE, reduces FeNO - but not sure how effective this is

Question 36

how does mepolizumab affect blood eosinophils?

Answer 36

COLUMBA study Approximately 80% reduction in blood eosinophils maintained for up to 4.5 years

Question 37

how effective is anti-IL-5(R) in severe eosinophilic asthma?

Answer 37

reduce OCS exacerbations effectively - work in 70-80% of cases - evidence that they work

Question 38

what has omalizumab been licensed for?

Answer 38

allergic asthma: - used in IgE mediated (allergic) severe asthma 6yrs+, in patients with FEV1 <80% and high IgE range - Maintenance OCS or intermittent => 4 per year - Optimised standard treatment (step4+) - Specialist centres delivery - 16 weeks treatment trial to see if patient symptoms improve - used since 2005 long term omalizumab outcomes: - reduces admissions from 4.8 a year to 0.9 - improves FEV1 from 59.2 to 75.7 - improves ACQ from 4 to 2.3 - improves FeNO

Question 39

is dupilimab effective?

Answer 39

Effective in T2 high asthma with high FeNO and high hosinophils - reduces dose of steroids needed - improves lung function - improves symptoms, reduces exacerbations

Question 40

what is infective asthma?

Answer 40

- other cytokines like IL-17, IL-22 - Th17-inducing cytokines - Th17 cells induced - tends to be driven by bacteria - sputum culture shows influenzas - chronic cough - neutrophilic asthma

Question 41

how can infectious asthma e.g. fungal asthma be treated?

Answer 41

Anti-inflammatory effect of Itraconazole in stable allergic bronchopulmonary aspergillosis - reduces sputum neutrophil count and ECP levels in sputum

Question 42

how can a bacterial infectious asthma be treated?

Answer 42

azithromycin antibiotic in AMAZES study - can reduce exacerbations and flare ups and improve symptoms Exacerbation-free days: Azithromycin: 344 days Placebo: 148 days

Question 43

is tezepelumab effective?

Answer 43

Blocking TSLP with TEZSPIRE reduces a broad spectrum of biomarkers and cytokines associated with airway inflammation - multitude of effects - reduces IL-5 to reduce eosinophils - reduces IgE - reduces IL-4, IL-13 - reduces FeNO - can work in neutrophilic asthma too, should work across all asthma phenotypes, including allergic, eosinophilic

Question 44

what are the treatable traits in severe asthma?

Answer 44

- phenotypes/treatable traits - things that can be measured that respond to treatments - eosinophilic and FeNO high (type 2 high) - many eosinophils = bad disease, more likely to respond to mepolizumab - allergic with high IgE, eczema = respond better to omalizumab, dupilumab - infective asthma - treat with antimicrobials - tezepilumab will work across all phenotypes, specifically in T2 inflammation high, less effective in neutrophilic - most treatments effective in T2 high inflammatory asthma - can reduce exacerbations by 70% - neutrophilic asthma will rely moreso on antimicrobials - only 30% response however

Question 45

which patients should be referred to severe asthma centre?

Answer 45

The NHS definition of patients who should be referred is as follows: Patients fulfilling the ERS/ATS definition of severe asthma and one of the following: An event of acute severe asthma which is life threatening requiring invasive ventilation with elevated inflation pressures within the last 10 years Continuous or frequent treatment with oral corticosteroids (defined as 2 or more courses in the previous year) Fixed airflow obstruction, with a post bronchodilator FEV1 less than 70% of predicted normal Referred as an adolescent transition patient from a paediatric severe asthma service