asthma Flashcards
definition
o Heterogenous disease usually characterised by chronic airway inflammation.
o history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation – measure by lung func tests (FEV1 or PEF)
what is asthma
• common and potentially serious chronic disease that can be controlled but not cured
symptoms
• wheezing, shortness of breath, chest tightness and cough that vary over time in their occurrence, frequency and intensity
cause of symptoms
o variable expiratory airflow:
o Bronchoconstriction (airway narrowing)
o Airway wall thickening
o Increased mucus
• Things that trigger/worsen symptoms
o viral infections, allergens, tobacco smoke, exercise and stress
pathogenesis
o chronic inflamm disease narrow airways
o Airway hyperresponsiveness to bronchoconstrictor substances – shown in lab with histamine/methacholine, airway remodelling, goblet cell hyperplasia, mucus production, smooth muscle contractility and proliferation
o Lead to exacerbations, fixed airway obstruction
Airway remodelling in asthma
o Thicker
o Fibrosis under epithelium
o Increase number of bv
o Increase mucus production
Diagnosis of asthma
o A history of characteristic symptom patterns
o Evidence of variable airflow limitation, from bronchodilator reversibility testing or other tests
o Document evidence for diagnosis before starting treatment – difficult to confirm diagnosis when treatment has been started
asthma control
o Assess asthma – measure components of control: symptoms, nighttime awakenings, interference with normal activity, short acting B2 agonist use for symptom control (not prevention of EIB), FEV1 or peak flow, validated questionnaires (ATAQ, ACQ, ACT)
• Drugs for asthma – relievers
o Use when get symptom of asthma – from trigger
o Short-acting β2 -adrenoceptor agonists (SABA) – for few hrs inhaled
o Long-acting β2 -adrenoceptor agonists (LABA) –for 12 hrs or more inhaled
o Muscarinic receptor antagonists (SAMA, LAMA) – inhaled
• Drugs – controllers – anti-inflamm agents
o Glucocorticosteroids (GCS) – inhaled/oral
o COMBINATIONS – LABA/GCS, LABA/LAMA, triple therapy LABA/LAMA/GCS – inhaled
o Leukotriene (cysteinyl) receptor antagonists (LTRA) – oral
o Theophylline – controller – not used as much now
previous management of asthma GINA
o Stepwise management
o Assess - Diagnosis, symptom control and RF (including lung function), inhaler technique and adherence, patient preference
o Adjust treatment - Asthma med, non-pharm strategies, treat modifiable RF
o Review response – symptoms, exacerbations, SE, patient satisfaction, lung function
o Initiate treatment in pt with no treatment before – determine severity and then judge at what step start
o 1 - Few/occasional symptom – consider low dose ICS, SABA as needed
o 2 - If not as good control – low dose ICS and SABA as needed
o 3 - Then combination ICS/LABA – as needed SBA, low dose ICS/formoterol
o 4 -Increase dose– as needed SBA, low dose ICS/formoterol
o Max dose at step 5, and add on other treatment – oral corticosteroids – as needed SBA, low dose ICS/formoterol
• Synergistic action of ICS and LABA
o ICS = budesonide
o LABA = formoterol
o Synergistic = combination is more efficacious than either on own
o Budesonide acts on glucocorticoid receptor to have anti-inflamm effect
o formoterol on B2-adrenoceptor for bronchodilation
o causes less exacerbations
• combination of Seretide and fluticasone proprionate
o seretide = salmeterol (LABA) and fluticasone propionate (ICS)
o end point – well controlled asthma after 1yr
o more go from poorly controlled asthma to well controlled with combined med than ICS alone
mild asthma treatment change
o step 1 – was just reliever SABA usually salbutamol – but can get exacerbations of disease that might need treatment in hospital so now advised that they start anti-inflamm/controller treatment – consider ICS/LABA or ICS/formoterol
o risk of moderate/severe exacerbation (exacerbation needing extra treatment) – with SABA high compared to ICS and LABA wither continuous or as needed
clinical phenotypes of asthma
o treat asthma on degree of control/severity, not what type of asthma
o allergic asthma eg provoked with animals – childhood onset
o occupational asthma – sensitiser induced or not
o intrinsic asthma
o air pollution induced
o infection related
o cigarette smoke induced
o obese asthma
o aspirin exacerbated
o cough variant asthma
o exacerbation prone asthma
o asthma persistent airflow limitation
o air pollution induced
o elite athelete exercise induced asthma
o categories: childhood-onset, adult-onset, eosinophilic, non-eosinophilic
eosinophils in asthma
o if eosinophilia – respond well to ICS
o eosinophils damage epithelium -produce biomarkers that have effect on sm cells that cause contraction, cytokines effect fibroblasts, mast cell activation
type 2 inflammation
o eosinophils drive asthma through type 2 inflammation
o Th2 cells are central mediators of the adaptive response in type 2 immunity
o adaptive cells – Tfh cell, Th2 cell
o innate – ILC2, mast cell, basophil, eosinophil
o Both Th2 and innate cells produce the key cytokines involved in type 2 inflammation
o cytokines – IL4, Il13, IL5
IL5
effect on eosinophil maturation in bone marrow – when mature they kleave marrow and target lungs
o In lungs IL 5 increase survival of eosinophils in lungs
IL4 and IL13
o Mediate adhesion of eosinophils and migration from endothelium into the lung tissue o IL13 – increase mucus goblet cells and secretion and increase proliferation of sm proliferation = subepithelial fibrosis and collagen deposition o Mainly IL4, but some IL13 – involved in B cell class switching and IgE production – switch B cell from producing IgG to IgE – IgE latch onto receptors on mast cell = activation of mast cell = mast cell production of leukotrienes, histamine, PGD2 = airflow obstruction -> exacerbation, bronchial obstruction, impaired lung function, symptoms
affect of allergens, viruses and irritants
o Activate type 2 inflammation
• Relevance of type 2 inflamm
o Med target the cytokines
o Anti-IgE: omalizumab – recommended for allergic asthma
o Anti-IL5 (mepolizumab, reslizumab), anti-IL-5Ra (benralizumab)
o Anti-IL-4Ra blocking IL-4/IL13 signalling (dupilumab)
o Treatments recommended aty step 5 in pts with sever asthma
severe asthma
o 5% pts with asthma
o Pts get treatment recommended and still not responding – poor symptom control, serious/frequent exacerbations, airflow obstruction (FEV1)
o “asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.”
o Uncontrolled asthma while on high dose therapy = GINA step 4 and 5
o Controlled asthma that becomes uncontrolled on tapering of high-dose corticosteroids – GINA 5
• Effectiveness of mepolizumab
o Block the eosinophils
o Reduction of approx. 50% rate of exacerbations, and improvement in FEV1 and QOL
when do you treat for severe asthma
o Step 5
o Criteria of type 2 inflammation:
o Blood eosinophils ≥150/μL and/or • FeNO ≥20 ppb and/or • Sputum eosinophils ≥2% and/or • Clinically allergen-driven • Need for maintenance OC
what are other types of asthma than T2 inflammation
o Neutrophilic inflammation
o Remodelling/repair
precision medicine
o an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.
• Systems biology of asthma
o Clinical phenotypes – symptoms, physiology, inflamm markers
o Molecular phenotypes – RNA, DNA, proteins – tell mechanism driving disease = specific treatment
o Endotypes
o Biological responses
o Therefore understand how exposome, lifestyle and genome influence the biological responses
• T2-high mechanisms/pathways
o TAC1
o IL-33R, TSLPR, CCR3
o Severe airflow obstruction Highest exacerbation Nasal polyps Oral corticosteroid dependent Highly Eosinophilic (some neutrophilia)
• T2-low/non-T2 mechanisms/pathways - TAC2
IFN & TNF pathways Moderate airflow obstruction More eczema High C-Reactive protein levels Highly Neutrophilic (+ eosinophilia)
• T2-low/non-T2 mechanisms/pathways TAC3
Oxidative stress Ageing
Moderate airflow obstruction Least exacerbations Paucigranulocytic/ eosinophilic
• Type 2 inflammation types of asthma
o Allergic
o Late onset eosinophilic
o Exercise induced
• Non-type 2 inflammation
o Very late onset
o Obesity associated
o Smoking associated neutrophilic
o Smooth-muscle mediated, paucigranulocytic
GINA treatment
step 1: As-needed low-dose ICS-formoterol, Low-dose ICS taken whenever SABA is taken, step 2 Daily low-dose inhaled corticosteroid (ICS), or as-needed low-dose ICS-formoterol, Leukotriene receptor antagonist (LTRA), or low-dose ICS taken whenever SABA taken, step 3 Low-dose ICS-LABA, Medium-dose ICS, or low-dose ICS + LTRA step 4 Medium-dose ICS-LABA, High-dose ICS, add-on tiotropium, or add-on LTRA step 5 High-dose ICS-LABA Refer for phenotypic assessment ± add-on therapy, eg tiotropium, anti-IgE, anti-IL-5/-5R, anti-IL-4R, Add low-dose OCS, but consider side effects
relievers used - GINA
As-needed low-dose ICS-formoterol
As-needed short-acting β2 agonist (SABA)
