JC17 (Medicine) - Asthma and Allergic Lung Diseases Flashcards
Define Asthma
Asthma: defined a chronic inflammatory disorder of airways
□ Leading to widespread but variable airflow obstruction
□ R_eversible_ either spontaneously or with treatment
□ Inflammation is a/w bronchial hyper-responsiveness to a variety of stimuli
4 types of asthma
□ Atopic asthma: individuals with tendency to atopy
→ Predisposition to synthesize IgE to common allergens
→ Hx of infantile eczema and allergic rhinitis
□ Non-atopic asthma: individuals with no evidence of atopy
→ Usually in adults
→ Often triggered by respiratory infections and inhaled air pollutants
□ Drug-induced asthma: asthma provoked by drugs (eg. aspirin)
□ Occupational asthma: provoked by occupational pollutants (eg. fumes, organic dusts)
4 host risk factors to asthma
□ Genetics: certain genes with ↑risk of asthma (eg. IL-3, IL-4, TNF-α…)
□ Atopy: ↑asthma prevalence with ↑serum IgE level
□ Gender: M>F in children/young adults, F>M in adults
□ Obesity: asthma more common and difficult to control if BMI >30kg/m2
→ Obese subjects usually have poorer lung function and more co-morbidities
Environmental triggers of Asthma
□ Allergens:
→ Indoor: fecal pellets of house dust mites, pets, cockroaches
→ Outdoor: alternaria (a genus of Ascomycete fungi), air pollution, tobacco smoke/ second hand smoke
→ Occupational (5-15% of adult onset asthma)
□ Infection
□ Other triggers: exercise, cold air
Describe the T-helper cell response to Intracellular vs Extracellular pathogens
Naïve CD4+ T cells (Th0) activated by interaction with Ag presented by MHC-II
Further differentiation based on predominant cytokine profile
- Th1 differentiation facilitated by IFN-γ, IL-12 → promotes cell-mediated immunity → ↑macrophage, neutrophil, CD8+ T cells activity → elimination of intracellular bacteria and viruses
- Th2 differentiation facilitated by IL-4, IL-5 → promotes humoral immunity → ↑IgE production, mast cell and eosinophil recruitment, growth and differentiation → elimination of extracellular pathogens (eg. parasites)
- Reciprocal inhibition
Compare Th1 vs Th2 mediated immune response
Naïve CD4+ T cells (Th0) activated by interaction with Ag presented by MHC-II
Th1 differentiation facilitated by IFN-γ, IL-12 → promotes cell-mediated immunity → ↑macrophage, neutrophil, CD8+ T cells activity → elimination of intracellular bacteria and viruses
Th2 differentiation facilitated by IL-4, IL-5 → promotes humoral immunity→ ↑IgE production, mast cell and eosinophil recruitment, growth and differentiation → elimination of extracellular pathogens (eg. parasites)
Explain the Hygiene Hypothesis and propensity of atopy
Hygiene hypothesis: proposed mechanism behind atopic tendency in some individuals
□ Childhood microbial exposure associated with ↓allergy and asthma
→ Lifestyle: ↑family size, older siblings, day care
→ Farming: animal contact, stable exposure, drinking unpasteurized farm milk
→ Animal exposure: pet keeping
□ Reason: ↓childhood Th1 activation → poor Th1 development → hyperactive Th2 system → overreaction to allergens (Type I hypersensitivity)
Explain the effects of hypersensitivity reaction on airway
→ Bronchoconstriction due to abnormal smooth muscle response to inflammation
→ Airway inflammation due to vasogenic oedema and inflammatory infiltrate
→ Mucous hypersecretion
Describe Type I hypersensitivity reaction against allergens
Atopic asthma: type I HS reaction towards allergens
Allergen exposure → Th2 response activated → IL-4 → ↑IgE production
→ binds to and sensitizes mast cells
→ further exposure to same allergen results in release of mast cell mediators (immediate phase) → IL-5
→ eosinophil activation and recruitment (delayed phase)
Explain mechanism of aspirin-induced asthma
Aspirin-induced asthma: inhibition of cyclooxygenase → arachidonic acid shunted towards lipoxygenase pathway → ↑leukotrienes (potent bronchoconstrictors)
Explain exercise-induced asthma
Exercise-induced asthma: hyperventilation → water + heat loss from mucosa → lining irritated → inflammatory mediator release
Describe the sequalae of chronic airway inflammation
1) Airway hyper-reactivity
2) Airway remodeling
□ Chronic inflammation results in irreversible structural changes predisposing to airflow obstruction
□ Includes:
→ Smooth muscle hyperplasia → ↑bronchoconstriction
→ Goblet cell hyperplasia → ↑mucus secretion
→ Fibrosis → airway wall thickening
Define the clinical features of asthma
- S/S
- Temporal pattern
- Associated symptoms
Recurrent episodic attacks of wheezing, chest tightness, breathlessness, cough
Characteristically occurs following exposure (5-15min) and resolve with trigger avoidance or asthma medications
Classically with diurnal variation → worse at night or early morning
± signs of atopy: allergic rhinitis, eczema
Ddx of generalized wheeze and localized wheeze
D/dx of generalized wheeze:
- COPD
- Bronchiectasis
- Bronchiolitis obliterans
- Viral bronchiolitis (in children)
D/dx of localized wheeze:
- Tumour
- Foreign body
Outline Diagnosis for Asthma
- Clinical features
- Lung Function test metrics
1) Predominantly clinical based on compatible Hx ± P/E
□ Hx: variable symptoms of wheezes, cough, chest tightness, SOB
□ P/E: characteristic widespread, polyphonic wheezes during attacks
2) Lung Function Test: Spirometry or Peak flow meter
≥1 instance of ↓FEV1/FVC, i.e. ≤75% in adult, ≤85% in children
≥12% and 200mL ↑FEV1 after bronchodilator or ICS
>10% diurnal variability in twice daily PEF over 1-2w
Specific test for airway hypersensitivity
Airway hyper-reactivity: by bronchoprovocation test
≥20% ↓FEV1 post-methacholine/histamine at standard dose
≥15% ↓FEV1 post-hyperventilation, hypertonic saline or mannitol challenge
Second line investigations for Asthma
□ Allergic status: skin prick test, total/allergen-specific IgE, serum eosinophil count
□ CXR: normal or hyperinflated ± lobar collapse (2o to mucus obstruction) → mainly to exclude alternative d/dx
□ Flow-volume loop: ‘scooped out’ concave appearance signifying diffuse intrathoracic airflow obstruction
□ Airway inflammation tests:
→ Sputum eosinophil count >2%
→ Exhaled breath NO concentration (FENO)
Characteristic spirometry graph shape for asthma
“Scooped out appearance”
Major Ddx of Asthma
COPD
asthma-COPD overlap syndrome (ACOS)
Bronchiectasis
Central airway obstruction
Tests to rule out major Ddx of Asthma
1) COPD: Diagnosed by abnormal post-bronchodilator spirometry
2) Bronchiectasis: Diagnosed by CXR/HRCT demonstrating airway dilatation (‘tram-line’ appearance)
3) Central airway obstruction: Spirometry also shows obstructive pattern but flow volume loop is characteristic for upper airway obstruction (expiratory plateau)
Assessment of asthma control
Assessment of asthma control by two domains:
□ Symptom control: should have daytime asthma symptoms and reliever use ≤2×/w + no night waking + no activity limitation
□ Risk assessment: based on risk factors for exacerbation, fixed airflow limitation and medication S/E
Assessmnet of severity of asthma
Severity of asthma: retrospectively from level of Tx required to control symptoms and exacerbation
□ Assessed at a few months after starting on controller Tx
□ Mild asthma: well-controlled with steps 1 or 2
□ Moderate asthma: well-controlled with step 3
□ Severe asthma: well- or poorly controlled with steps 4 or 5
Measures to decrease house dust and mites
- Encasement of mattresses, pillows and duvets with vinyl covers
- Wash all bedding with hot water regularly every ≤2w
- Remove carpets and stuffed toys
Aims of asthma management
□ Complete control
→ No attacks, A/E visits, hospitalization
→ No or minimal symptoms
→ No limitation of activity
→ Normal or near normal lung function
□ With least medications and least S/E
3 pillars of asthma management
- Patient education: stop smoking, weight loss…
- Avoidance of triggers
- Control-based asthma management
Outline classes of drugs used for asthma control
- Reliever: short-acting bronchodilators → for breakthrough symptoms and preventing exercise-related symptoms
- Controller: should be initiated asap after diagnosis of asthma for an improvement in outcome
→ Anti-inflammatory drugs to ↓airway inflammation
→ Long-acting bronchodilators to ↓bronchoconstriction - Add-on therapy: for patients with severe asthma
Explain the principle of control-based asthma management (steps)
Review response and adjust treatment at 1-3mo after starting and every 3-12mo thereafter:
□ Stepping up: after reviewing alternative causes of poor control as below
□ Stepping down: considered when sustained control for >3mo + low risk of exacerbation
List controller and reliever needed for Step 1 asthma control
Reliever: Low dose ICS + Formoterol
Controller: As-needed Low dose ICS + Formoterol
List controller and reliever needed for Step 2 asthma control
Reliever: SABA or Low-dose ICS/ formoterol
Controller:
- Regular low-dose ICS
- LTRA* (alternative to ICS)
- Low dose ICS/ LABA (same efficacy as ICS)
List controller and reliever needed for Step 3 asthma control
Reliever: SABA or low dose ICS/ Formoterol
Controller:
- Low dose ICS + formoterol
- Medium dose ICS
- Low dose ICS + LTRA + Theophylline SR* (C/O children)
List controller and reliever needed for Step 4 asthma control
Reliever: SABA or low-dose ICS/formoterol
Controller:
- Medium-dose ICS/LABA or low-dose ICS/formoterol (also as reliever)
- High-dose ICS/LABA
- Theophylline SR or LTRA as add-on (C/O children)
- Tiotropium (LAMA) as add-on (C/O children)
List reliever and controller for step 5 asthma control
Reliever: SABA or low-dose ICS/formoterol
Controller:
- ICS/LABA
- Oral maintenance corticosteroids
- Tiotropium (LAMA)/ Omalizumab (anti-IgE)/ Anti-IL-5 as add-on
- Mast cell stabilizers
- Sputum-guided treatment for Eosinophil count
- Non-pharmacological treatment: bronchial thermoplasty, high-altitude treatment, psychological interventions
Management of patient with poor asthma control after medication
□ Inhaler use: inhaler technique, adherence and barriers to use
□ Other/ Alternative diagnosis: esp if variable airflow limitation has not been demonstrated
□ Remove exacerbators: triggers, inducers (smoking, β-blockers, NSAIDs), comorbidities (eg. rhinitis, obesity, GERD, OSA)
□ step up treatment
Routes of controller and reliever administration for astham control
□ Nebulizer: use of medication solution to generate a mist for inhalation
□ Inhaler: different types, which MDI can be used with or without spacer
Advantage and disadvantage of Nebulizer
Advantage: (1) no need hand-mouth coordination (2) Use in status asthmaticus
Disadvantage: (1) requires electricity (2) may transmit infection (3) high dose side effect
Advantage of using a spacer with inhaler
Spacer: suspends aerosol inside spacer → Decrease oropharyngeal deposition of aerosol
List 4 bronchodilator classes with examples
- Short-acting β2-agonist (SABA) e.g. salbutamol (Ventolin), terbutaline (Bricanyl)
- Long-acting β2-agonist (LABA) e.g. salmeterol (Serevent), formoterol (Oxis)
- Long-acting muscarinic antagonist (LAMA) e.g. tiotropium bromide
- Methylxanthines e.g. theophylline, aminophylline
MoA and S/E of SABA
MoA: β2 activation → Gsα → ↑cAMP → smooth muscle relaxation
S/E: β-agonistic effects include tremor, headache, arrhythmia, hypoK
MoA and function of LAMA
MoA: ↓mAChR activation → ↓Gq → ↓Ca2+ → smooth muscle relaxation
Use: as add-on therapy in step 4 onwards
S/E: Acute close angle glaucoma
MoA and S/E of methylxanthines
MoA: inhibition of phosphodiesterase → ↑cAMP → SM relaxation
add-on therapy from step 3 onwards
S/E: diuresis, CNS/CVS stimulant effect, GI disturbance, unpredictable drug interactions
List 5 anti-inflammatory drugs for asthma control with examples
Inhaled corticosteroids (ICS) Examples: beclomethasone (Becloforte (250μg), Beclotide (50μg)), budesonide (Pulmicort), fluticasone (Flixotide)
Leukotriene receptor antagonist (LTRA) Examples: montelukast (Singulair), zafirlukast
Anti-IgE antibody Examples: omalizumab
Anti-IL-5 therapy Examples: mepolizumab, reslizumab (anti-IL5), benralizumab (anti-IL5r)
Mast cell stabilizer Examples: cromolyn sodium, nedocromil sodium
S/E of ICS
S/E: minimal systemic effect, oral candidiasis (5-10%)
→ reassure (harmless), then treat by nystatin suspension for gargle or lozenge
MoA and use of LTRA
MoA: block action of leukotriene (AA derivative) → ↓bronchoconstriction
Use: as steroid-sparing therapy in mild/moderate asthma, esp effective in exercise- and aspirin-induced asthma
MoA and use of Anti-IgE antibody
MoA: binds IgE → ↓activation of mast cells and basophils
Use: reserved for atopic asthma (with documented ↑IgE, +ve skin prick test)
or as steroid-sparing therapy in steroid-dependent asthma
MoA and use of Anti-IL5 therapy
MoA: block action of IL-5 → ↓eosinophilic airway inflammation
Use: reserved for eosinophilic asthma with (↑serum eosinophil count)
Example, MoA and use of Mast cell stabilizer
Nedocromil sodium, Sodium chromoglycate
MoA: ↓mast cell degranulation and activation + ↓exaggerated irritant receptor neuronal reflex
Use: rarely used due to limited benefit in severe asthma and ↓availability
2 main types of inhaler
Metered dose inhaler - more common aerosol form with hand-eye coordination
Dry powder inhaler - breath activated powder form for poor technique, multiple inhalation per go
Life threatening features of acute asthmatic attack
Silent chest
Hypotension
One-third of best/predicted PEF
Cyanosis
Confusion
Compare presentation of Mild/ moderate to severe acute exacerbation of asthma
Mild:
- Talk in phrases, prefer sitting, calm
- Increase RR, no use of accessory muscles
- HR 100-120, SpO2 90-95%, PEF > 50% predicted
Severe:
- Talk in words, lean forward, agitated
- RR >30, use of accessory muscles
- HR >120, SpO2 <90%, PEF <50% predicted
Management of mild acute exacerbation of asthma
Monitor vital signs, pulse oximetry, PEF/FEV1, ABG, electrolytes, CX
□ Controlled O2 therapy aiming SpO2 93-95% by nasal cannulae or mask
□ SABA: salbutamol 4 puffs Q4H with spacer + PRN use
□ Oral corticosteroids
Management of severe acute exacerbation of asthma
Monitor: vital signs, pulse oximetry, PEF/FEV1, ABG, electrolytes, CXR
O2 therapy SpO2 93-95% target
SABA
Oral/ IV corticosteroids
Add-on Ipratropium bromide
Monitoring of acute exacerbation of asthma
Reassessment in ALL patients 1h after initial treatment
Assess: clinical status, response to treatment, lung function measurement (PEF, FEV1)
Adjust dose of SABA and increase/ taper corticosteroid
Adjust O2 and wean after 95% O2
Discharge when PEF/FEV1 > 60% predicted
