Asthma – Comprehensive Study Notes (Monash BMS3052)

Asthma – Comprehensive Study Notes (Monash BMS3052)

Objectives and scope

• Understand how measurement of lung function can be used to differentiate between asthma, COPD and fibrotic lung diseases.
• Understand basic principles of inhaled drug delivery.
• Describe the major characteristics of asthma and how they drive treatment.
• Understand the mechanisms of action, uses and adverse effects of different classes of medication used to treat asthma.
• Reiterated in slide set: compatible respiratory symptoms with reversible obstruction or variable airflow obstruction; inflammatory and remodeling processes; pharmacologic strategies (relievers, preventers, biologics) and non-pharmacologic options (e.g., bronchial thermoplasty).

Lung function and imaging/measurement framework

Factors that influence lung function

• Inflammation of airway and tissue
• Changes to airway smooth muscle
• Epithelial damage
• Mucus plugging
• Alveolar damage
• Fibrosis – airway and tissue
• Tumour
• Obesity
• Variable contributions in asthma, COPD, fibrotic lung diseases and comorbidities
• Core adage: "If you can’t breathe, nothing else matters" (motivational framing)

Lung function testing in the clinic – spirometry

• Requires specialised equipment and trained respiratory physiologists
• Tests are safe but physically demanding; implications for children, elderly, advanced disease
• Measurements include FEV1, FVC, and FEV1/FVC ratio

Spirometry definitions

• FEV1: forced expiratory volume in one second
  • Measures how quickly full lungs can be emptied; volume exhaled in the first second of maximal expiration initiated at full inspiration
• FVC: forced vital capacity
  • Volume expired from full inspiration to full expiration
• Values are compared to reference values for same sex, age, height
• Normal function: baseline reference values

Obstructive vs restrictive disease

• Obstructive: difficulty breathing out (e.g., asthma, COPD)
• Restrictive: difficulty breathing in (e.g., IPF, silicosis)

Lung function testing in diagnosis – asthma

• Increased airway resistance → decreased FEV1 and FEV1/FVC
• Measurements pre- and post-bronchodilator
• Values usually improve with asthma, less so with COPD or fibrosis

Home lung function testing – PEF

• Peak Expiratory Flow Rate (PEF) can be measured at home
• Normal adult values: males $[450,700]$ L/min; females $[300,500]$ L/min
• Values also depend on age, height, weight

Home measurements – variability and asthma indication

• Morning PEF is typically lower
• Variability of >20 ext{%} indicates asthma

Recap of objectives (re-stated in slides)

• See above objectives; emphasis on lung function differentiation, inhaled delivery, asthma characteristics, and medication mechanisms/side effects

Inhaled drug delivery – principles and devices

Drug delivery for lung diseases – inhaled route

• Devices designed to deposit drug locally in the lung
• Delivery depends on:
  • Inhaler technique
  • Particle/droplet size determines deposition site:
  • 5–10 μm deposited on upper airways
  • 0.5–5 μm deposited in small airways
  • <2 μm reach alveoli
• Some drug swallowed, with variable systemic effects

Inhaler technique and patient education

• Correct use of inhalers is critical; common misperceptions among patients (emphasized by video reference)
• Use an asthma action plan

Practical example and public health tip

• Only 1 in 3 people with asthma use regular daily medication; emphasis on adherence and plan-based management
• Example materials referenced: National Asthma Council Australia and Monash materials

Epidemiology and public health context

Population and economic burden in Australia

• Approximately ~2.8 million Australians with asthma (about 1 in 9)
• Age distribution:
  • Aged 0–14: boys > girls
  • Aged >15: women > men
• Healthcare costs and lost productivity (patients and caregivers)
• Yearly statistics cited:
  • 2016 – 455 deaths (312 F / 143 M)
  • 2018 – 389 deaths (250 F / 139 M)
  • 2020 – 417 deaths (274 F / 143 M)
  • 2022 – 467 deaths (299 F / 168 M)
• Asthma contributed to 2,472 deaths (1.3%) in the period cited

Asthma mortality trends (Australia)

• Mortality rates over time show fluctuations; data points include 1977–1986, 1989, 2010, 2020, 2021, 2022 with deaths per 10,000 population decreasing overall but with spikes in some years
• Noted factors: aging population, risk in elderly, adherence, access to safer drugs and better management

Thunderstorm asthma (2016)

• Mechanism: thunderstorms pull in pollen fragments that are inhaled into dangerous sizes, triggering severe allergic asthma in susceptible individuals
• Event dynamics and media coverage referenced; clinical relevance for management and public health alerts

Bushfires and asthma (2019/20)

• Air Quality Index reached hazardous levels in parts of Australia
• Health impacts from bushfire smoke included >400 deaths (all causes), >2,000 respiratory hospitalisations, >1,300 Emergency presentations for asthma
• Public health data cited from state/territory surveys

Definitions and classifications of asthma

Core definition

• Chronic inflammatory lung disease characterized by reversible airway narrowing and increased airway hyperresponsiveness (AHR)
• Recurring symptoms: shortness of breath, wheeze, chest tightness, night-time or early morning coughing
• Imbalance between airway contraction and relaxation

Extrinsic (allergic) vs intrinsic (non-allergic) asthma

• Extrinsic (allergic): involves IgE antibodies and mast cell degranulation; triggered by exposure to allergens (e.g., pollen, house dust mite, pets)
• Intrinsic (non-allergic): not driven by allergen exposure; can be more severe; triggers include cold, infection, exercise (exercise can reduce attack frequency in some cases)
• Therapeutic implications reflect different inflammatory pathways (IgE, IL-5, etc.)

Classification and sources

• Modern classification emphasizes onset, cause, cell type, severity, and treatment response
• Holgate et al. (Nat Rev Dis Primers, 2015) cited as a foundational framework

Diagnosis of asthma

Diagnostic criteria

• Compatible respiratory symptoms plus evidence of reversible airway obstruction (spirometry) or variable airflow obstruction (peak expiratory flow monitoring)
• If these criteria are not met but suspicion remains:
  • Bronchoprovocation testing with methacholine or mannitol (some contraindications)
  • Emerging approaches: evaluation of inflammatory cells in sputum and FeNO (fractional exhaled nitric oxide) in exhaled breath

Pathogenesis and airway remodeling

Pathophysiological cascade

• Inflammation drives airway changes and remodeling
• Pathogenesis components referenced include:
  • Inflammatory mediators and increased bulk of sensitised smooth muscle leading to excessive contraction
  • Basement membrane thickening and fibrosis contribute to remodeling
  • Targeted by preventer meds (inflammation) vs reliever meds (bronchoconstriction)
• Foundational review: Holgate et al., Nat Rev Dis Primers (2015)

Airway hyperresponsiveness (AHR)

• Inflammatory mediation and increased muscular bulk lead to airways contracting too easily and too much
• Structural changes include smooth muscle changes and basement membrane thickening
• Contributing factors include IgE, IL-5, eosinophils, leukotrienes, histamine, and other mediators

Immunologic pathways (historical schema)

• Healthy airways: TH1 response to aeroallergens
• Allergic asthma: TH2 deviation to aeroallergens
• Key mediators: IgE, histamine, leukotrienes, IL-5, IL-4/IL-13, eotaxins
• Induction phase: allergy-related inflammation; airway remodeling; smooth muscle shortening; difficult-to-prevent induction phase
• Targets for pharmacologic therapy include anti-IgE, anti-IL-5, anti-IL-4R, anti-TSLP, and other cytokine pathways

Pharmacology – core drug list and mechanisms

Core drug classes (as of slide deck)

• Dilators (bronchodilators)
  • β2-adrenoceptor agonists ( bronchodilators )
  • Salbutamol (SABA, short-acting)
  • Formoterol (LABA, long-acting) in combination with ICS
  • Antimuscarinics: Ipratropium (SAMA), Tiotropium (LAMA)
  • Theophylline (PDE inhibitor, bronchodilator)
  • Montelukast (leukotriene receptor antagonist)
• Anti-inflammatories
  • Inhaled corticosteroids (ICS): Fluticasone, Budesonide
• Biologics (targeted therapies)
  • Omalizumab (anti-IgE)
  • Mepolizumab (anti-IL-5)
  • Reslizumab (anti-IL-5)
  • Benralizumab (anti-IL-5 receptor)
  • Dupilumab (anti-IL-4R)
  • Tezepelumab (anti-TSLP)

Why use preventers vs relievers?

• Preventers target baseline inflammation and the late (chronic) phase of asthma.
• Relievers target the immediate (acute) phase to relieve airway smooth muscle spasm; they do not treat inflammation.
• Salbutamol is the most commonly used reliever

Short-acting β2-agonists (SABA) in practice

• Salbutamol discovered in the 1960s; selective for β2 and inhaled to minimize cardiac side effects
• Instant relief for mild symptoms but increased use signals more frequent/severe symptoms and potential adverse effects
• Drawbacks: can mask underlying inflammation, risk of tolerance, insufficient control of disease if used alone
• Recommendation: target inflammation in addition to bronchodilation

Track-based treatment approaches (current guidelines in slides)

• Track 1 (preferred when feasible): single inhaler with low-dose ICS-formoterol (Symbicort) as reliever; ICS provides anti-inflammatory effect
  • Low-dose corticosteroid (e.g., budesonide) combined with rapid-onset, long-acting β2-agonist (eFormoterol)
  • Provides instant relief plus anti-inflammatory activity; aims for ongoing disease control
• Track 2 (less preferred, two inhalers): Step 1 – Salbutamol as needed plus low-dose ICS as needed; Step 2 – Salbutamol as needed plus daily low-dose ICS
• For Track 1 and Track 2, Steps 3–5 involve daily ICS with LABA/ICS combinations, escalating doses as needed; biologics for severe asthma only

Relievers – mechanism of action (SABA)

• Contraction pathways involve mediators of allergy (histamine, leukotrienes) and parasympathetic signaling (ACh via M3 receptors)
• IP3-mediated Ca2+ release leads to contraction; MLC phosphorylation drives contraction
• Relaxation pathways involve β2-adrenoceptor activation:
  • Gs protein activation → adenylate cyclase → ↑cAMP → PKA activation
  • PKA leads to reduced IP3-mediated Ca2+ release and activation of MLCP (myosin light chain phosphatase) → dephosphorylation of MLC → relaxation

Detailed pharmacology – SABA mechanism (summary from slides)

• Contraction mediators: ACh, histamine, cysteinyl leukotrienes (cys-LTs) act via GPCRs → PLC → IP3 → Ca2+ release → MLC phosphorylation
• Relaxation mediators: β2-adrenergic agonists increase cAMP via adenylate cyclase → PKA → reduce Ca2+ release and promote MLCP activity
• Net effect: bronchodilation with SABA; in parallel, inflammation remains addressed by preventers in combination therapies

Adverse effects and limitations of SABA

• Acute systemic effects at high doses: tachycardia (β1), tremor (β2)
• Chronic receptor desensitization/downregulation with overuse, smoking, infection
• No effect on chronic airway remodeling when used alone
• Role of SABA is limited when used as the sole therapy; must address inflammation

Long-acting β2-agonists (LABA) and combination use

• Salmeterol: slow onset, ~12 hours duration
• Formoterol: rapid onset, ~12 hours duration
• Major limitations when used as monotherapy: may mask inflammation and increase mortality risk; therefore always in combination with ICS when used for asthma
• LABA provides protection against exercise-induced or nocturnal asthma in some regimens

Adverse pharmacology – adrenergic and antimuscarinic targets

• ß1 blockade risks: many cardiovascular drugs are ß-adrenergic antagonists; in asthma, non-selective or ß-blockers can provoke bronchoconstriction and are generally contra-indicated
• Muscarinic antagonists (ipratropium, tiotropium) block vagal tone to promote bronchodilation; do not directly affect response to other mediators of contraction
• PDE inhibitors (theophylline) bronchodilate but require monitoring due to narrow therapeutic index and side effects

Montelukast (LTRAs)

• Orally active, prophylactic use (preventer/controller)
• Modest bronchodilatation against leukotrienes compared with β2-agonists
• Not included in stepwise guidelines as a universal controller; useful for aspirin-exacerbated or exercise-induced asthma; can be combined with ICS/LABA
• Limited systemic side effects but possible lipid enzyme interactions and liver function considerations

Inhaled corticosteroids (ICS) – Preventers

• Central anti-inflammatory therapy used at all stages of asthma; most effective at reducing baseline inflammation and airway hyperresponsiveness
• Mechanism (in broad terms): increases anti-inflammatory proteins (e.g., annexin A1) and decreases pro-inflammatory proteins (COX-2, PLA2, IL-1, TNFα); influences transcription factors like NFκB and AP-1
• Onset of anti-inflammatory action precedes clinical bronchodilation; not an acute bronchodilator
• Delivery and technique-critical for efficacy; ICS penetration enhanced when used with β-agonists
• Common local side effects: dysphonia, oral candidiasis; mouthwash recommended to reduce local absorption
• Systemic corticosteroids (oral) used for exacerbations; risks include iatrogenic Cushing’s syndrome, growth suppression in children, metabolic effects, infection risk, behavioral changes, cataracts/glaucoma
• Weaning is important to avoid withdrawal if chronic use is stopped

Track-based ICS use and stepwise escalation (Details)

• Track 1 (one inhaler preferred): single puffer with low-dose ICS/LABA as needed; Steps 1–2 provide instant relief and anti-inflammatory treatment; Steps 3–5 add daily ICS and LABA; Biologics for severe asthma only
• Track 2 (two inhalers): Step 1 – SABA + low-dose ICS as needed; Step 2 – SABA + daily ICS; Steps 3–5 add daily LABA/ICS; may involve two inhalers (Salbutamol + Budesonide or Fluticasone)
• Preventers focus on ICS; relapse management and escalation may include oral steroids during exacerbations; biologics considered for severe cases

Inhaled corticosteroid mechanism – key references

• Mechanism includes upregulation of anti-inflammatory proteins and suppression of inflammatory mediators; example molecular targets include COX-2, PLA2, IL-1, TNFα; also modulation of NFκB and AP-1 transcription factors
• See slides detailing ICS molecular mechanism and annexin A1 involvement

Biologics for severe asthma – overview

• Omalizumab (anti-IgE): blocks IgE to prevent mast cell degranulation and mediator release; subcutaneous every 2–4 weeks; Step 5 for severe allergic asthma uncontrolled on high-dose corticosteroids; low risk of anaphylaxis (~0.1%)
• Mepolizumab (anti-IL-5): reduces eosinophils; subcutaneous every 4 weeks; Step 5 for severe eosinophilic asthma
• Reslizumab (anti-IL-5) and Benralizumab (anti-IL-5R) are alternative IL-5 pathway inhibitors
• Dupilumab (anti-IL-4R) targets IL-4/IL-13 pathway; Tezepelumab (anti-TSLP) targets upstream allergen-sensing pathway
• Selection depends on inflammatory phenotype (Type 2 vs non-Type 2) and biomarker profiles; some patients may require switching to alternative biologics if response is inadequate

Criteria for use – Nucala (mepolizumab) example

• Age: 6 years or older
• Baseline blood eosinophil count: at least 150 cells/μL
• Inadequate asthma control despite optimized ICS and additional controller (LABA, leukotriene modifier, or theophylline)
• Not to be used as monotherapy; not to be combined with other asthma biologics
• Dosing: subcutaneous injections every 4 weeks (as per guidelines)

Clinical remission concept (biologics era)

• A relatively new concept based on success of biologics in selected populations
• Criteria for remission may include:
  • Absence of exacerbations
  • No oral corticosteroid treatment
  • Improvement in lung function for at least 12 months
• Some patients are non-responders or do not meet the right inflammatory phenotype for response

Type 2 versus non-Type 2 inflammation and tailoring therapy

• Type 2 inflammation: often responsive to biologics targeting IgE, IL-5, IL-4/IL-13, and TSLP
  • Anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab), anti-IL-5R (benralizumab), anti-IL-4R (dupilumab), anti-TSLP (tezepelumab)
• Non-Type 2 inflammation: poorer response to classic Type 2 biologics; alternative strategies may include bronchial thermoplasty or non-Type 2 targeted therapies
• If good response, continue the specific biologic; if poor response, consider alternative biologic eligibility

Bronchial Thermoplasty (BT) – non-pharmacologic interventional therapy

• BT applies thermal energy to the airways to reduce airway smooth muscle and improve asthma control
• Approval and evidence base:
  • AIR-2 randomized, double-blind, sham-controlled trial ( Castro et al., AJRCCM 2010 )
  • N = 288; BT delivered to different lobes over three sessions at 3-week intervals
  • Acute worsening of symptoms typically precedes longer-term improvements; primary endpoints focused on quality of life rather than function
• BT is the first non-pharmacologic interventional therapy approved by the FDA for asthma
• TASMA: Targets of Bronchial Thermoplasty in Severe Asthma; outcomes show reduced ASM beyond targeted sites; response correlated with serum IgE and eosinophils rather than ASM mass
• Evidence base summarized in Goorsenberg et al., AJRCCM 2021

Key pathophysiology summary – inflammation, remodeling, and treatment implications

• Inflammation drives airway narrowing and hyperresponsiveness; remodeling involves thickening of basement membrane and smooth muscle hypertrophy
• The balance of contraction vs relaxation is mediated by inflammatory mediators (histamine, leukotrienes, ACh) and by β2-adrenergic signaling (cAMP/PKA) and MLCP activity
• Treatments target inflammation (ICS, biologics) and/or bronchoconstriction (SABA, SAMAs/LAMAs, PDE inhibitors), with combination regimens designed to address both

Practical takeaways for exam-ready knowledge

• Distinguish obstructive vs restrictive disease using spirometry metrics and clinical context
• Recognize the role of PEF variability as a diagnostic/monitoring tool for asthma at home
• Understand the deposition science behind inhaled therapies and why technique matters
• Be able to explain the differences between relievers and preventers, and why guideline-based single-inhaler strategies (ICS-LABA) are favored for mild asthma
• Know the major asthma biologics and typical criteria for their use (e.g., eosinophilic phenotype; IgE-mediated allergic asthma; Type 2 inflammation)
• Understand non-pharmacologic options like bronchial thermoplasty and when they might be considered
• Be aware of public health contexts (thunderstorm asthma, bushfire smoke) and their implications for management and patient education

Key numerical references and formulas (LaTeX)

• Normal adult peak expiratory flow (PEF):
  • Male: $ext{PEF}_{ ext{male}} ext{ in } [450,700] ext{ L/min}$
  • Female: $ext{PEF}_{ ext{female}} ext{ in } [300,500] ext{ L/min}$
• PEF variability indicating asthma: ext{Variability} > 20 ext{%}
• Spirometry definitions:
  • $FEV_1 = ext{Forced expiratory volume in 1 s}$
  • $FVC = ext{Forced vital capacity}$
  • $rac{FEV_1}{FVC} ext{ ratio (reduced in obstructive disease)}$
• Pathophysiology sequences (illustrative):
  • Contraction: $ext{Ca}^{2+} + ext{CaM} <br /> ightarrow ext{Ca}^{2+} ext{-CaM} ext{ activates MLCK} <br /> ightarrow ext{MLC-P} <br /> ightarrow ext{contraction}$
  • Relaxation: $ext{cAMP} <br /> ightarrow ext{PKA} <br /> ightarrow ext{MLCP activation} <br /> ightarrow ext{MLC dephosphorylation} <br /> ightarrow ext{relaxation}$
• Oxygenation and inflammatory markers: FeNO (fractional exhaled nitric oxide) as an inflammatory biomarker (mentioned as a diagnostic development)

References and further reading (as cited in slides)

• Holgate et al., Nat Rev Dis Primers. 2015 (Asthma pathogenesis and classifications)
• Golan et al. Principles of Pharmacology, 3rd Edition, 2011 (Mechanisms and pharmacology)
• Crooks and Faruqi, Eur Respir J Open, 2023 (SABA overuse and guidelines)
• Kavanagh et al., Breathe 2021 (Biologics for severe asthma – overview)
• AIR-2 trial (Castro et al., AJRCCM, 2010) – Bronchial Thermoplasty evidence
• Nucala (mepolizumab) clinical trial and approval criteria (N Engl J Med 2009; Ther Adv Respir Dis. 2018)
• Asthma Australia and National Asthma Council Australia resources on thunderstorm asthma and asthma management
• Asthma review and Lancet reference (Porsberg et al., 2023) and other Moodle resources

Appendix: Practical implications for testing and exams

• Be able to differentiate diagnostic criteria for asthma using spirometry, peak flow, and provocation tests
• Explain the rationale for ICS-LABA single-inhaler regimens in mild asthma and why monotherapy with SABA is discouraged
• Describe the rationale for using biologics in severe asthma and match the mechanism to inflammatory phenotype
• Recognize non-pharmacologic options (BT) and the current evidence base
• Understand the public health context of asthma, including epidemiology, mortality trends, and climate-related triggers (thunderstorm asthma, bushfire smoke)