RespiratoryTier 1Disease (DEADMAN)

Chronic obstructive pulmonary disease (COPD)

Description

Persistent respiratory symptoms + not fully reversible airflow limitation
- Post-BD FEV1/FVC <0.70 (GOLD); LLN if using GLI reference
- GOLD 2026: routine reversibility testing discouraged - poor diagnostic utility, poor reproducibility

Pathological components - coexist in varying proportion

	Site	Correlate
Emphysema	Alveolar destruction, loss of elastic recoil	dec DLCO, hyperinflation, bullae
Small airways disease	Bronchiolar fibrosis, mucus plugging	Fixed obstruction, gas trapping
Chronic bronchitis	Mucus hypersecretion	Cough + sputum >=3 months x 2 yrs. Symptom definition - can exist with normal spirometry

Emphysema pattern -> aetiology

Centriacinar, upper zone = smoking
Panacinar, lower zone = alpha-1 antitrypsin deficiency
Paraseptal = subpleural blebs -> spontaneous pneumothorax

Pre-COPD and PRISm

Pre-COPD - symptoms/structural change, normal spirometry
PRISm - preserved ratio, impaired spirometry (FEV1 <80% with ratio >=0.7)
- Both carry inc mortality and progress to COPD in a substantial minority

Assessment groups (GOLD ABE)

	Symptoms	Exacerbations/yr
A	mMRC 0-1 / CAT <10	0-1 not hospitalised
B	mMRC >=2 / CAT >=10	0-1 not hospitalised
E	any	>=1 moderate or >=1 hospitalisation

E replaced C+D; the threshold dropped from >=2 to >=1 moderate exacerbation
Spirometric grade (GOLD 1-4 by FEV1 %pred) reported separately - does not drive drug choice

Epidemiology

~7.5% of Australians >40yr; ~1 in 7 over 40 have COPD (much undiagnosed)
5th leading cause of death in Australia; leading cause of preventable hospitalisation
Aboriginal and Torres Strait Islander peoples: 2-3x prevalence, death rates >2x, onset a decade earlier
Smoking ~80% of attributable risk in high-income settings
- But only ~20-25% of smokers develop COPD - susceptibility varies
Globally: biomass fuel exposure is the dominant non-smoking cause (F>M in those settings)
Under-diagnosed in women and never-smokers

Aetiopathogenesis

Host + exposure

Smoking - dominant; dose-related, cumulative pack-years
Biomass fuel / indoor cooking smoke
Occupational - dusts, vapours, fumes (~15% of cases; compensable)
alpha-1 antitrypsin deficiency
- PiZZ, ~1:2000-5000; SERPINA1
- Emphysema by 40s, lower zone, accelerated by smoking
- +/- cirrhosis, panniculitis
- *Test level once in every COPD patient* - esp. <45yr, lower-zone/panacinar, family history, minimal smoking, unexplained LFTs
Impaired lung growth - prematurity, childhood infection, maternal smoking
- Up to half of COPD arises from a low peak FEV1, not accelerated decline
Asthma, airway hyper-responsiveness, chronic childhood asthma
Poverty, HIV, prior TB, bronchiectasis

Mechanism

Noxious particles -> neutrophil/macrophage/CD8 T-cell influx
- inc proteases (neutrophil elastase, MMP-9/12) vs dec antiproteases
- -> protease-antiprotease imbalance -> alveolar wall destruction
- Oxidative stress -> inactivates AAT, inc inflammation, corticosteroid resistance (dec HDAC2)
Small airway remodelling -> fibrosis + mucus plugging -> fixed obstruction
Loss of elastic recoil -> dynamic airway collapse on expiration
- -> gas trapping -> hyperinflation -> flat diaphragm, inefficient mechanics
- -> dynamic hyperinflation on exertion = the mechanism of exertional dyspnoea
- This, not FEV1, is why bronchodilators help symptoms more than they change FEV1
V/Q mismatch -> hypoxaemia; later dec ventilatory drive + inc dead space -> hypercapnia
Chronic hypoxia -> pulmonary vasoconstriction + remodelling -> cor pulmonale

Diagnosis

Think COPD if

Age >35-40 + risk exposure + dyspnoea/chronic cough/sputum/recurrent LRTI

Confirm - spirometry is mandatory

Post-BD FEV1/FVC <0.70 = obstruction
- Fixed ratio over-diagnoses in the elderly, under-diagnoses in the young - LLN is more accurate
Never diagnose COPD on symptoms or CXR alone

Grade	FEV1 %pred
GOLD 1 mild	>=80
GOLD 2 moderate	50-79
GOLD 3 severe	30-49
GOLD 4 very severe	<30

Full lung function

inc TLC, inc RV, inc RV/TLC = gas trapping
dec DLCO = emphysema (normal DLCO with obstruction -> asthma or bronchiolitis)
Flow-volume loop: concave expiratory limb

Distinguishing from asthma

	COPD	Asthma
Onset	>40, smoker	Any age, atopy
Variability	Fixed	Diurnal, episodic
BD response	Small	>12% AND >200 mL
DLCO	dec	Normal/inc
Eosinophils/FeNO	Usually low	Often raised

Both may coexist. Marked reversibility does not exclude COPD, and its absence does not exclude asthma

Baseline workup

CXR - hyperinflation (>6 anterior ribs, flat diaphragms), bullae; mainly to exclude alternatives
HRCT - if bullae, bronchiectasis, discordant DLCO, suspected malignancy, LVRS/valve assessment
FBE - polycythaemia (hypoxia), blood eosinophil count (drives ICS decision)
Alpha-1 antitrypsin level
ABG if FEV1 <50%, SpO2 <=92%, or considering home oxygen
Echo if signs of pulmonary hypertension

Grading exacerbation severity - Rome criteria (adopted GOLD 2026)

Classified by dyspnoea VAS, RR, HR, CRP, SpO2, ABG - not by the treatment given
Mild / moderate / severe (severe = hypercapnic acidosis or need for ventilatory support)
Replaces the old circular definition "severe = needed hospital"

Assess impact, not just FEV1

mMRC dyspnoea scale, CAT score
6MWT, BODE index
Exacerbation history in the last 12 months - the best predictor of future exacerbations

Management

1. Disease-modifying - do these first, in everyone

The only interventions with mortality benefit.

Smoking cessation - nicotine replacement + varenicline or bupropion + behavioural support
Pulmonary rehabilitation - dyspnoea, exercise capacity, QoL, readmission
- Refer within 4 weeks of an exacerbation - the highest-yield window
Vaccination - annual influenza, pneumococcal, COVID-19, RSV (>=60yr), pertussis
Long-term oxygen if PaO2 <=55 mmHg, or <=60 with cor pulmonale/polycythaemia
- >=15-16 h/day required for mortality benefit
- No benefit for isolated exercise or nocturnal desaturation
Optimise comorbidity, nutrition, physical activity

2. Inhaled therapy - by group, then by response

GOLD 2026: dual bronchodilation is the default start for anyone symptomatic. ICS is biomarker-guided, not routine.

Group	Start
A	SABA/SAMA prn; long-acting bronchodilator if persistent
B	LABA/LAMA
E	LABA/LAMA; go straight to LABA/LAMA/ICS if eos >=300

Escalate to triple (LABA/LAMA/ICS) if further exacerbations on optimised dual therapy
- Direct escalation preferred over adding ICS stepwise
Blood eosinophils drive the ICS decision
- >=300 - favours ICS; *do not withdraw ICS at this level (GOLD 2026)*
- 100-299 - intermediate benefit
- <100 - little benefit; pneumonia risk dominates
ICS harms: pneumonia, oral candidiasis, dysphonia, bruising, cataract, bone loss
Check inhaler technique and adherence at every visit before escalating - the commonest reason therapy "fails"

3. Persistent exacerbations despite triple therapy

Dupilumab - eos >=300 on triple therapy; ~30% exacerbation reduction (BOREAS, NOTUS)
Mepolizumab - eos >=300; ~20% reduction (MATINEE)
Azithromycin 250-500 mg 3x/week - check QTc, hearing, mycobacterial sputum first; drives macrolide resistance
Roflumilast - chronic bronchitis + FEV1 <50% + exacerbations. Diarrhoea, weight loss, psychiatric effects
Ensifentrine (PDE3/4) - adjunct for symptoms inadequately controlled; smaller effect than triple, no active-comparator data
N-acetylcysteine, mucolytics - modest

4. Interventional

Endobronchial valves - heterogeneous emphysema, no collateral ventilation (intact fissure), RV >175%
LVRS - upper-lobe predominant emphysema + low exercise capacity (NETT)
- inc early mortality; harmful if FEV1 <20% AND homogeneous emphysema or DLCO <20%
Transplant - BODE 7-10, FEV1 <25%, hypercapnia, pulmonary hypertension
Bullectomy for a giant bulla >1/3 hemithorax

5. Acute exacerbation

Controlled oxygen - target SpO2 88-92%
- Uncontrolled high-flow O2 -> V/Q mismatch, Haldane effect -> hypercapnia; increases mortality
Bronchodilators - salbutamol +/- ipratropium, spacer as effective as nebuliser
Prednisolone 30-50 mg for 5 days - oral = IV, no taper needed
Antibiotics if 2 of 3 Anthonisen criteria (inc dyspnoea, inc sputum volume, inc purulence) or ventilated
- Amoxicillin or doxycycline 5 days
NIV (BiPAP) if pH <7.35 + PaCO2 >45 despite optimal therapy - reduces intubation and mortality; the single highest-yield intervention
Home NIV now recommended for persistent hypercapnia after a severe exacerbation (GOLD 2026)
Investigate the trigger: PE (~1 in 6 of unexplained exacerbations), pneumonia, pneumothorax, LVF, arrhythmia

6. Post-exacerbation bundle

Review within 1-4 weeks, pulmonary rehab, inhaler technique, action plan, escalate therapy

7. Advanced disease

Opioids for refractory dyspnoea, fan therapy, advance care planning
Prognosis is worse than most solid cancers - start these conversations early

Associations

Cardiovascular disease - the commonest cause of death in mild-moderate COPD
- Shared smoking risk + systemic inflammation
- Cardioselective beta blockers are safe and should not be withheld
Lung cancer - independent risk beyond smoking
Pulmonary hypertension - usually mild-moderate; *if severe, look for another cause*
Osteoporosis - smoking, steroids, inactivity, low BMI
Skeletal muscle dysfunction and cachexia - independent mortality predictor
Anxiety and depression - up to 40%, under-treated
OSA ("overlap syndrome") - worse hypoxaemia, higher mortality
GORD - independent exacerbation risk factor
Bronchiectasis - overlap phenotype, worse outcomes
Anaemia and polycythaemia
Alpha-1 antitrypsin deficiency -> cirrhosis, panniculitis, ANCA vasculitis

Natural history & complications

Accelerated FEV1 decline (~60 mL/yr vs ~30 normal); smoking cessation returns the slope toward normal but does not recover lost function
Course is punctuated by exacerbations - each accelerates decline and each raises the risk of the next
- Frequent-exacerbator phenotype is stable over time; past history is the best predictor
In-hospital mortality of a severe exacerbation ~5-10%; ~25-40% at 1 year after a hypercapnic admission

Prognostic markers

FEV1, BODE index, exercise capacity, BMI/cachexia
Hypercapnia, cor pulmonale, home oxygen requirement
Exacerbation frequency and hospitalisation

Complications

Respiratory failure - type 2, acute and chronic
Cor pulmonale
Pneumothorax (bullae) - may be catastrophic in poor reserve
Secondary polycythaemia
Pneumonia
Depression, cachexia, falls, osteoporotic fracture

Death is more often cardiovascular or malignant in mild-moderate disease, and respiratory in severe

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