Phenotyping emphysema and airways disease: Clinical value of quantitative radiological techniques

Table 1 Summary of studies dividing patients as HRCT defined phenotypes and their significant differences clinical and physiological (P < 0.05)

Ref.	HRCT defined phenotypes	Variables studied	Significant variable difference
Kitaguchi et al[8], 2006	A: Little or none of either emphysema or BWT E: Emphysema but no BWT M: Emphysema and BWT	Gas exchange Gas transfer Lung function Response to beta-agonist Response to treatment with ICS Sputum cell differentiation	A: ↑ BMI ↑DLCO ↓ hyperinflation ↑ reversibility ↑response to ICS ↑ % of sputum eosinophils E: No response to ICS M: ↑ response to ICS ↑ % of sputum eosinophils
Fujimoto et al[9], 2006	A: Little or none of either emphysema or BWT E: Emphysema but no BWT M: Emphysema and BWT	Exacerbation rates Gas exchange Gas transfer Hospital admissions Lung function Response to beta-agonist Symptoms	M: ↑ volume of sputum, exacerbation rate and admission to hospital
Pistolesi et al[10], 2008	From derivation set, created new validation set Group A and B	CT parameters Gas exchange Gas transfer Lung function	A: ↓ FEV1, ↑ TLC ↓ DLCO. ↑ pixel index (threshold -950HU) B: ↑ BMI purulent sputum worse bronchial wall thickening
Han et al[7], 2011	Emphysema predominant or Airway predominant	BWT Exacerbation rates lung function % emphysema	Emphysema Predominant (> 35% -950HU): ↓ FEV1 and 6MWD ↑ SGRQ and MRC grade For every 5% ↑ in emphysema, 1.18 fold ↑ exacerbation frequency Airways predominant: For 1 mm ↑ in segmental BWT 1.84 fold ↑ in exacerbation frequency
Subramanian et al[3], 2016	Emphysema dominant, airways disease dominant, mixed pathology and mild disease	Blood parameters CT parameters Gas exchange Gas transfer Lung volumes Spirometry	Compared with airway disease dominant group, emphysema dominant group had ↑ lung volumes, ↓ gas transfer ↓ pO2 + pCO2↓BMI ↑Hb No difference between age, and smoking history between the groups
Da Silva et al[2], 2016	Emphysema or airways disease	Clinical + functional evaluation HRCT	Emphysema group: ↑ airflow obstruction ↓ BMI ↓ 6MWD

A: Airways; E: Emphysema; M: Mixed; BWT: Bronchial wall thickening; 6MWD: 6 minute walk distance; CT: Computed tomography; BWT: Bronchial wall thickness; DLCO: Transfer factor for carbon monoxide; ICS: Inhaled corticosteroid; FEV1: Forced Expiratory Volume in 1 second; TLC: Total lung capacity; HU: Hounsfield units; SGRQ: St Georges Respiratory Questionnaire; MRC: Medical reseach council; HRCT: High resolution computed tomography.

Table 2 Treatment of chronic obstructive pulmonary disease as defined by computed tomography phenotypes

CT phenotype	CT defining features	Clinical features	Findings	Treatments	Ref.
Emphysema	↓ Perc15 Emphysema Centrilobular Panlobular Paraseptal Bullous	Health status	↓ BMI[2] ↑ SGRQ + MRC[7]	Rehabilitation Nutritional support Palliative care	GOLD 2016[5]
		Exercise tolerance	↓ 6MWD[2] ↓ pO2↓ pCO2[3]	Rehabilitation Maintenance of physical activity Oxygen	GOLD 2016[5]
		Lung function	↑ TLC ↓ KCO ↓ FEV1/FVC	LAMA/LABA LVRS/BVLS Transplant Bullectomy[11] LVRS[11]	GOLD 2016[5] NICE 2010[11]
		Symptoms	↑ Hb[3] No significant response to ICS[8]	Theophylline Rehabilitation typically MRC > 3	GOLD 2016[5] NICE 2010[11]
Airways disease		Exacerbation frequency/ severity	↑ Exacerbations hospital admissions[7]	LABA/phosphodiesterase-4 inhibitor LAMA/phosphodiesterase-4 inhibitor Mucolytics Add in ICS Prophylactic antibiotics	GOLD 2016[5] NICE 2010[11] Brown et al[12], 2007 Fabbri et al[13], 2009 Calverley et al[14], 2009 Herath et al[15], 2013
	Lower wall area/body Surface area ratio (WA/BSA) Lower luminal area/BSA Higher %WA	Symptoms	Significant response to ICS+ Significantly higher % of sputum eosinophils[8] Peribronchial thickening[10] Air trapping	Physiotherapy and active breathing techniques Mucolytics Roflumilast Bronchodilators	NICE 2010[11]

6MWD: 6 minute walk distance; CT: Computed tomography; ICS: Inhaled corticosteroid; FEV1/FVC: Forced expiratory volume in 1 second/forced vital capacity; TLC: Total lung capacity; HU: Hounsfield units; SGRQ: St georges respiratory questionnaire; MRC: Medical reseach council; HRCT: High resolution computed tomography; Perc15: 15^th percentile point; KCO: Gas transfer co-efficient; LVRS: Lung volume reduction surgery; LAMA: Long acting muscarinic antagonist.

Table 3 Table to summarise studies performed in alpha one antitrypsin deficiency and chronic obstructive pulmonary disease directly comparing the most accurate measure of computed tomography density

Condition	Type of study	910	950	Perc15	Conclusion of superior measure	Ref.
Alpha one	RCT	x	x		950	Parr et al[29]
	RCT		x	x	950 and Perc15	Parr et al[30]
	RCT	x	x	x	Perc15	Parr et al[26]
	Review	x	x	x	Perc15	Hogg et al[28]
Chronic obstructive pulmonary disease	RCT	x	x	x	Perc15	Shaker et al[31]
	Review	x		x	Perc15	Dirksen et al[27]
	RCT		x	x	950	Chong et al[32]

Variables tested, type of study and conclusion of the most superior measure shown. RCT: Randomised controlled trial.

Table 4 Summary of interventional drug trials using computed tomography measures as an outcome measure

Ref.	Study design	Pt N°	Duration	CT measure	Drug	Result
Usual COPD
Shaker et al[75]	RCT	254	2-4 yr	Perc15 and -910HU	Budesonide or placebo	Annual fall in Perc15 ↑in the placebo arm vs budesonide (P = 0.09) Annual increase in -910HU↓in the budesonide arm (P = 0.02)
Hoshino et al[76]	RCT	54	16 wk	%WA, LA, BWT	Tiotropium, Indacaterol or both	Combination therapy resulted in a ↓in %WA and wall thickness (P < 0.01)
Nordenmark et al[77]	RCT	36	12 wk	BWT, air trapping index and %WA	Reversible neutrophil elastase inhibitor 60 mg BD	No difference
Shimizu et al[78]	Inter-ventional trial	23	1 wk	Airway inner luminal area	SFC	Ct detected the significant change in airway inner luminal area r = 0.65, P < 0.001
Alpha 1 Antitrypsin deficiency
Stolk et al[79]	RCT	262	1 yr	Perc15	Parlovarotene	No benefit on lung density
Mao et al[80]	RCT-pilot study	20	9 mo	-910HU	ATRA	No benefit
Roth et al[81]	RCT feasibility study	148	9 mo	-910HU	Patients received ATRA either LD, HD, 13-cRA or placebo	No definitive clinical benefits
Dirksen et al[82]	RCT	32	3 yr	Perc15	Alpha1-antitrysin	CT analysis showed a non-significant trend towards a favourable effect. CT lung density twice as sensitive as PFTs
Dirksen et al[72] (EXACTLE)	RCT	77	2-2.5 yr	Perc15	Prolastin	CT densitometry more sensitive measure for the detection of emphysema progression than PFTs or health status indices
Chapman et al[73]	RCT	180	2 yr	Perc15	Alpha 1 proteinase inhibitor	Annual rate of density decline at TLC ↓in treatment group (P = 0.03)

CT: Computed tomography; WA: Wall area; LA: Luminal area; BWT: Bronchial wall thickening; SFC: Salmeterol/fluticasone; LD: Low dose; HD: High dose; 13-cRA: 13-cis retinoic acid; ATRA: All trans retinoic acid; RCT: Randomised controlled trial; TLC: Total lung capacity.

Table 5 Magnetic resonance imaging modalities to phenotype and treat chronic obstructive pulmonary disease

Phenotype	MRI modality	Findings	Suggested treatments
Airways disease	Hyperpolarised MRI	Detailed anatomical information of airway inflammation, oedema and mucus plugging[84,85]	Nebulised antibiotics Chest clearance techniques[83]
		Regional information re. lung volumes, e.g., focal bronchoconstriction	Broncho-thermoplasty[91] BVRS
Emphysema	Hyperpolarised MRI	Global high ADC[87]	Early disease detection
		Low PaO2[92]	Future alpha one augmentation therapy1
	Oxygen enhanced MRI	↑↓Relative enhancement signal[93,94]	Targets for resection
			Early emphysema detection
	Dynamic contrast MRI	Global microvascular reduction blood flow[95]	Lifestyle moderation
		Focal defects, small pulmonary emboli	Anticoagulation
		Increased pulmonary pressure	Treat as pulmonary hypertension

Potential treatments based on the phenotypes identified by the technique, but that have not yet been tested are noted by

¹in the table. MRI: Magnetic resonance imaging; BVRS: Bronchoscopic volume reduction surgery; ADC: Apparent diffusion co-efficient; KCO: Transfer co-efficient.

Table 6 Studies correlating magnetic resonance imaging with other clinical variables

MRI modality	FEV1	Gas transfer	CT density (LAA% 950HU)
Hyperpolarised gas	-0.632-0.76[38,86,92,96,97]	-0.45-0.82[38,92,98,99]	0.8-0.9[96,100]
O2 enhanced	-0.74[93]	DLCO: 0.911[94] KCO: 0.66[93]
DCE-MRI	10.677[101]
UTE-MRI2		0.6[102]	0.72[102]

¹Dynamic contrast measured by the signal intensity perfusion defect (SIpd);

²Ultra-short echo time-MRI. CT: Computed tomography; DLCO: Transfer factor for carbon monoxide; FEV1: Forced expiratory volume in 1 second; UTE-MRI: Ultra-short echo time-MRI; DCE-MRI: Dynamic contrast enhanced magnetic resonance imaging measured by the signal intensity perfusion defect (SIpd).

Table 7 Summary of studies comparing magnetic resonance imaging and computed tomography in chronic obstructive pulmonary disease

Ref.	Year	Pt No.	Variables	Results
Ley et al[96]	2004	13	ADC and EI vs FEV1	ADC vs FEV1, R = 0.7 EI vs FEV1, R = 0.5 MLD vs FEV1, R = 0.4
Ohno et al[93]	2008	71	O2 enhanced MRI (mean wash in time and relative enhancement ratio), CT defined lung volumes vs lung function	Mean wash in time vs FEV1, r = -0.74 Relative Enhancement Ratio vs KCO, r = 0.66 CT lung volume vs FEV1, r = 0.61 CT lung volume vs KCO, r = 0.56
Van Beek et al[98]	2009	94	ADC and MLD vs FEV1/FVC and DLCO	ADC vs Fev1/fvc, r = 0.5 MLD vs Fev1/fvc, r = 0.52 ADC vs DLCO, r = 0.59 MLD vs DLCO, r = 0.29
Diaz et al[38]	2009	27	ADC and EI vs FEV1 and DLCO	ADC vs FEV1, r = 0.67 EI vs FEV1, r = 0.55 ADC vs DLCO, r = -0.82 Perc15 vs DLCO, r = 0.6
Quirk et al[114]	2011	30	Hyperpolarised He vs CT density in at risk smokers	Lung morphometry vs %LAA 950: Significant difference seen in those still smoke, not on CT
Xia et al[101]	2014	55	+ve rate of Perfusion defects vs CT changes	Early COPD: MRI detected 8/8, vs CT 3/8 P = 0.003 Mod. COPD: MRI detected 9/9, vs CT 7/9 P = 0.47
Hueper et al[95]	2015	144	DCE-MRI vs CT density	PMBF vs %LAA 950: Evidence of non-linearity, P = 0.015

ADC: Apparent diffusion co-efficient; EI: Emphysema index; FEV1: Forced expiratory volume in 1 second; MLD: Mean lung density; MRI: Magnetic resonance imaging; DLCO: Transfer factor for carbon monoxide; KCO: Transfer co-efficient; COPD: Chronic obstructive pulmonary disease; DCE-MRI: Dynamic contrast enhanced-magnetic resonance imaging.

Table 8 Practical considerations for positron emission tomography vs single photon emission computed tomography

Modality	Advantages	Disadvantages
PET	Increased resolution	Cyclotron and radiopharmaceutical preparation Rapid repeat testing not possible[87]
SPECT	Lower cost More widely available. Dynamic SPECT give time course of ventilation	Lower spatial and contrast resolution

PET: Positron emission tomography; SPECT: Single photon emission computed tomography.

Table 9 Studies correlating single photon emission computed tomography with other clinical variables

Modality	R value	Ref.
DCE-MRI	0.50-0.67	Molinari et al[127]
FEV1	-0.64	Bajc et al[121] Jögi et al[122]
FEV/FVC	-0.63, 0.67	Bajc et al[121] Jögi et al[122]
He-MRI	0.45	Stavngaard et al[128]
DLCO	0.57	Sandek et al[123]

DCE-MRI: Dynamic contrast enhanced magnetic resonance imaging; FEV1: Forced expiratory volume in 1 second; FEV1/FVC: Forced expiratory volume in 1 second/forced expiratory volume; He-MRI: Helium-magnetic resonance imaging; DLCO: Transfer co-efficient of carbon monoxide.

Table 10 Demonstration of how optical coherence tomography could phenotype in chronic obstructive pulmonary disease

Condition	OCT method	Findings	Suggested treatments
Chronic bronchitis	Endoscopic	Increased volume of submucosal glands; central airway inflammation[133-135]	Investigations directed towards asthma overlap syndrome; targeted inhaled steroids
Emphysema	Anatomical OCT	Can visualise collapsibility dynamically[136]	Bronchodilators; smoking cessation

OCT: Optical coherence tomography.