CT densitometry in emphysema: a systematic review of its clinical utility

Figures & data

Figure 1 PRISMA flow diagram.

Abbreviations: CENTRAL, Cochrane Central Register of Controlled Trials; CT, computed tomography; COPD, chronic obstructive pulmonary disease; AATD, alpha-1 anti-trypsin deficiency.

Table 1 Summary of all studies included in meta-analyses

Statistical method	Density measure	No of studies	No of patients	Age	FEV1pp	DLCOpp	KCOpp
Correlation coefficient	−900	7	551	66 (10)	54.96 (20.19)	65.47 (20.97)	63.73 (20.13)
	−910	2	69	64.67 (8.34)	58.93 (24.27)	57.46 (19.63)	61.59 (22.47)
	−950	46	10,764	62.45 (10.77)	58.04 (33.59)	59.90 (31.43)	85.19 (21.86)
	−960	6	639	67.96 (8.76)	54.86 (23.75)	–	–
	PD15	7	4,544	60.91 (9.22)	53.99 (24.52)	–	67.16 (24.58)
Multivariate regression	−910	3	425	62.04 (8.93)	64.17 (27.27)	–	–
	−950	14	18,984	60.59 (9.56)	78.71 (26.29)	66.23 (23.44)	87.06 (18.07)
	−960	2	161	70.33 (8.69)	54.81 (20.13)	–	–
	PD15	8	7,251	59.89 (9.51)	93.06 (20.63)	–	85.19 (18.86)
Trials
• ICS ± LABA	−950	2	482	64.50 (7.37)	50.50 (12.21)	75.15 (29.50)	46.70 (39.08)
• ATRA	PD15	2	375	58.83 (9.91)	44.99 (15.70)	43.82 (14.79)	43.70 (13.57)
• Prolastin	PD15	4	369	51.83 (7.39)	47.39 (12.35)	36.14 (23.39)	54.70 (11.77)
Mortality	Mixed	6	3,584	61.66 (9.68)	69.39 (31.27)	–	–
Exacerbations	Mixed	7	2,637	66.10 (8.22)	60.54 (25.44)	–	–
SGRQ	Mixed	8	4,864	58.82 (13.75)	45.01 (19.03)	35.68 (18.17)	60.40 (22.22)
BODE	Mixed	4	2,440	65.58 (6.44)	44.43 (21.19)	35.08 (19.87)	–
6MWT	Mixed	3	2,481	61.63 (9.38)	56.03 (48.57)	–	–
MRC	Mixed	4	694	64.84 (10.85)	56.97 (18.99)	–	–

Notes: Studies of lung function, sub-divided by statistical techniques, were used to assess relationship to CT density, followed by trials, and those using quality of life measures. All quantitative measures are shown as mean (SD). ‘–’ indicates data not available.

Abbreviations: FEV₁, forced expiratory volume in 1 second; DLCO, diffusing capacity of the lungs for carbon monoxide; KCO, transfer factor divided by the alveolar volume; pp, percent predicted; PD15, 15th percentile point; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; ATRA, all-trans retinoic acid; SGRQ, St Georges Respiratory Questionnaire; BODE, BMI, airflow obstruction, dyspnea and exercise tolerance; 6MWT, 6-minute walk test; MRC, Medical Research Council; CT, computed tomography.

Table 2 Summary of meta-analyses performed on all studies using Pearson’s correlation coefficient to compare FEV₁ and FEV₁ percent predicted with CT density

PFT	Density variable	No of studies	SH pooled correlation	Lower 95% CI	Higher 95% CI	p-value	I^2	χ^2	p-value
FEV1	−950	6	−0.37	−0.53	−0.21	<0.0001	90.7	48.54	<0.0001
	−960	3	−0.33	−0.43	−0.22	<0.0001	46.9	3.78	0.15
	PD15	4	0.40	0.20	0.59	<0.0001	84.9	18.90	0.0003
FEV1pp	−900	3	−0.53	−0.63	−0.43	<0.0001	0	1.96	0.37
	−910	9	−0.29	−0.38	−0.20	<0.0001	80.5	36.45	<0.0001
	−950	14	−0.54	−0.66	−0.42	<0.0001	97.2	591.46	<0.0001
	−960	4	−0.35	−0.51	−0.19	0.0003	84.5	17.70	0.0005
	PD15	4	0.45	0.27	0.63	<0.0001	98.8	288.78	<0.0001

Notes: SH weighted mean correlation coefficient, heterogeneity scores (I²) and chi-square values (χ²) are shown.

Abbreviations: FEV₁, forced expiratory volume in 1 second; CT, computed tomography; SH, Schmidt-Hunter; CI, confidence interval; PD15, 15th percentile point; FEV₁pp, forced expiratory volume in one second percent predicted; PFT, pulmonary function test.

Figure 2 Forest plot of all studies included in the meta-analysis that correlated FEV₁ percent predicted with −950 HU.

Notes: The ranges of correlation coefficients are from −0.09 to −0.67. Pooled correlation coefficient =−0.54 (p<0.0001), χ² test for heterogeneity =591 and I² score for inconsistency =97.2%.
Abbreviation: FEV₁, forced expiratory volume in 1 second.

Figure 3 The effect of CT algorithm on heterogeneity of results with respect to −950 HU and FEV₁ percent predicted.

Notes: (A) Forest plot demonstrating individual Pearson’s correlation coefficients and pooled result for those studies comparing −950 HU and FEV₁ percent predicted. SH weighted mean correlation coefficient =−0.54, I²=99.3%, χ²=587.85. (B) Forest plot demonstrating the effect on heterogeneity once the same reconstruction algorithm, slice thickness and software program were used. SH weighted mean correlation coefficient =−0.66, I²=91.8%, χ²=33.59.
Abbreviations: CT, computed tomography; FEV₁, forced expiratory volume in 1 second; SH, Schmidt-Hunter.

Table 3 Summary of studies that performed multivariate linear regression analyses to examine the relationship between FEV₁ and CT density

Density measure	Study	Variables adjusted for	Results for adjusted FEV1	95 % CI
−950 HU	Kim et al^Citation16	Mean wall area Visual score of emphysema Visual score of lobe no with AWT	β=−0.4726	−0.8215, −0.1238
	Mohamed Hoesein et al^Citation17	Age Height Pack years Smoking status	β=−0.252	–
	Hong et al^Citation18	%LAA −950 HU Mean lung density Mean wall area Smoking status	β=−0.24	–
	Aziz et al^Citation19	DLCO FEV1	β=−1.27	−1.59, −0.94
PD15	Mohamed Hoesein et al^Citation20	Age FEV1/FVC Medical center Mucus production Smoking status	1 point change in PD15 results in a −0.824 mL 3-year change in FEV1	−1.473, −0.0174
	Mohamed Hosein et al^Citation21	Age Height Medical center Smoking status Years in study	1 HU change in PD15 results in a −4.75 mL 3-year change in FEV1	−3.3, −6.1
	Mohamed Hoesein et al^Citation22	Age FEV1 Pack years	10 HU drop in Perc15 caused a −10 mL change in FEV1	−15, −5

Note: ‘–’ indicates data not available.

Abbreviations: FEV₁, forced expiratory volume in 1 second; CT, computed tomography; CI, confidence interval; AWT, airway wall thickness; %LAA, percentage low attenuation area; DLCO, diffusing capacity of the lungs for carbon monoxide; FVC, forced vital capacity; PD15, 15th percentile point.

Table 4 Summary of studies comparing FEV₁/FVC with CT density, divided up in to the most commonly reported thresholds

PFT	Density variable	No of studies	SH pooled correlation	Lower 95% CI	Higher 95% CI	p-value	I^2	χ^2	p-value
FEV1/FVC	−910	5	−0.33	−0.49	−0.16	<0.0001	95.5	75.72	<0.0001
	−950	14	−0.38	−0.53	−0.23	<0.0001	95.6	251.72	<0.0001
	−960	3	−0.48	−0.71	−0.25	<0.0001	88.9	18.73	<0.0001
	PD15	6	0.26	0.09	0.43	0.0022	94.9	81.78	<0.0001

Note: Heterogeneity score (I²), chi-square value (χ²) and SH weighted mean correlation coefficient are shown.

Abbreviations: FEV₁/FVC, forced expiratory volume in 1 second/forced vital capacity; CT, computed tomography; SH, Schmidt-Hunter; CI, confidence interval; PD15, 15th percentile point.

Figure 4 The effect of CT algorithm on heterogeneity of results with respect to PD15 and FEV₁/FVC.

Notes: (A) Forest plot of all studies comparing FEV₁/FVC with PD15. SH weighted mean correlation coefficient =−0.26, I²=94.9%, χ²=81.78. (B) Forest plot of all studies comparing FEV/FVC with PD15 using the same CT parameters. SH weighted mean correlation coefficient =−0.47, I²=4.1%, χ²=3.23.
Abbreviations: CT, computed tomography; PD15, 15th percentile point; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; SH, Schmidt-Hunter.

Table 5 Studies subdivided into density parameter used, which compares gas transfer to CT measured density

PFT	Density variable	No of studies	SH pooled correlation	Lower 95% CI	Higher 95% CI	p-value	I^2	χ^2	p-value
DLCO	−950	5	−0.42	−0.53	−0.32	<0.0001	77.8	15.538	0.0036
DLCOpp	−910	3	−0.31	−0.40	−0.22	<0.0001	83.6	10.46	0.005
	−950	16	−0.43	−0.52	−0.34	<0.0001	88	100.34	<0.0001
	PD15	5	0.29	0.15	0.42	<0.0001	92.2	33.79	<0.0001
KCO	−950	3	−0.63	−0.71	−0.54	<0.0001	49.9	4.43	0.1091
	PD15	3	0.38	0.15	0.61	0.0012	96.4	45.67	<0.0001
KCOpp	−910	3	−0.61	−0.63	−0.59	<0.0001	0	0.29	0.8658
	−950	6	0.42	−0.6	−0.25	<0.0001	78.6	22.47	0.0004

Note: Heterogeneity score (I²); chi-square value (χ²) and SH weighted mean correlation coefficient are shown.

Abbreviations: CT, computed tomography; SH, Schmidt-Hunter; CI, confidence interval; DLCO, diffusing capacity of the lungs for carbon monoxide; pp, percent predicted; PD15, 15th percentile point; KCO, transfer factor divided by the alveolar volume.

Figure 5 The effect of CT algorithm on heterogeneity of results with respect to PD15 and DLCO percent predicted.

Notes: (A) Forest plot demonstrating correlation coefficient confidence intervals and pooled correlation coefficient for those studies comparing DLCO percent predicted with PD15. SH weighted mean correlation coefficient =0.3, I²=91.5%, χ²=40.98. (B) Forest plot of those studies comparing PD15 and DLCO percent predicted once all studies using the same CT variables have been re-analyzed. SH weighted mean correlation coefficient =0.69, I²=0%, χ²=2.72.
Abbreviations: CT, computed tomography; PD15, 15th percentile point; DLCO, diffusing capacity of the lungs for carbon monoxide; SH, Schmidt-Hunter.

Table 6 Summary of studies that correlated CT density with SGRQ

References	COPD or AATD	%LAA parameter	Statistical technique	Results	p-value
Univariate analysis
Stolk et al^Citation23	AATD	PD15	Spearman’s CC	−0.56	<0.007
		−950 HU		0.6	0.003
Dowson et al^Citation24	AATD	−910	Spearman’s CC	0.39	<0.001
Barjaktarevic et al^Citation25	COPD	−950	Pearson’s CC	0.028	0.572
Motohashi et al^Citation26	COPD	−940	Pearson’s CC	0.501	<0.001
de Torres et al^Citation27	COPD	−960	Pearson’s CC	−0.12	0.39
Martinez et al^Citation28	COPD	−950	Un-normalized and normalized (value – mean/SD) parameters in univariate analysis	Un-normalized estimate 0.53 (95% CI 0.45, 0.61) Normalized estimate 5.82 (95% CI 4.91, 6.72)	<0.001 <0.001
Multivariate analysis
Martinez et al^Citation29	COPD	−950	Adjusted for age, pack years and FEV1 percent predicted	Beta value =−7.69 (95% CI −14.09, −1.3)	0.02
Gietema et al^Citation30	COPD	−950	Adjusted for sex, age, smoking status, pack years, BMI and FEV1 percent predicted and Pi10	Coefficient =1.43 SE =0.57	<0.05

Abbreviations: CT, computed tomography; SGRQ, St Georges Respiratory Questionnaire; COPD, chronic obstructive pulmonary disease; AATD, alpha-1 antitrypsin deficiency; %LAA, percentage low attenuation area; PD15, 15th percentile point; CC, correlation coefficient; SD, standard deviation; CI, confidence interval; BMI, body mass index; FEV₁, forced expiratory volume in 1 second; Pi10, 10 mm luminal perimeter; SE, standard error.

Table 7 Summary of studies that compare BODE and MRC with CT density, subdivided into univariate or multivariate models used

References	COPD or AATD	Severity measure	%LAA	Statistical technique	Results	p-value
Univariate analysis
Camiciottoli et al^Citation31	COPD	BODE	−950	Pearson’s CC	R=0.58	<0.0001
Martinez et al^Citation28	COPD	BODE	−950	Un-normalized and normalized (value – mean/SD) parameters in univariate analysis	Un-normalized estimate 1.02 (95% CI 1.02–1.02) Normalized estimate 1.23 (95% CI 1.2–1.26)	<0.001 <0.001
de Torres et al^Citation27	COPD	BODE	−960	Pearson’s CC	R=−0.08	0.53
Camiciottoli et al^Citation6	COPD	MRC	−950	Odds ratio	1.41 (95% CI 1.11–1.78)	<0.005
Haruna et al^Citation32	COPD	MRC	−960	Pearson’s CC	R=0.41	<0.05
Haruna et al^Citation33	COPD	MRC	−960	Pearson’s CC	0.41	<0.05
de Torres et al^Citation27	COPD	MRC	−960	Pearson’s CC	R=−0.19	0.14
Multivariate analysis
Martinez et al^Citation29	COPD	BODE	−910	Adjusted for age, pack years and FEV1% predicted	Beta value =0.01 7.69 (95% CI 0.005, 0.02)	0.002
Camiciottoli et al^Citation31	COPD	BODE	−950	Adjusted for FEV1, BMI, MRC, 6MWT	R=0.61	<0.0001
Haruna et al^Citation32	COPD	MRC	−960	Adjusted for FEV1, RV/TLC R5-R20, X5	R=0.06	<0.05

Abbreviations: BODE, BMI, airflow obstruction, dyspnea and exercise tolerance; MRC, Medical Research Council; CT, computed tomography; COPD, chronic obstructive pulmonary disease; AATD, alpha-1 antitrypsin deficiency; %LAA, percentage low attenuation area; CC, correlation co-efficient; SD, standard deviation; CI, confidence interval; MRC, Medical Research Council; 6MWT, 6-minute walk test; FEV₁, forced expiratory volume in 1 second; RV/TLC, residual volume/total lung capacity; R5-R20, measure of airway resistance at 5 and 20 Hz; X5, airway reactance at 5 Hz.

Table 8 Studies reporting an all-cause mortality HR for emphysema as defined by CT density

References	Patient source	%LAA	Statistical technique	Confounding variables in model	Results	HR	Lower CI	Upper CI	p-value
Haruna et al^Citation33	COPD OPA clinic	−960	Univariate and multivariate Cox proportional hazards	Univariate analysis and therefore N/A	↑%LAA significantly related to mortality	1.52	1.2	1.91	<0.001
					Upper lung field	1.55	1.22	1.95	<0.001
					Lower lung field	1.41	1.09	1.78	0.009
				Age, BMI, FEV1, RV/TLC and KCO	%LAA independent predictor of mortality	1.74	1.18	2.54	<0.01
Martinez et al^Citation34	NETT	−950	Univariate and multivariate Cox proportional hazards	N/A	Whole lung % emphysema not associated with mortality	1.14	0.85	1.52	0.38
					Lower zone emphysema associated with ↑mortality	1.39	1.04	1.85	0.02
				Age, LTOT, Hb, BODE, RV%, TLC%, DLCO%, maximal CPET workload, lower lung emphysema and nuclear perfusion scan result	Difference between upper and lower lungs % emphysema remained predictive in multivariate model	1.80	1.22	2.66	0.003
Dawkinset al^Citation35	ADAPT	−910	Univariate Cox proportional hazards	Age HR for mortality (Exp B) comparing those with FEV1>80 pp with FEV1<30 pp	Survival curves indicate a relationship of ↑VI to ↑mortality ↑%LAA associated with ↑mortality	0.111	0.026	0.473	0.003

Note:↑ represents as increased.

Abbreviations: HR, hazard ratio; CT, computed tomography; %LAA, percentage low attenuation area; CI, confidence interval; COPD, chronic obstructive pulmonary disease; N/A, not applicable; BMI, body mass index; FEV₁, forced expiratory volume in 1 second; RV, residual volume; TLC, total lung capacity; KCO, transfer factor divided by the alveolar volume; LTOT, long-term oxygen therapy; Hb, hemoglobin; BODE, BMI, airflow obstruction, dyspnea and exercise tolerance; DLCO, diffusing capacity of the lungs for carbon monoxide; CPET, cardiopulmonary exercise testing; pp, percent predicted; VI, voxel index; OPA, outpatient; NETT, National Emphysema Treatment Trial; ADAPT, Antitrypsin Deficiency Assessment and Programme for Treatment.

Table 9 Summary of papers describing the association between CT density and exacerbations, subdivided into the risk of exacerbations from a low density score, and the impact exacerbations have on CT density decline

References	%LAA parameter	Statistical technique	Variable adjusted for	Results	p-value
Yoo et al^Citation36	−950	Univariate logistic regression		OR =1.02 (95% CI 1.01, 1.04)	0.01
		Multiple logistic regression	Sex, gender, current smoker, exacerbation leading to hospitalization in past year, Charlson index, BMI, MMRCS, 6MWD, SGRQ, FEV1%, CT wall area %, CT air trapping index	OR =1.01 (95% CI 0.987, 1.034)	0.39
Vijayasaratha and Stockley^Citation38	PD15	Stepwise linear regression; spearman’s CC	FEV1, FEV/FVC, KCO% predicted, delay in treatment initiation in days, Anthonisen criteria, cold symptoms	PD15 associated with exacerbation length and (r=−0.361) Treatment delay (r=−0.786)	0.003 0.004
McAllister et al^Citation39	−910	Multivariate RR	Age, sex, race/ethnicity and cotinine	% Emphysema predicts episodes of care RR 1.45 (95% CI 1.04, 2.03)	0.03
				↑Hospital admissions RR 1.62 (95% CI 1.08, 2.44)	0.02
Han et al^Citation40	−950	Multivariate analyses and forward selection regression	Scanner model, age, sex, smoking status and FEV1	>35% emphysema associated with a 1.18-fold increase in exacerbation	0.047
				5% ↑in emphysema associated with a 0.86-fold ↑in exacerbation frequency	0.001

Note:↑ represents as increased.

Abbreviations: CT, computed tomography; %LAA, percentage low attenuation area; OR, odds ratio; CI, confidence interval; BMI, body mass index; MMRCS, Modified Medical Research Council Dyspnea Scale; 6MWD, 6-minute walk distance; SGRQ, St Georges Respiratory Questionnaire; FEV₁, forced expiratory volume in 1 second; PD15, 15th percentile point; CC, correlation co-efficient; FVC, forced vital capacity; KCO, transfer factor divided by the alveolar volume; RR, rate ratios.

Figure 6 (A) Bar chart to demonstrate variety of software programs used in all studies. (B) Bar chart to demonstrate the variety of reconstruction algorithms reported. (C) Bar chart to demonstrate variety of slice thicknesses reported in all studies.

Table 10 Summary of the risk of bias assessment

Risk of bias	Low	High	Unclear
Patient selection	81 (72)	8 (7)	24 (21)
Index and reference test	36 (32)	8 (7)	69 (61)
Flow and timing	60 (53)	28 (25)	25 (22)
Reporting	59 (52)	39 (35)	15 (13)

Note: Data presented as number of studies (% of studies).

Figure 7 (A) Funnel plot for studies correlating −950 HU with FEV₁ percent predicted. (B) Funnel plot for studies correlating −950 HU with DLCO percent predicted.

Abbreviations: FEV₁, forced expiratory volume in 1 second; DLCO, diffusing capacity of the lungs for carbon monoxide.

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