Are interstitial lung abnormalities associated with COPD? A nested case–control study

Figures & data

Figure 1 A CONSORT diagram illustrating the selection of patients included in the data analysis.

Abbreviations: CONSORT, Consolidated Standards Of Reporting Trials; GOLD, Global Initiative for Chronic Obstructive Lung Disease; MILD, Multicentric Italian Lung Detection; GOLD-U, GOLD unclassified.

Table 1 Classification of LDCT patterns in subjects with definite and equivocal ILA

Predominant LDCT pattern	LDCT features
Definite UIP pattern	Predominant lower lung zone subpleural reticular opacities and honeycombing With or without traction bronchiectasis/bronchiolectasis and signs of architectural distortion (eg, lung fissure displacement) Focal ground glass
Possible UIP pattern	Predominant lower lung zone subpleural reticular opacities With or without traction bronchiectasis/bronchiolectasis and signs of architectural distortion (eg, lung fissure displacement) Focal ground glass
RB	Predominant upper middle lung zone fluffy centrilobular nodules with or without GGO
Indeterminate	Any combination of features that do not fit UIP or RB patterns and do not consist of AEF (eg, bilateral GGO and predominant upper lung zone subpleural reticular opacities)

Abbreviations: LDCT, low-dose computed tomography; ILA, interstitial lung abnormality; UIP, usual interstitial pneumonia; RB, respiratory bronchiolitis; GGO, ground glass opacity; AEF, airspace enlargement and fibrosis.

Table 2 Characteristics of cases vs controls

Variables	Subjects with airflow obstruction (cases)	Subjects without airflow obstruction (controls)	P-value
Sex, n (%)
Female	154 (33.5%)	306 (66.5%)	0.9
Male	303 (33.3%)	608 (66.7%)
Age, years, mean ± SD	63.2±7.4	57.9±6.2	<0.001
BMI, mean ± SD	26±4.2	26.4±4	0.4
Smoking status, n
Current	263	635	0.0009
Former	194	279
Pack-years of smoking
Mean ± SD	48.3±24.2	44±20.7	0.01
FEV1 %
Mean ± SD	80.4±19.1	101.4±14.2	<0.0001
FVC%
Mean ± SD	104.2±18.3	104.8±17.2	0.1
FEV1/FVC
Mean ± SD	59.6±8.8	79.3±7.9	<0.0001

Abbreviations: BMI, body mass index; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FEV₁/FVC, Tiffenau index; SD, standard deviation.

Table 3 LDCT patterns frequency

LDCT patterns	Subjects with airflow obstruction (n=457 cases)	Subjects without airflow obstruction (n=914 controls)	P-valuea
Definite ILA, n (%)	32 (7%)	83 (9%)	0.22
Definite UIP, n (%)	–	2 (0.2%)	N/A
Possible UIP, n (%)	4 (0.9%)	8 (0.9%)	0.2
RB, n (%)	21 (4.6%)	71 (7.8%)	0.04
Indeterminate, n (%)	9 (2%)	3 (0.3%)	0.006
Fibrotic ILA, n	4	12	0.6
Equivocal ILA, n (%)	14 (3.1%)	–	<0.0001
AEF, n (%)	8 (1.7%)	–	0.02
Unilateral opacities, n (%)	6 (1.3%)	–	N/A
Fibrotic ILA, n (%)	9 (1.9%)a	–	<0.0001

Note:

a In two cases, unilateral reticulation and AEF coexisted.

Abbreviations: LDCT, low-dose computed tomography; ILA, interstitial lung disease; UIP, usual interstitial pneumonia; N/A, not applicable; RB, respiratory bronchiolitis; AEF, airspace enlargement with fibrosis.

Table 4 Characteristics of subjects stratified for the presence of ILA

Variables	Subjects with any ILA (n=129)	Subjects with no ILA (n=1,242)	P-value
Sex (n)
Female	33	427	0.04
Male	96	815
Age, years (mean ± SD)	59.8±7.6	59.6±7	0.8
BMI (mean ± SD)	25.9±3.6	26.3±4.2	0.07
Smoking status (n)
Current	109	791	<0.0001
Former	20	433
Pack-years of smoking (mean ± SD)	49.5±24	44.9±21.7	0.03
FEV1 % (mean ± SD)	92.8±17.8	94.6±18.9	0.3
FVC% (mean ± SD)	102.7±17.8	104.8±17.4	0.6
FEV1/FVC (mean ± SD)	71.8±12	72.8±12.5	0.7

Abbreviations: ILA, interstitial lung disease; BMI, body mass index; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FEV₁/FVC, Tiffenau index.

Figure 2 A 57-year-old former male smoker with clinical chronic obstructive lung disease (COPD).

Notes: (A) Both study observers jointly considered the thick-walled low attenuation areas in the lower lobes as consistent with reticular opacities superimposed to pulmonary emphysema (ie, not as honeycombing). (B) The latter was also abundant in the upper middle lung regions. The LDCT pattern was indeed rated as possible UIP.

Abbreviations: LDCT, low-dose computed tomography; UIP, usual interstitial pneumonia.

Figure 3 A 67-year-old male current smoker with no airflow obstruction on PFT (control) and a possible UIP pattern on LDCT.

Note: Subpleural basal reticular opacities containing traction bronchiectasis without evidence of honeycombing can be appreciated.

Abbreviations: PFT, pulmonary function test; UIP, usual interstitial pneumonia; LDCT, low-dose computed tomography.

Figure 4 A 59-year-old control current female smoker with an LDCT showing patchy GGO and poorly defined centrilobular nodules consistent with signs of RB.

Abbreviations: LDCT, low-dose computed tomography; GGO, ground glass opacity; RB, respiratory bronchiolitis.

Figure 5 An axial LDCT image of a 79-year-old former male smoker with clinical COPD showing thick-walled, bizarre-shaped emphysematous areas in the right lower lobe that were regarded as consistent with AEF.

Abbreviations: LDCT, low-dose computed tomography; AEF, airspace enlargement with fibrosis.

Figure 6 The plots (A and B) show FEV₁ (percentage of predicted value) plotted against FEV₁/FVC (percent of predicted value) for the participants with (red circle) and without any ILA (black cross) and participants with (red circle) and without any fibrotic ILA (black cross), respectively, and classify them according to the GOLD criteria.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ILA, interstitial lung abnormality; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Table 5 Univariate and multivariate logistic regression models predicting the likelihood of definite ILA

Variables	Univariate					Multivariate
	β	SE	OR	95% CI	P-value	β	SE	OR	95% CI	P-value
Age, years	−0.018	0.014	0.982	0.955–1.010	0.208
Sex
Female	–	–	1	–	–
Male	0.293	0.216	1.341	0.877–2.049	0.175
FEV1, % of predicted	−0.003	0.005	0.997	0.987–1.008	0.621
BMI, kg/m^2	−0.036	0.025	0.965	0.919–1.013	0.148
Smoking status
Former	–	–	1	–	–	–	–	1	–	–
Current	1.456	0.301	4.289	2.380–7.731	<0.001	1.476 (1.400)a	0.302 (0.309)a	4.377 (4.054)a	2.422–7.910 (2.214–7.421)a	<0.001 (<0.001)a
Pack-years	0.010	0.004	1.010	1.003–1.018	0.009	0.012 (0.014)a	0.004 (0.004)a	1.012 (1.014)a	1.004–1.020 (1.005–1.022)a	0.004 (0.001)a
Airflow obstruction
Absent	–	–	1	–	–
Present	−0.226	0.220	0.798	0.519–1.227	0.303

Notes: Hosmer and Lemeshow test shows χ²=4.971, P=0.761 and χ²=7.394, P=0.495 for multivariate and multivariate adjusted models, respectively.

a Multivariate adjusted model for presence of airflow obstruction, age, and sex. Statistically significant P-values are indicated by bold font.

Abbreviations: ILA, interstitial lung disease; SE, standard error; OR, odds ratio; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; BMI, body mass index.

Table 6 Univariate and multivariate logistic regression models predicting the likelihood of any fibrotic ILA

Variables	Univariate					Multivariate
	β	SE	OR	95% CI	P-value	β	SE	OR	95% CI	P-value
Age, years	0.160	0.028	1.174	1.111–1.240	<0.001	0.159 (0.165)	0.033 (0.031)	1.172 (1.179)	1.098–1.251 (1.109–1.254)	<0.001 (<0.001)
Sex
Female	–	–	1	–	–			1
Male	2.519	1.022	12.419	1.675–92.094	0.014	2.110 (2.150)	1.032 (1.032)	8.245 (8.582)	1.091–62.289 (1.134–64.920)	0.041 (0.037)
FEV1, % of predicted	−0.008	0.010	0.992	0.972–1.012	0.437
BMI, kg/m^2	−0.003	0.049	0.951	0.905–1.098	0.951
Smoking status
Former	–	–	1	–	–
Current	−0.452	0.407	0.636	0.287–1.413	0.267
Pack-years	0.013	0.008	1.013	0.998–1.028	0.078
Airflow obstruction
Absent	–	–	1	–	–	–	–	1	–	–
Present	0.923	0.425	2.517	1.095–5.787	0.030	0.009	0.482	1.009	0.393–2.594	0.985

Notes: Hosmer and Lemeshow test shows χ²=7.727, P=0.461 for multivariate model. Statistically significant P-values are indicated by bold font.

Abbreviations: ILA, interstitial lung disease; SE, standard error; OR, odds ratio; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; BMI, body mass index.

Table S1 Individual LDCT features

Individual LDCT features	Subjects with airflow obstruction (n=457 cases)	Subjects without airflow obstruction (n=914 controls)	P-value
Upper lung zone predominance	29	56	0.1
Upper middle lung zone predominance	17	41	0.07
Lower zone predominance	13	14	0.9
Diffuse	8	21	0.02
Traction bronchiectasis	2	11	0.0001
Honeycombing	–	2	N/A
Bilateral reticular opacities	7	13	0.4
Fluffy centrilobular nodules	23	72	<0.001
Bilateral ground glass opacities	11	4	0.02
Reticular opacities outlining emphysematous holes	8	2	0.001
Unilateral reticular opacities	6	–	N/A
Unilateral ground glass opacities	1	–	N/A

Abbreviations: ILA, interstitial lung disease; N/A, not applicable; LDCT, low-dose computed tomography.

Table S2 Any ILA or fibrotic ILA distributions across GOLD stages

Presence and type of ILA	GOLD stages						P-value
	0	1	2	3	4	U
Subjects with no ILA	787	163	173	58	13	48	0.45
Subjects with any ILA	75	17	23	6	0	8
Subjects with no fibrotic ILA	852	177	190	60	13	54	0.03
Subjects with any fibrotic ILA	10	3	6	4	0	2

Abbreviations: ILA, interstitial lung disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; U, unclassified.