Impact of Interstitial Lung Abnormalities on Disease Expression and Outcomes in COPD or Emphysema: A Systematic Review

Figures & data

Figure 1 Flowchart of critical review and selection for inclusion of article.

Table 1 Characteristics of Included Studies Focusing on the Association Between ILAs and COPD/Emphysema

Author (Year)	Type of Study	Quality of Study Assessed by NOS Tool or AHRQ Scale^a	Image Features, Image Subtypes, and Classification Assessed by Chest CT	Measurement Parameters	Main Manifestations and Outcomes	Sample Size	Prevalence of ILAs	Main Results
Washko GR (2011)^Citation7	Cross-sectional study	8	Classification 1: Definite ILAs, equivocal ILAs Classification 2: Centrilobular, subpleural, mixed centrilobular and subpleural, radiologic ILD	Age, gender, BMI, smoking status, smoking pack-years, PFTs, chest CT	1. PFTs 2. Prevalence of COPD and Emphysema	2416 smokers in COPDGene cohort (1210 with COPD and 905 without COPD, others are unclassified)	Definite ILAs: 194(8%) participants indeterminate ILAs: 861(36%) participants	1. The participants with ILAs were significantly older, had a higher BMI, and had greater smoking pack-years than those without ILAs. 2. The participants with ILAs were less likely to have COPD, and had a lower percentage of emphysema. 3. ILAs were associated with reduced total lung capacity in individuals with or without COPD. The reductions in total lung capacity were similar between the two groups after adjustment for emphysema. 4. ILAs odds were associated with smoking pack-years and smoking status.
Araki T (2015)^Citation28	Cross-sectional study	7	Definite ILAs, indeterminate ILAs	Age, gender, BMI, smoking status, smoking pack-years, Respiratory symptoms, PFTs, chest CT	Subtypes of emphysema	2633 participants in the FHS	Definite ILAs: 177(7%) participants Indeterminate ILAs: 1086(41%) participants	Participants with paraseptal emphysema had a higher rate of combined ILAs than those without paraseptal emphysema (24% vs 6%).
Bozzetti F (2016)^Citation18	Case-control study	********	Classification 1: definite UIP, possible UIP, RB, indeterminate Classification 2: fibrotic, nonfibrotic	Age, gender, BMI, smoking status, smoking pack-years, PFTs, LDCT, GOLD stage	PFTs	457 COPD and 914 control subjects	Definite ILAs: 32(7%)in COPD and 89(9%)in control subjects Equivocal ILAs: 14(3.1%) in COPD and none in control subjects	1. The prevalence of ILAs was similar between COPD cases and control subjects. 2. ILAs was distributed across GOLD stages homogeneously. There is no significant difference between the PFTs of individuals with and without ILAs. 3. Definite ILAs were associated with current smoking status (OR 4.05) and increasing smoking index (OR 1.01). 4. Individuals with fibrotic ILAs were more likely to be older (OR 1.17) and male (OR 8.58). 5. RB was more frequent in control subjects whereas the indeterminate pattern was more frequent in COPD cases. Equivocal ILAs were observed only among COPD cases. Fibrotic ILAs was less frequent in control subjects as compared to subjects with GOLD 1, 2, 3, or U of COPD.
Putman RK (2016)^Citation13	Cohort study	*******	Definite ILAs, indeterminate ILAs	Age, race, gender, BMI, smoking status, smoking pack-years, PFTs, chest CT, GOLD stage	1. All-cause mortality with a median follow-up of 3–9 years 2. PFTs	2068 participants from the COPDGene cohort and 1670 COPD patients from the ECLIPSE cohort	Definite ILAs: 156 (8%) in the COPDGene cohort, and 157 (9%) in the ECLIPSE cohort Indeterminate ILAs: 739 (36%) in the COPDGene cohort, and 985 (59%) in the ECLIPSE cohort	1. In the individuals with ILAs, compared to those without ILAs, age was older in the COPDGene cohort and the ECLIPSE cohort, gender was not different, BMI was higher in the COPDGene cohort and no different difference in the ECLIPSE cohort. Smoking pack-year was higher in the COPDGene cohort but no difference in the ECLIPSE. COPD prevalence was lower in the COPDGene but higher in the FHS. 2. ILAs were associated with a high FEV1 and FEV1-to-FVC ratio in the COPDGene and the ECLIPSE. In contrast, ILAs were associated with a higher prevalence of COPD and a lower FEV1-to-FVC ratio in the FHS cohort. TLC was lower in the COPDGene but no difference in the ECLIPSE. 3. ILAs were associated with a higher mortality compared to those without ILAs. (HR, 1.8 in the COPDGene cohort, and HR, 1.4 in the ECLIPSE cohort)
Chiba S (2017)^Citation21	Cross-sectional study	6	Unclassifiable, nonspecific interstitial pneumonia	Age, gender, BMI, smoking status, smoking pack-years, prevalence and number of comorbidities, serum KL-6, serum SP-D, serum total and antigen-specific IgE, PFTs, HRCT	1. PFTs 2. IgE, SP-D, and KL-6	30 ACOS	7(23.3%) with interstitial changes	1. In ACOS with interstitial changes, the age was older, and smoking pack-years were higher, the airway walls in HRCT were thicker and serum KL-6 was higher than those in ACOS without interstitial changes significantly. 2. PFTs were similar between the two groups. 3. The fungal-specific IgE was higher in ACOS with interstitial changes but not significantly. There was no significant difference in serum total IgE and SP-D between the two groups.
Ohgiya M (2017)^Citation20	Cross-sectional study	4	Honeycombing, reticular abnormalities, GGOs	Age, BMI, serum KL-6, PFTs, HRCT	PFTs	349 COPD	20(10.3%) patients in Group A, 17(22.5%) patients in Group B, 3(5.6%) patients in Group C, 10(23.1%) patients in Group D, total 50(14.3%) in all	1. In Group B, the frequency of ILAs was higher and the area of ILAs was greater significantly compared with those in Group C. 2. In Group B, patients with ILAs had higher FEV1% predicted and low attenuation area scores than patients without ILAs, but not significantly. 3. The area of honeycombing in Group B was significantly greater than that in Group C. The rates and severity of GGOs were similar in all 4 groups.
Ash SY (2018)^Citation17	Case-control study	******	-	Age, gender, BMI, smoking status, smoking pack-years, 6MWD, SGRQ, mortality, PFTs, chest CT, The RVLV volume ratio	1. Mortality with a median follow-up of 6.3 years 2. PFTs 3. 6MWD, RVLV volume ratio, and SGRQ score	8266 participants in COPDGene cohort	1069 (12.9%) participants with interstitial features	Subjects with emphysema and interstitial features had a higher FEV1% predicted, a lower DLCO% predicted, a higher RVLV ratio, a shorter 6MWD, a higher SGRQ score, and higher mortality, compared with the subjects with emphysema alone. Interstitial features enhanced the effect of emphysema on DLCO% predicted, 6MWD, RVLV volume ratio, and SGRQ score.
Hoyer N (2020)^Citation29	Cohort study	****	-	Age, gender, BMI, smoking status, smoking pack-years, PFTs, LDCT, comorbid disease, hospital admission	Hospital admission	1990 participants (322 with ILA, 214 with COPD)	55(25.7%) subjects in COPD patients	1. Frequency of comorbid COPD was increased in ILAs subjects. 2. In COPD patients, those with ILAs had more frequent hospital admissions (HR 2.1) when considering the primary and contributing discharge diagnoses, whereas the hospital admissions for COPD were not associated with ILAs when only considering the primary discharge diagnosis.
Ono M (2020)^Citation19	Case-control study	*******	-	Age, gender, BMI, smoking status, mMRC scales, CAT scores, exacerbation frequency, PFTs, HRCT	1. Exacerbations of COPD 2. PFTs	463 COPD (30 patients with ILAs and 90 patients without ILAs after propensity score matching)	30(6.5%) patients with ILAs	1. The annualized rate of COPD exacerbations per patient was lower in the ILAs compared with those without ILAs (0.06 vs 0.23). 2. Patients with ILAs showed greater FEV1 and FEV1% predicted, as well as lower mMRC scale and CAT scores compared with those without ILAs, but not significantly.
Lee TS (2021)^Citation16	Cross-sectional study	7	Classification 1: Definite ILAs, equivocal ILAs Classification 2: Centrilobular, subpleural, mixed, radiologic ILD	Age, gender, BMI, smoking status, smoking pack-years, annual incidence of acute exacerbations of COPD (history and follow-up), Charlson Comorbidity Index, 6MWD, PFTs (baseline and follow-up), positive bronchodilator response, chest CT (baseline and follow-up)	1. Exacerbation of COPD 2. Longitudinal decline in lung function	363 COPD	Definite ILAs: 103(28.4%) patients Equivocal ILAs: 44(12.1%) patients	1. The COPD patients with ILAs were significantly older and had lower FEV1 and FVC than patients without ILAs. 2. ILAs were significantly associated with the annual incidence of moderate to severe acute exacerbation of COPD and with the risk of frequent exacerbation (HR 2.04). 3. The patients with ILAs had lower FEV1% predicted, FVC%predicted, DLCO, and 6MWD, but not significantly. Smoking status and intensity were similar between the two groups. 4. Patients with progressive ILAs showed a significantly higher rate of annual decline in FEV1 and FVC than those showing no change in, or improved, ILAs. The decline in DLCO was not significantly different according to ILAs status. 5. The changes of PFTs showed no significantly different according to ILAs subtype during the follow-up.
Menon A (2022)^Citation27	Case-control study	*******	Definite ILAs, indeterminate ILAs	Age, gender, BMI, smoking status, smoking pack-years, PFTs, chest CT	1. PFTs 2. Emphysema	9579 participants from phase 1 and 5277 participants from phase 2 in the COPDGene cohort	Definite ILAs: 528 (6%) in phase 1, and 580 (11%) in phase 2	1. Participants with ILAs were older, have a higher BMI, a heavier smoking intensity, a lower FEV1, a lower FVC, a lower DLCO% predicted, a lower TLC, and a lower emphysema score compared with those without ILAs. FEV1-to-FVC ratios were not different between the two groups with and without ILAs. In phase 1, the FRC to TLC ratio and measures of Pi10 were higher in participants with ILAs compared with those without ILAs, but not in phase 2. 2. The decrement in FVC associated with increased emphysema was less in the ILAs group than that in the group without ILAs. In phase 1, the FVC was negatively associated with the amount of emphysema in participants without ILAs, whereas in participants with ILAs, the reduction of FVC was not associated with an increase in the amount of emphysema. In the longitudinal analysis, in participants with ILAs (in phase 1), the decline in FVC associated with emphysema was less than that noted in those without ILAs. ILAs modified the effect of emphysema on FEV1 and the FEV1-to-FVC ratio, but not the TLC and DLCO.

Note: ^aThe quality of studies assessed by the NOS tool is presented as stars, and the quality of studies assessed by the AHRQ scale is presented as numbers.

Abbreviations: 6MWD, Six minutes walk distance; ACOS, Asthma-COPD overlap syndrome; AHRQ, Agency for Healthcare Research and Quality; BMI, body mass index; CAT, COPD Assessment Test; COPDGene, Genetic Epidemiology of COPD Study; D_LCO, diffusion capacity of the lung for carbon monoxide; ECLIPSE, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points; FHS, Framingham Heart Study; FRC, functional residual capacity; GGO, ground-glass opacity; GOLD, global initiative for chronic obstructive lung disease; HRCT, High Resolution Computed Tomography; IgE, immunoglobulin E; ILAs, interstitial lung abnormalities; ILD, interstitial lung disease; KL-6, Krebs Von den Lungen-6; LDCT, Low-Dose Computed Tomography; mMRC, Modified British Medical Research Council; NOS, Newcastle-Ottawa Scale; PFTs, pulmonary function tests; Pi10, square root of wall area of airway with internal perimeter of 10 mm; RB, respiratory bronchiolitis; RVLV, right ventricular to left ventricular; SGRQ, St George’s Respiratory Questionnaire; SP-D, serum surfactant protein D; TLC, total lung capacity; UIP, usual interstitial pneumonia.

Table 2 PFTs in Subjects with and without ILAs in Included Studies

	Populations	Subjects with ILAs		Subjects without ILAs	P value	Author (Year)
		Total or Definite ILAs	Equivocal/Indeterminate ILAs
FVC % predicted (%) (mean (SD))	COPD patients	102.7 (17.8)	–	104.8 (17.4)	0.6	Bozzetti F (2016)^Citation18
		80 (20)	–	79 (19)	0.78	Putman RK (2016)^Citation13
		86.4 (18.0)	81.5 (18.4)	87.0 (18.0)	0.222	Lee TS (2021)^Citation16
	Smoking subjects	88 (77–98)	87 (74–99)	88 (75–100)	0.80	Washko GR (2011)^Citation7
		99.5 (17.7)	–	101.7 (15.3)	0.04	Hoyer N (2020)^Citation29
		88 (17)	–	87 (19)	0.49	Putman RK (2016)^Citation13
		87.0 (17.5)	–	89.8 (18.0)	<0.001	Ash SY (2018)^Citation17
FVC (L)	COPD patients	3.13 (0.63)	–	3.02 (0.68)	0.442	Ono M (2020)^Citation19
		3.0 (0.7)	2.9 (0.8)	3.2 (0.8)	0.032	Lee TS (2021)^Citation16
	Smoking subjects	4.03(1.0)	–	4.13 (0.99)	0.10	Hoyer N (2020)^Citation29
		2.98 (2.5–3.7)	–	3.32 (2.7–4.1)	< 0.0001	Menon A (2022)^Citation27
		2.94 (2.37–3.63)	–	3.13 (2.52–3.90)	< 0.0001
FEV1% predicted (%)	COPD patients	92.8 (17.8)	–	94.6 (18.9)	0.3	Bozzetti F (2016)^Citation18
		68.1 (19.5)	–	64.0 (21.4)	0.354	Ono M (2020)^Citation19
		61.9 (20.0)	58.2 (18.2)	62.8 (18.0)	0.264	Lee TS (2021)^Citation16
		47 (14)	–	44 (15)	0.02	Putman RK (2016)^Citation13
	Smoking subjects	76.8 (23.8)	–	77.8 (27.0)	0.200	Ash SY (2018)^Citation17
		87.9 (18.6)	–	92.4 (16.3)	< 0.001	Hoyer N (2020)^Citation29
		82 (67–93)	77 (55–92)	80 (52–97)	0.15	Washko GR (2011)^Citation7
		78 (22)	–	75 (28)	0.10	Putman RK (2016)^Citation13
FEV1 (L)	COPD patients	1.74 (0.50)	–	1.58 (0.59)	0.184	Ono M (2020)^Citation19
		1.5 (0.5)	1.5 (0.6)	1.6 (0.5)	0.025	Lee TS (2021)^Citation16
	Smoking subjects	2.75 (0.76)	–	2.91 (0.75)	< 0.001	Hoyer N (2020)^Citation29
		2.06 (1.6–2.6)	–	2.35 (1.7–3.0)	< 0.0001	Menon A (2022)^Citation27
		2.06 (1.61–2.57)	–	2.26 (1.61–2.83)	0.0005
FEV1-to-FVC ratio (%)	COPD patients	71.8±12	–	72.8 (12.5)	0.7	Bozzetti F (2016)^Citation18
		48.6 (12.3)	49.6 (12.7)	50.4 (11.5)	0.585	Lee TS (2021)^Citation16
		48 (11)	–	45(12)	0.006	Putman RK (2016)^Citation13
	Smoking subjects	71 (60–80)	–	72 (60–80)	0.37	Menon A (2022)^Citation27
		72(64–78)	–	73 (62–79)	0.76
		71 (61–77)	68 (53–76)	70 (51–79)	0.32	Washko GR (2011)^Citation7
		67 (14)	–	64 (18)	0.03	Putman RK (2016)^Citation13
DLCO % predicted (%)	COPD patients	82.1 (25.0)	77.1 (27.2)	81.0 (23.7)	0.718	Lee TS (2021)^Citation16
	Smoking subjects	50.9 (20.8)	–	49.8 (20.5)	0.764	Ash SY^Citation17
		70.6 (57.7–84.5)	–	83.4 (68–97.9)	< 0.0001	Menon A (2022)^Citation27
DLCO(mL/mmHg/min)	COPD patients	12.7 (4.5)	13.3 (6.0)	14.0 (4.9)	0.147	Lee TS (2021)^Citation16
TLC (L)	COPD patients	5.7 (1.4)	–	5.9 (1.5)	0.16	Putman RK (2016)^Citation13
	Smoking subjects	5.0 (4.1–6.0)	–	5.6 (4.7–6.7)	< 0.0001	Menon A (2022)^Citation27
		5.04 (4.22–6.05)	–	5.38 (4.57–6.54)	< 0.0001
		5.02 (4.15–5.96)	5.21 (4.38–6.27)	5.70 (4.80–6.78)	<0.001	Washko GR (2011)^Citation7
		5.2 (1.4)	–	5.8 (1.4)	<0 0.001	Putman RK (2016)^Citation13
TLC % predicted (%)	Smoking subjects	95 (81–109)	100 (84–112)	107 (92–120)	<0.001	Washko GR (2011)^Citation7
FRC-to-TLC ratio (%)	Smoking subjects	0.6 (0.5–0.7)	–	0.6 (0.5–0.7)	0.0001	Menon A (2022)^Citation27
		0.56 (0.50–0.63)	–	0.56 (0.49–0.65)	0.87

Note: Data are presented as No. (%) or mean (SD), unless otherwise indicated.

Abbreviations: D_LCO, diffusion capacity of the lung for carbon monoxide; FRC, functional residual capacity; ILAs, interstitial lung abnormalities; TLC, total lung capacity.

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