Radiographic Phenotypes Affect the Risk of Inhaled Corticosteroid-Associated Pneumonia in Patients with COPD

Figures & data

Table 1 Baseline Characteristics of COPD Patients Treated with Inhaled Corticosteroid Containing Therapy

	Total (N=90)	No Pneumonia (n=49)	Pneumonia (n=41)	P-value
Age, years	66 (0.9)	63.69 (9.81)	68.73 (7.11)	0.007
Male	83 (92.2)	46 (93.9)	37 (90.2)	0.522
BMI, kg/m^2	23.52 (0.37)	23.51 (3.67)	23.53 (3.41)	0.977
Smoking history				0.166
Never smoker	10 (11.11)	5 (10.2)	5 (12.2)
Former smoker	61 (67.78)	30 (61.2)	31 (75.6)
Current smoker	19 (21.11)	14 (28.6)	5 (12.1)
Smoking amount, pack-years	38.7 (3.1)	35.27 (24.52)	42.76 (33.5)	0.225
mMRC grade				0.409
0–1	48 (53.4)	25 (51)	23 (56.1)
2	32 (35.6)	20 (40.8)	12 (29.3)
3–4	10 (11.1)	4 (8.2)	6 (14.6)
Respiratory comorbidity
Asthma	9 (10)	6 (12.2)	3 (7.3)	0.438
ACO	22 (24.4)	16 (32.7)	6 (14.6)	0.048
NTM–PD	8 (8.9)	4 (8.2)	4 (9.8)	0.791
Bronchiectasis	15 (16.7)	6 (12.2)	9 (22)	0.219
Tuberculous destroyed lung	26 (28.9)	14 (28.6)	12 (29.3)	0.942
Interstitial lung disease	1 (1.1)	1 (2)	0 (0)	0.358
Lung cancer	5 (5.6)	1 (2)	4 (9.8)	0.112
Rhinitis or sinusitis	15 (16.7)	12 (24.5)	3 (7.3)	0.029
Other comorbid disease
Hypertension	19 (21.1)	6 (12.2)	13 (31.7)	0.024
Diabetes mellitus	19 (21.1)	10 (20.4)	9 (22)	0.858
Chronic kidney disease	3 (3.3)	1 (2)	2 (4.9)	0.455
Chronic liver disease	4 (4.4)	1 (2)	3 (7.3)	0.226
Cerebrovascular disease	9 (10)	3 (6.1)	6 (14.6)	0.18
Cardiovascular disease	23 (25.6)	12 (24.5)	11 (26.8)	0.8
Malignancy other than lung cancer	9 (10)	3 (6.1)	6 (14.6)	0.358
Gastroesophageal reflux disease	2 (2.2)	2 (4.1)	0	0.191
Peptic ulcer	1 (1.1)	1 (2)	0	0.358
GOLD stage				0.212
1–2	63 (70)	37 (75.5)	26 (63.4)
3–4	27 (30)	12 (24.5)	15 (36.6)
ABCD classification				<0.0001
A-B	73 (54.4)	47 (95.9)	26 (63.4)
C-D	17 (18.9)	2 (4.1)	15 (36.6)
Baseline spirometry
FEV1, predicted %	60.26 (1.99)	63.57 (18.98)	56.29 (18.2)	0.068
FVC, predicted %	90.03 (1.78)	91.82 (16.67)	87.9 (17.15)	0.277
FEV1/FVC, predicted %	46.39 (1.37)	48.63 (12.85)	43.71 (12.73)	0.072
DLCO, predicted %	81.08 (2.55)	83.73 (22.94)	77.9 (25.53)	0.257
Serum total IgE level, UI/mL	401.59 (136.38)	326.41 (156.62)	1234.11 (233.23)	0.560
Blood eosinophil count, cells/µL	262.26 (22.85)	292.44 (37.06)	226.19 (22.82)	0.132
Blood eosinophil count >300 µL, n (%)	26 (28.9)	15 (30.6)	11 (26.8)	0.693

Note: Data presented as n (%) or mean (SD) and median (SE).

Abbreviations: BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; COPD, chronic obstructive pulmonary disease; ACO, asthma and COPD overlap; DLCO, diffusing capacity of the lungs for carbon monoxide; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; NTM–PD, nontuberculous mycobacteria pulmonary disease.

Table 2 Clinical Features of COPD Patients Treated with Inhaled Corticosteroid Containing Therapy

	Total (N=90)	No Pneumonia (N=49)	Pneumonia (N=41)	P-value
Follow-up duration, months	29.09 (0.72)	27.55 (8.01)	30.93 (4.46)	0.014
Duration of dominant ICS use, months	22.13 (1.05)	19.69 (9.84)	25.05 (9.43)	0.01
Dominant ICS type
Fluticasone propionate	15 (16.66)	4 (8.2)	11 (26.8)	0.018
Fluticasone furoate	30 (33.33)	18 (36.7)	12 (29.3)	0.454
Budesonide	27 (30)	17 (34.7)	10 (24.4)	0.288
Others^a	18 (20)	10 (20.4)	8 (19.5)	0.916
ICS dose				0.08
Low-to-medium dose	82 (91.11)	47 (95.9)	35 (85.4)
High dose	8 (8.89)	2 (4.1)	6 (14.6)
Inhaler formulation				0.852
Disc powder inhaler	58 (64.44)	32 (65.3)	26 (63.4)
Metered dose inhaler	32 (35.56)	17 (34.7)	15 (36.6)
Previous dominant ICS type
Fluticasone propionate	21 (31.82)	11 (22.4)	10 (24.4)	0.828
Fluticasone furoate	17 (25.76)	8 (16.3)	9 (22)	0.497
Budesonide	22 (33.33)	13 (26.5)	9 (22)	0.615
Others^a	6 (9.09)	3 (6.1)	3 (7.3)	0.821
Combined therapy
SABA	55 (61.11)	26 (53.1)	29 (70.7)	0.087
LAMA	2 (2.2)	2 (4.1)	0 (0)	0.191
LABA	38 (42.2)	17 (34.7)	21 (51.2)	0.114
LABA/LAMA	35 (38.9)	15 (30.6)	20 (48.8)	0.078
Bronchodilator oral agent	32 (35.56)	16 (32.7)	16 (39)	0.529
Systemic steroid	15 (16.67)	6 (12.2)	9 (22)	0.219
Annual acute exacerbation
Moderate exacerbation events, n (%)	36 (40)	11 (22.45)	25 (60.98)	<0.001
Severe exacerbation events, n (%)	15 (6.7)	3 (6.12)	12 (29.27)	0.003
Moderate-to-severe exacerbation events, n (%)	43 (47.8)	12 (24.49)	31 (75.61)	<0.001
Total annual events, mean (SD)	1.03 (1.8)	0.53 (1.72)	1.63 (1.71)	0.003

Notes: ^aCiclesonide and beclomethasone. Data presented as n (%) or mean (SD) and median (SE).

Abbreviations: ICS, inhaled corticosteroid; SABA, short-acting β2-agonist; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; SD, standard deviation; SE, standard error.

Table 3 Hazard Ratio of Pneumonia in COPD Patients Treated with Inhaled Corticosteroid Therapy in Univariable Cox Regression Model

	Univariable Cox Regression Model
	HR (95% CI)	P-value
Age	1.043 (1.005–1.083)	0.026
Male	1.525 (0.539–4.313)	0.426
BMI	0.941 (0.858–1.033)	0.205
Smoking history		0.663
Never smoker	Reference
Former smoker	1.121 (0.433–2.903)	0.815
Current smoker	1.719 (0.474–6.243)	0.410
Smoking amount, pack-years	1.001 (0.993–1.01)	0.735
mMRC grade		0.140
0–1	Reference
2	0.878 (0.431–1.786)	0.719
3–4	2.354 (0.914–6.060)	0.076
Respiratory comorbidity
Asthma	1.504 (0.454–4.982)	0.504
ACO	0.607 (0.252–1.463)	0.266
NTM-PD	0.713 (0.245–2.08)	0.536
Bronchiectasis	1.371 (0.643–2.925)	0.415
Tuberculous destroyed lung	0.717 (0.346–1.486)	0.371
Interstitial lung disease	0.049 (0–79,731,637.033)	0.780
Lung cancer	3.496 (1.214–10.069)	0.020
Rhinitis or sinusitis	0.567 (0.174–1.85)	0.347
Other comorbid disease
Hypertension	2.385 (1.195–4.76)	0.014
Diabetes mellitus	1.059 (0.5–2.242)	0.882
Chronic kidney disease	2.469 (0.585–10.423)	0.219
Chronic liver disease	0.962 (0.271–3.412)	0.952
Cerebrovascular disease	1.348 (0.561–3.242)	0.505
Cardiovascular disease	1.351 (0.668–2.732)	0.403
Malignancy other than lung cancer	1.791 (0.746–4.297)	0.192
Gastroesophageal reflux disease	0.047 (0–736.146)	0.535
Peptic ulcer	–	–
GOLD stage		0.616
1–2	Reference
3–4	1.519 (0.795–2.903)	0.205
ABCD classification
A-B	Reference
C-D	1.452 (0.738–2.857)	0.28
Baseline spirometric examination
Predicted value
FEV1, L	0.442 (0.209–0.934)	0.032
FEV1, %	0.986 (0.966–1.006)	0.170
FVC, L	0.71 (0.475–1.062)	0.095
FVC, %	0.987 (0.969–1.006)	0.190
FEV1/FVC, %	0.985 (0.96–1.011)	0.250
Post-bronchodilator value
FEV1, L	0.469 (0.248–0.888)	0.020
FEV1, %	0.985 (0.968–1.002)	0.088
FVC, L	0.722 (0.492–1.06)	0.097
FVC, %	0.987 (0.969–1.006)	0.181
FEV1/FVC, %	0.983 (0.96–1.006)	0.148
DLCO, L	0.889 (0.828–0.955)	0.001
DLCO, %	0.984 (0.97–0.997)	0.019
Serum total IgE level (UI/mL)	1	0.993
Eosinophil count (µL)	0.998 (0.997–1)	0.056
Eosinophil count >300µL	0.651 (0.323–1.312)	0.23
Duration of ICS use	1.018 (0.982–1.055)	0.333
Dominant ICS type
Fluticasone propionate	5.748 (2.572–12.843)	<0.001
Fluticasone furoate	0.541 (0.272–1.074)	0.079
Budesonide	0.616 (0.3–1.263)	0.186
Others^a	1.332 (0.61–2.909)	0.472
ICS dose (High)	0.832 (0.343–2.017)	0.683
ICS formulation type (MDI)	2.145 (1.111–4.139)	0.023
Previous ICS use	0.48 (0.232–0.996)	0.049
Previous dominant ICS type
Fluticasone propionate	2.06 (0.983–4.317)	0.055
Fluticasone furoate	0.7 (0.332–1.478)	0.349
Budesonide	0.479 (0.227–1.007)	0.052
Others^a	1.054 (0.322–3.455)	0.931
Adjuvant therapy
SABA	1.337 (0.677–2.642)	0.403
LAMA	1.252 (0.664–2.360)	0.488
LABA	–	–
LABA/LAMA	2.317 (1.224–4.385)	0.01
Bronchodilator oral agent	1.378 (0.725–2.616)	0.328
Systemic steroid	1.469 (0.696–3.101)	0.313
Annual acute exacerbation
Moderate exacerbation events	1.049 (0.547–2.011)	0.886
Severe exacerbation events	2.115 (1.045–4.278)	0.037
Moderate-to-severe exacerbation events	1.411 (0.679–2.932)	0.356
Mean of annual total exacerbation events	1.097 (0.961–1.253)	0.168

Notes: ^aCiclesonide and beclomethasone. Data were analyzed with univariable and multivariable Cox regression models and are presented as adjusted hazard ratio (95% confidence interval).

Abbreviations: BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CT, computed tomography; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea scale.

Table 4 Association of Pneumonia and CT Phenotype in COPD Patients Treated with Inhaled Corticosteroid Therapy in Univariable Cox Regression Model

	Univariable Cox Regression Model
	HR (95% CI)	P-value
Emphysema	3.924 (1.374–11.206)	0.011
Visual sum score		0.033
Absence	1
Mild to moderate (<3 lobes)	5.206 (1.136–23.853)	0.034
Severe (3–5 lobes)	3.877 (1.352–11.116)	0.012
Goddard sum score		0.014
Absence	1
Mild to moderate (≤50%)	2.976 (0.987–8.979)	0.053
Severe (<50%)	5.511 (1.850–16.416)	0.002
LAA% score		0.007
Low (<3%)	1
Medium (3–10%)	1.539 (0.522–4.538)	0.434
High (<10%)	3.712 (1.391–9.907)	0.009
Subtype		0.043
Absence	1
CLE	3.768 (1.257–11.293)	0.018
PSE	2.206 (0.395–12.302)	0.367
PLE	4.766 (1.565–14.513)	0.006
Lobe distribution
Absence	1
Upper lobe	3.953 (1.385–11.283)	0.01
Lower lobe	2.99 (1.24–7.207)	0.015
Bronchial wall thickening	2.555 (0.892–7.314)	0.081
Visual sum score		0.019
Absence	1
Mild to moderate (<3 lobes)	2.362 (0.956–5.838)	0.063
Severe (3–5 lobes)	0.818 (0.366–1.826)	0.624
Bronchiectasis	2.382 (1.243–4.566)	0.009
Visual sum score		0.155
Absence	1
Mild to moderate (<3 lobes)	1.77 (0.83–3.77)	0.136
Severe (3–5 lobes)	1.98 (0.91–4.28)	0.083
Emphysema/bronchiectasis overlap	2.81 (1.42–5.54)	0.003

Notes: Data were analyzed with univariable Cox regression and are presented as Cox regression coefficient and 95% confidence interval.

Abbreviations: LAA%, low attenuation area; CLE, centrilobular emphysema; PSE, paraseptal emphysema; PLE, panlobular emphysema.

Table 5 Association of Pneumonia and CT Phenotype in COPD Patients Treated with Inhaled Corticosteroid Therapy in Multivariable Cox Regression Model

	Model 1*		Model 2*		Model 3*
	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
Emphysema	3.73 (1.11–12.53)	0.033	3.69 (1.07–12.81)	0.039	3.72 (1.07–12.97)	0.039
Visual sum score		0.045		0.058		0.055
Mild to moderate (<3 lobes)	8.58 (1.49–49.37)	0.016	7.86 (1.35–45.79)	0.022	8.46 (1.39–51.37)	0.02
Severe (3–5 lobes)	3.58 (1.05–12.25)	0.042	3.59 (1.03–12.55)	0.045	3.63 (1.03–12.79)	0.044
Goddard sum score		0.046		0.061		0.061
Mild to moderate (≤50%)	3.31 (0.96–11.37)	0.058	3.4 (0.97–11.9)	0.056	3.39 (0.96–11.9)	0.057
Severe (<50%)	5.38 (1.41–20.44)	0.014	5.29 (1.33–21.04)	0.018	5.31 (1.33–21.19)	0.018
%LAA score		0.182		0.189		0.190
Medium (3–10%)	1.34 (0.38–4.72)	0.653	1.25 (0.34–4.56)	0.738	1.25 (0.34–4.65)	0.737
High (<10%)	2.66 (0.69–10.22)	0.153	2.49 (0.63–9.81)	0.191	2.5 (0.63–9.87)	0.191
Subtype		0.076		0.089		0.088
CLE	3.98 (1.12–14.14)	0.033	3.91 (1.08–14.22)	0.038	3.94 (1.08–14.35)	0.038
PSE	2.74 (0.4–18.76)	0.304	3.09 (0.44–21.91)	0.260	3.16 (0.44–22.77)	0.254
PLE	3.91 (1.06–14.45)	0.041	3.75 (0.99–14.18)	0.051	3.75 (0.99–14.19)	0.052
Lobe distribution
Upper lobe^a	3.76 (1.12–12.58)	0.032	3.74 (1.09–12.87)	0.037	3.76 (1.09–13.01)	0.036
Lower lobe^b	2.42 (0.87–6.72)	0.09	2.4 (0.85–6.81)	0.1	2.4 (0.84–6.81)	0.101
Bronchiectasis	2.41 (1.15–5.05)	0.02	2.55 (1.19–5.46)	0.016	2.56 (1.2–5.49)	0.015
Visual sum score		0.161		0.154		0.152
Mild to moderate (<3 lobes)	2.06 (0.91–4.65)	0.082	1.99 (0.84–4.67)	0.116	2 (0.84–4.75)	0.115
Severe (3–5 lobes)	1.82 (0.76–4.36)	0.181	2.08 (0.85–5.06)	0.107	2.08 (0.85–5.06)	0.107
Emphysema/bronchiectasis overlap	2.19 (0.99–4.85)	0.053	3.34 (1.44–7.72)	0.005	3.33 (1.44–7.72)	0.005

Notes: Model 1* Age, sex, BMI, smoking amount (packyears), mMRC grade, pulmonary function test (post-BDR FEV₁L). Model 2* Model 1+ FP use, ICS dose, ICS formulation. Model 3* Model 2+ severe exacerbation event. ^aRight upper lobe, right middle lobe, left upper lobe, left lingula. ^bRight lower lobe, left lower lobe. Data were analyzed with multivariable Cox regression and are presented as Cox regression coefficient and 95% confidence interval.

Abbreviations: BDR, bronchodilator responsiveness; LAA%, low attenuation area; CLE, centrilobular emphysema; PSE, paraseptal emphysema; PLE, panlobular emphysema.

Figure 1 Adjusted hazard ratio of pneumonia according to the radiographic phenotypes.

Note: Data were analyzed with Cox regression with adjustment for the covariates in Model 1.

Abbreviations: aHR, adjusted hazard ratio; CLE, centrilobular emphysema; PSE, paraseptal emphysema; PLE, panlobular emphysema.