COPD, 12:38–45, 2015 ISSN: 1541-2555 print / 1541-2563 online Copyright © Informa Healthcare USA, Inc. DOI: 10.3109/15412555.2014.903916
ORIGINAL RESEARCH
Severe COPD Exacerbation: CT Features Maxime Hackx,1 Benoît Ghaye,2 Emmanuel Coche,2 Alain Van Muylem,3 and Pierre Alain Gevenois1
COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
1
Department of Radiology (MH, PAG), Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium
2
Department of Medical Imaging (BG, EC), Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
3
Department of Chest Medicine (AVM), Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium
Abstract Objective: To describe CT features associated with severe exacerbations of Chronic Obstructive Pulmonary Disease (COPD). Materials and Methods: In this prospective ethical-committee-approved study, 44 COPD patients (34 men, 10 women, age range 49–83 years) who provided written informed consent were included at the time of hospital admission for severe exacerbation. Pulmonary function tests (PFT) and chest CT scans were performed at admission and after resolution of the episode following a minimum of 4 weeks free of any acute symptom. For each CT scan, two radiologists independently scored 15 features in each lobe and side. CT features and PFT results were compared for exacerbation and control through Mac-Nemar tests and paired t-tests, respectively. Results: Forced expiratory volume in 1 second and vital capacity improved significantly after exacerbation (p = 0.023 and 0.012, respectively). Bronchial wall thickening and lymphadenopathy were graded significantly higher at exacerbation than at control by both readers (p ranging from < 0.001 to 0.028). Other CT features were not observed during exacerbation, or were so only by one reader (p ranging from < 0.001 to 0.928). Conclusion: Only lymphadenopathy and bronchial wall thickening are CT features associated with severe COPD exacerbation, respectively in 25% and 50% of patients. Our findings do not advocate a role for CT in the routine work-up of patients with severe COPD exacerbation.
Introduction
Keywords: bronchial wall, emphysema, lymphadenopathy, pulmonary embolism Correspondence to: P.A. Gevenois, Department of Radiology - Hôpital Erasme, Route de Lennik, 808 - 1070 Brussels, Belgium, phone: (322)5553220, fax: (322)5554388, email: [email protected]
38
The natural course of Chronic Obstructive Pulmonary Disease (COPD) is associated with episodes of exacerbation which are clinically defined as acute events characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and which leads to a change in medication (1). Moreover, these episodes can be classified into mild, moderate, or severe exacerbations, following patient’s need for medical environment (2). Although the cause of about one-third of severe exacerbation episodes cannot be identified (1), two-thirds are associated with certain conditions such as respiratory tract infections (viral or bacterial) (3–9), air pollution (10–12), as well as pulmonary embolism (PE), pulmonary edema, cardiac arrhythmia, pneumothorax, or pleural effusion (13–15). As COPD exacerbations are associated with increased morbidity and mortality, as well as with increased healthcare costs, their prevention and treatment are two major objectives in COPD management with subsequent requirement for appropriate assessment tools (16). As imaging tool, chest radiography is limited to the detection of pneumonia and pleural abnormalities, and only leads to change in managements in a marginal proportion of patients (17, 18). However, while CT scans allows detecting more chest abnormalities, the knowledge of CT features at the time of exacerbation is
CT features of severe COPD exacerbation
a pre-requisite for determining possible role of CT in routine work-up of exacerbation. Nevertheless these features remain widely unknown, previous studies having focused on the prevalence of PE (19, 20). The aim of our study was therefore to describe these features by comparing CT scans performed at severe exacerbation with control scans.
COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
Materials and Methods Study population This prospective study was approved by the institutional ethical committee and written informed consent was obtained from all patients. In addition, its registration identifier on ClinicalTrials.gov was NCT01922180. Between July 2007 and August 2009, 44 COPD patients followed in our hospital (mean age, 69 years ± 9 (standard error of mean); range 49–83 years), including 34 men and 10 women were prospectively included in this trial at the time of an exacerbation episode leading to admission in our hospital, which corresponds to a severe episode (2). There were no exclusion criteria. COPD was graded as GOLD I in 2 patients, GOLD II in 13 patients, GOLD III in 18 patients, and GOLD IV in 11 patients (1). At the time of admission, pulmonary function tests (PFT) and chest CT scans were performed. As there is no definition of the resolution of an exacerbation episode, we arbitrarily considered that a minimum of 4 weeks free of any acute symptom after discharge was reasonable before redoing PFT and chest CT scan. The mean interval between CT scans at exacerbation and at control was 76 days. Pulmonary function tests PFT were carried out with the patient in the seated position. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured with a Lilly-type pneumotachograph, while functional residual capacity (FRC) was measured in a constant volume body plethysmograph (MasterScreen Body, Jaeger, Würzburg, Germany). Total lung capacity (TLC) and residual volume (RV) were calculated using the values of FRC and the subdivisions of FVC. The measured values were then compared to the predicted values established by the European Respiratory Society (21). CT examinations CT examinations were performed with a commercially available 64-detector row scanner (Somatom Sensation, Siemens Healthcare, Forchheim, Germany). Images were acquired in supine position after full inspiration and full expiration, using the following parameters: slice thickness, 0.6 mm; pitch, 1.4; rotation time, 330 msec; tube voltage, 120 kV; and tube current-time product, 100 mAs, with automatic exposure control (CareDose 4D, Siemens Healthcare) switched on. From raw data, 1-mm-thick section images were reconstructed at 0.7mm intervals by using a high spatial algorithm (B60S, www.copdjournal.com
Siemens Healthcare) and a soft-tissue algorithm (B30S). The inspiratory CT scan at the time of exacerbation was performed with intravenous iodinated contrast material (100 mL of iomeprol administrated at a rate of 3.5 mL/sec, Iomeron 400; Bracco Diagnostics, Milan, Italy), whereas the control scan was unenhanced.
Image analysis Informations on CT images that could identify the patients were removed and examinations were randomly numbered by using tables from Fisher and Yates (22). Thereafter, two independent radiologists with 21 (reader 1) and 23 (reader 2) years of experience in chest imaging analyzed the CT images utilizing a reading sheet adapted from that used for scoring exacerbation in cystic fibrosis (23). A preliminary reading session of eight CT examinations obtained in patients not involved in the present study was performed in consensus to learn the grading system and improve inter-reader agreement. For each lobe (with the lingula considered as a separate lobe), readers were asked to grade severity of the following seven features: bronchiectasis, mucous plugging, bronchial wall thickening, pulmonary consolidation, ground glass opacity, cysts or bullae, and air trapping. All features with the exception of air trapping (24) and bronchial wall thickening (25) were defined according to the Fleischner Society Glossary of Terms for Thoracic Imaging (26). Air trapping was considered to be present on the expiratory CT images when lung regions failed to increase in attenuation and/or failed to decrease in volume, when compared with the corresponding inspiratory images (24). Bronchial wall thickening was defined as thick and less well-defined bronchial walls (25). Bronchial wall thickening was graded as mild (wall thickness equal to the diameter of the adjacent vessel), moderate (wall thickness greater than up to twice the diameter of the adjacent vessel), or severe (wall thickness >2 times the diameter of the adjacent vessel). After the preliminary reading session, we decided to consider eight additional features possibly associated with COPD exacerbation: three were graded per lobe (centrilobular micronodules, platelike atelectasis, and emphysema) and five were graded per side (PE, pleural effusion, mediastinal or hilar lymphadenopathy, reticular pattern or honeycombing, and pulmonary mass or nodule). These eight additional features with the exception of PE (25) and pleural effusion (25) were also defined according to the Fleischner Society Glossary of Terms for Thoracic Imaging (26). PE was defined as a filling defect within an opacified pulmonary artery (25). Pleural effusion was defined as a homogeneous crescentic opacity in the most dependent part of the pleural cavity (25). An extract for one lobe of the reading sheet is shown in Figure 1. In order to keep readers blinded to the correspondence between enhanced CT scans at the time of exacerbation and unenhanced control CT scans, the reading sessions were spread over 6 months and reading sheets could not be modified after each session.
39
COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
40
Hackx et al.
Figure 1. Extraction for one lobe of the reading sheet.
Statistical analysis We began the analysis of reading sheets by transforming our results in a way that would allow for further computation. This resulted in four steps: 1) 2)
3)
4)
reading sheets for exacerbation and control were compared, and changes in grades were computed for each feature in each lobe/side of each patient; changes in grades were classified as “improvement” (grade of exacerbation > grade of control), “worsening” (grade of exacerbation < grade of control), and “no change” (grade of exacerbation = grade of control); four features (i.e. bronchiectasis, mucous plugging, bronchial wall thickening, and air trapping) had related subfeatures as detailed in Figure 1, whereby the subfeatures were considered if the primary feature was present at exacerbation and control; and, changes in feature/subfeature in various lobes/sides of a particular patient were classified as follows: if unchanged in each lobe/side, it was considered as “unchanged”, if unchanged in each lobe/side but improved in one, it was considered as “improved”, if unchanged in each lobe/side but worsened in one, it was considered as “worsened”, and if improved and simultaneously worsened in different lobes/ sides, it was considered as “unchanged”.
For each feature/subfeature, a Mac-Nemar test assessed whether the number of patients who improved or worsened from exacerbation to control was significant. Inter-reader agreement was evaluated through weighted Kappa statistics comparing the observed proportion of agreements with the proportion of agreements expected by chance. The observed worsening-unchanged, improvement-unchanged disagreements were weighted by a factor of 1, and the worsening-improvement disagreements were weighted by a factor of 2. All kappa values were interpreted
as proposed in the literature: a kappa value of 0.20 or less indicated poor agreement, 0.21–0.40 fair agreement, 0.41– 0.60 moderate agreement, 0.61–0.80 good agreement, and 0.81–1.00 excellent agreement (27). Finally, paired t-tests were used to compare PFT results obtained at exacerbation and control. All analyses were performed by using Statistica 6.0 (StatSoft France, Maisons-Alfort, France) except for the Kappa statistics (Prism 6, Graphpad Software, La Jolla, USA). p < 0.05 was considered to indicate a statistically significant difference.
Results Pulmonary function tests Table 1 shows comparisons between PFT at exacerbation and at control. There was a significant functional recovery of the airflow obstruction from exacerbation to control; shown through increases of FEV1 and FVC (p = 0.023 and 0.012, respectively). Table 1. Comparisons of PFT at Exacerbation and at Control Exacerbation
Control
p-value
1.1 ± 0.5
1.2 ± 0.5
.102
FEV1
39.6 ± 19.2
44.0 ± 19.1
.023
FVC
57.4 ± 21.7
62.7 ± 20.0
.012
FEV1/FVC (%)
54.1 ± 11.8
54.5 ± 13.2
.526
FEV1/FVC
FEV1 (L)
70.4 ± 15.1
70.5 ± 16.8
.579
FRC
143.8 ± 36.3
142.0 ± 33.8
.297
TLC
105.0 ± 19.6
106.6 ± 18.5
.746
RV
173.9 ± 49.8
167.1 ± 45.6
.088
Note. Abbreviations: PFT = pulmonary function tests, FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, FRC = functional residual capacity, TLC = total lung capacity, and RV = residual volume. Unless specified otherwise, data are expressed as percentages of predicted values established by the European Respiratory Society (30). Data are mean ± standard deviation of the mean.
Copyright © 2015 Informa Healthcare USA, Inc
CT features of severe COPD exacerbation
Table 2. Frequency of CT features detected by each reader at exacerbation and at control, and corresponding grades Grades 0 Exacerbation Reader Bronchiectasis
1 Control
Exacerbation
Exacerbation
1
2
1
2
1
2
1
2
124
194
126
196
134
64
136
66
1
3 Control
2
1
2
Exacerbation 1
2
Control 1
2
If yes: Largest size
122
55
116
54
9
3
13
5
3
6
7
7
Average size
128
63
130
65
5
1
5
1
1
0
1
0
59
28
53
24
44
4
37
7
22
9
32
7
17
5
14
8
2
6
6
8
Central extent Peripheral extent Mucous plugging If yes: Central extent Peripheral extent Bronchial wall thickening
9
23
14
28
55
16
62
8
60
37
54
42
148
192
191
222
110
66
71
40
15
17
16
18
52
40
37
22
33
5
15
0
10
4
3
0
46
21
34
15
42
36
27
24
17
4
9
1
5
5
1
0
8
25
39
45
If yes: Severity COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
2 Control
Central extent Peripheral extent
1
0
250
234
223
216
190
187
195
187
52
36
26
28
8
10
2
2
5
0
20
18
28
23
53
40
69
43
176
175
121
151
43
146
59
156
107
43
91
34
77
21
61
18
23
23
12
9
Pulmonary consolidation
214
209
226
226
29
46
30
36
14
3
6
0
1
0
0
0
Ground glass opacity
236
248
235
256
14
8
18
5
8
2
9
1
0
0
0
0
Cysts or bullae
245
246
240
252
12
12
22
10
0
0
1
0
0
0
0
0
163
247
160
244
37
4
35
8
42
5
43
6
19
2
21
4
64
6
50
6
34
5
49
12
209
62
44
53
51
46
1
26
0
16
0
0
1
Air trapping extent If yes: Air trapping appearance Centrolobular micronodules
134
214
183
Platelike atelectasis
98
225
103
219
141
34
139
41
17
1
20
0
2
0
0
0
Emphysema extent
82
133
80
117
67
53
65
71
56
33
42
34
53
41
75
38
Pulmonary embolus
75
76
NA
NA
3
2
NA
NA
Pleural effusion
79
79
80
82
10
9
7
6
Mediastinal or hilar lymphadenopathy
65
75
83
85
24
13
4
3
Reticular pattern or honeycombing
86
88
84
80
3
2
3
6
Pulmonary mass or nodule
72
77
67
76
17
11
20
12
Note. Abbreviation: NA = not applicable.
CT examinations One patient had a left upper lobectomy, one had a left lower lobectomy, and one had both middle and right lower lobectomy. Our readers thus reviewed 520 lobes and 88 sides. The frequencies of a CT feature graded by each reader at exacerbation and at control are listed in Table 2. Almost all CT features were detected with various grades at both exacerbation and control, indicating that they could remain present after an exacerbation episode, even without any acute symptom. Reader 1 and 2, respectively, detected 3/39 (7.7%) and 2/39 (5.1%) of patients with PE, with five CT examinations at exacerbation where enhancement was missing or inappropriate for evaluating PE for both readers. Nevertheless, as control scans were unenhanced, we did not investigate the evolution of PE at control. All patients showed at least one significant change at CT between exacerbation and control. A comparison of the numbers of patients with worsening, improvement, or no change from exacerbation to control for each CT feature by both readers are shown in www.copdjournal.com
Table 3. The severity of bronchial wall thickening (Figure 2) and the presence of mediastinal or hilar lymphadenopathy (Figure 3) were graded significantly higher by both readers (p ranging from < 0.001 to 0.028), during exacerbation than at control. The proportion of patients with mediastinal or hilar lymphadenopathy present at exacerbation were 13/44 (29.5%) for reader 1 and 8/44 (18.2%) for reader 2. In patients with bronchial wall thickening present at both exacerbation and control, the proportion with increased severity at exacerbation were 14/27 (51.8%) for reader 1 and 12/27 (44.4%) for reader 2. In addition, other items, such as the presence of bronchial wall thickening, the central extent of bronchial wall thickening, the peripheral extent of bronchial wall thickening, and the extent of centrilobular micronodules were graded significantly higher at exacerbation than at control by only one of our readers (p ranging from < 0.001 to 0.039). Results of weighted kappa statistics are listed in Table 4. Agreement between readers was fair for the
41
42
Hackx et al.
Table 3. Comparisons of numbers of patients with improvement, worsening or no change from exacerbation to control Reader 1 Improvement
Worsening
No change
p-value
Improvement
Worsening
No change
p-value
14
16
14
.784
13
15
16
.777
Bronchiectasis largest size
0
2
6
.289
0
1
2
.617
Bronchiectasis average size
0
0
8
NA
0
0
3
NA
Bronchiectasis central extent
2
1
5
.773
1
0
2
.617
Bronchiectasis peripheral extent
1
2
5
.773
1
0
2
.617
17
9
18
.141
15
9
20
.262
Mucous plugging central extent
1
1
4
.724
3
0
0
.149
Mucous plugging peripheral extent
2
1
3
.773
3
0
0
.149
Bronchial wall thickening
15
1
28
ORIGINAL RESEARCH
Severe COPD Exacerbation: CT Features Maxime Hackx,1 Benoît Ghaye,2 Emmanuel Coche,2 Alain Van Muylem,3 and Pierre Alain Gevenois1
COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
1
Department of Radiology (MH, PAG), Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium
2
Department of Medical Imaging (BG, EC), Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
3
Department of Chest Medicine (AVM), Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium
Abstract Objective: To describe CT features associated with severe exacerbations of Chronic Obstructive Pulmonary Disease (COPD). Materials and Methods: In this prospective ethical-committee-approved study, 44 COPD patients (34 men, 10 women, age range 49–83 years) who provided written informed consent were included at the time of hospital admission for severe exacerbation. Pulmonary function tests (PFT) and chest CT scans were performed at admission and after resolution of the episode following a minimum of 4 weeks free of any acute symptom. For each CT scan, two radiologists independently scored 15 features in each lobe and side. CT features and PFT results were compared for exacerbation and control through Mac-Nemar tests and paired t-tests, respectively. Results: Forced expiratory volume in 1 second and vital capacity improved significantly after exacerbation (p = 0.023 and 0.012, respectively). Bronchial wall thickening and lymphadenopathy were graded significantly higher at exacerbation than at control by both readers (p ranging from < 0.001 to 0.028). Other CT features were not observed during exacerbation, or were so only by one reader (p ranging from < 0.001 to 0.928). Conclusion: Only lymphadenopathy and bronchial wall thickening are CT features associated with severe COPD exacerbation, respectively in 25% and 50% of patients. Our findings do not advocate a role for CT in the routine work-up of patients with severe COPD exacerbation.
Introduction
Keywords: bronchial wall, emphysema, lymphadenopathy, pulmonary embolism Correspondence to: P.A. Gevenois, Department of Radiology - Hôpital Erasme, Route de Lennik, 808 - 1070 Brussels, Belgium, phone: (322)5553220, fax: (322)5554388, email: [email protected]
38
The natural course of Chronic Obstructive Pulmonary Disease (COPD) is associated with episodes of exacerbation which are clinically defined as acute events characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and which leads to a change in medication (1). Moreover, these episodes can be classified into mild, moderate, or severe exacerbations, following patient’s need for medical environment (2). Although the cause of about one-third of severe exacerbation episodes cannot be identified (1), two-thirds are associated with certain conditions such as respiratory tract infections (viral or bacterial) (3–9), air pollution (10–12), as well as pulmonary embolism (PE), pulmonary edema, cardiac arrhythmia, pneumothorax, or pleural effusion (13–15). As COPD exacerbations are associated with increased morbidity and mortality, as well as with increased healthcare costs, their prevention and treatment are two major objectives in COPD management with subsequent requirement for appropriate assessment tools (16). As imaging tool, chest radiography is limited to the detection of pneumonia and pleural abnormalities, and only leads to change in managements in a marginal proportion of patients (17, 18). However, while CT scans allows detecting more chest abnormalities, the knowledge of CT features at the time of exacerbation is
CT features of severe COPD exacerbation
a pre-requisite for determining possible role of CT in routine work-up of exacerbation. Nevertheless these features remain widely unknown, previous studies having focused on the prevalence of PE (19, 20). The aim of our study was therefore to describe these features by comparing CT scans performed at severe exacerbation with control scans.
COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
Materials and Methods Study population This prospective study was approved by the institutional ethical committee and written informed consent was obtained from all patients. In addition, its registration identifier on ClinicalTrials.gov was NCT01922180. Between July 2007 and August 2009, 44 COPD patients followed in our hospital (mean age, 69 years ± 9 (standard error of mean); range 49–83 years), including 34 men and 10 women were prospectively included in this trial at the time of an exacerbation episode leading to admission in our hospital, which corresponds to a severe episode (2). There were no exclusion criteria. COPD was graded as GOLD I in 2 patients, GOLD II in 13 patients, GOLD III in 18 patients, and GOLD IV in 11 patients (1). At the time of admission, pulmonary function tests (PFT) and chest CT scans were performed. As there is no definition of the resolution of an exacerbation episode, we arbitrarily considered that a minimum of 4 weeks free of any acute symptom after discharge was reasonable before redoing PFT and chest CT scan. The mean interval between CT scans at exacerbation and at control was 76 days. Pulmonary function tests PFT were carried out with the patient in the seated position. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured with a Lilly-type pneumotachograph, while functional residual capacity (FRC) was measured in a constant volume body plethysmograph (MasterScreen Body, Jaeger, Würzburg, Germany). Total lung capacity (TLC) and residual volume (RV) were calculated using the values of FRC and the subdivisions of FVC. The measured values were then compared to the predicted values established by the European Respiratory Society (21). CT examinations CT examinations were performed with a commercially available 64-detector row scanner (Somatom Sensation, Siemens Healthcare, Forchheim, Germany). Images were acquired in supine position after full inspiration and full expiration, using the following parameters: slice thickness, 0.6 mm; pitch, 1.4; rotation time, 330 msec; tube voltage, 120 kV; and tube current-time product, 100 mAs, with automatic exposure control (CareDose 4D, Siemens Healthcare) switched on. From raw data, 1-mm-thick section images were reconstructed at 0.7mm intervals by using a high spatial algorithm (B60S, www.copdjournal.com
Siemens Healthcare) and a soft-tissue algorithm (B30S). The inspiratory CT scan at the time of exacerbation was performed with intravenous iodinated contrast material (100 mL of iomeprol administrated at a rate of 3.5 mL/sec, Iomeron 400; Bracco Diagnostics, Milan, Italy), whereas the control scan was unenhanced.
Image analysis Informations on CT images that could identify the patients were removed and examinations were randomly numbered by using tables from Fisher and Yates (22). Thereafter, two independent radiologists with 21 (reader 1) and 23 (reader 2) years of experience in chest imaging analyzed the CT images utilizing a reading sheet adapted from that used for scoring exacerbation in cystic fibrosis (23). A preliminary reading session of eight CT examinations obtained in patients not involved in the present study was performed in consensus to learn the grading system and improve inter-reader agreement. For each lobe (with the lingula considered as a separate lobe), readers were asked to grade severity of the following seven features: bronchiectasis, mucous plugging, bronchial wall thickening, pulmonary consolidation, ground glass opacity, cysts or bullae, and air trapping. All features with the exception of air trapping (24) and bronchial wall thickening (25) were defined according to the Fleischner Society Glossary of Terms for Thoracic Imaging (26). Air trapping was considered to be present on the expiratory CT images when lung regions failed to increase in attenuation and/or failed to decrease in volume, when compared with the corresponding inspiratory images (24). Bronchial wall thickening was defined as thick and less well-defined bronchial walls (25). Bronchial wall thickening was graded as mild (wall thickness equal to the diameter of the adjacent vessel), moderate (wall thickness greater than up to twice the diameter of the adjacent vessel), or severe (wall thickness >2 times the diameter of the adjacent vessel). After the preliminary reading session, we decided to consider eight additional features possibly associated with COPD exacerbation: three were graded per lobe (centrilobular micronodules, platelike atelectasis, and emphysema) and five were graded per side (PE, pleural effusion, mediastinal or hilar lymphadenopathy, reticular pattern or honeycombing, and pulmonary mass or nodule). These eight additional features with the exception of PE (25) and pleural effusion (25) were also defined according to the Fleischner Society Glossary of Terms for Thoracic Imaging (26). PE was defined as a filling defect within an opacified pulmonary artery (25). Pleural effusion was defined as a homogeneous crescentic opacity in the most dependent part of the pleural cavity (25). An extract for one lobe of the reading sheet is shown in Figure 1. In order to keep readers blinded to the correspondence between enhanced CT scans at the time of exacerbation and unenhanced control CT scans, the reading sessions were spread over 6 months and reading sheets could not be modified after each session.
39
COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
40
Hackx et al.
Figure 1. Extraction for one lobe of the reading sheet.
Statistical analysis We began the analysis of reading sheets by transforming our results in a way that would allow for further computation. This resulted in four steps: 1) 2)
3)
4)
reading sheets for exacerbation and control were compared, and changes in grades were computed for each feature in each lobe/side of each patient; changes in grades were classified as “improvement” (grade of exacerbation > grade of control), “worsening” (grade of exacerbation < grade of control), and “no change” (grade of exacerbation = grade of control); four features (i.e. bronchiectasis, mucous plugging, bronchial wall thickening, and air trapping) had related subfeatures as detailed in Figure 1, whereby the subfeatures were considered if the primary feature was present at exacerbation and control; and, changes in feature/subfeature in various lobes/sides of a particular patient were classified as follows: if unchanged in each lobe/side, it was considered as “unchanged”, if unchanged in each lobe/side but improved in one, it was considered as “improved”, if unchanged in each lobe/side but worsened in one, it was considered as “worsened”, and if improved and simultaneously worsened in different lobes/ sides, it was considered as “unchanged”.
For each feature/subfeature, a Mac-Nemar test assessed whether the number of patients who improved or worsened from exacerbation to control was significant. Inter-reader agreement was evaluated through weighted Kappa statistics comparing the observed proportion of agreements with the proportion of agreements expected by chance. The observed worsening-unchanged, improvement-unchanged disagreements were weighted by a factor of 1, and the worsening-improvement disagreements were weighted by a factor of 2. All kappa values were interpreted
as proposed in the literature: a kappa value of 0.20 or less indicated poor agreement, 0.21–0.40 fair agreement, 0.41– 0.60 moderate agreement, 0.61–0.80 good agreement, and 0.81–1.00 excellent agreement (27). Finally, paired t-tests were used to compare PFT results obtained at exacerbation and control. All analyses were performed by using Statistica 6.0 (StatSoft France, Maisons-Alfort, France) except for the Kappa statistics (Prism 6, Graphpad Software, La Jolla, USA). p < 0.05 was considered to indicate a statistically significant difference.
Results Pulmonary function tests Table 1 shows comparisons between PFT at exacerbation and at control. There was a significant functional recovery of the airflow obstruction from exacerbation to control; shown through increases of FEV1 and FVC (p = 0.023 and 0.012, respectively). Table 1. Comparisons of PFT at Exacerbation and at Control Exacerbation
Control
p-value
1.1 ± 0.5
1.2 ± 0.5
.102
FEV1
39.6 ± 19.2
44.0 ± 19.1
.023
FVC
57.4 ± 21.7
62.7 ± 20.0
.012
FEV1/FVC (%)
54.1 ± 11.8
54.5 ± 13.2
.526
FEV1/FVC
FEV1 (L)
70.4 ± 15.1
70.5 ± 16.8
.579
FRC
143.8 ± 36.3
142.0 ± 33.8
.297
TLC
105.0 ± 19.6
106.6 ± 18.5
.746
RV
173.9 ± 49.8
167.1 ± 45.6
.088
Note. Abbreviations: PFT = pulmonary function tests, FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, FRC = functional residual capacity, TLC = total lung capacity, and RV = residual volume. Unless specified otherwise, data are expressed as percentages of predicted values established by the European Respiratory Society (30). Data are mean ± standard deviation of the mean.
Copyright © 2015 Informa Healthcare USA, Inc
CT features of severe COPD exacerbation
Table 2. Frequency of CT features detected by each reader at exacerbation and at control, and corresponding grades Grades 0 Exacerbation Reader Bronchiectasis
1 Control
Exacerbation
Exacerbation
1
2
1
2
1
2
1
2
124
194
126
196
134
64
136
66
1
3 Control
2
1
2
Exacerbation 1
2
Control 1
2
If yes: Largest size
122
55
116
54
9
3
13
5
3
6
7
7
Average size
128
63
130
65
5
1
5
1
1
0
1
0
59
28
53
24
44
4
37
7
22
9
32
7
17
5
14
8
2
6
6
8
Central extent Peripheral extent Mucous plugging If yes: Central extent Peripheral extent Bronchial wall thickening
9
23
14
28
55
16
62
8
60
37
54
42
148
192
191
222
110
66
71
40
15
17
16
18
52
40
37
22
33
5
15
0
10
4
3
0
46
21
34
15
42
36
27
24
17
4
9
1
5
5
1
0
8
25
39
45
If yes: Severity COPD Downloaded from informahealthcare.com by Mcgill University on 02/06/15 For personal use only.
2 Control
Central extent Peripheral extent
1
0
250
234
223
216
190
187
195
187
52
36
26
28
8
10
2
2
5
0
20
18
28
23
53
40
69
43
176
175
121
151
43
146
59
156
107
43
91
34
77
21
61
18
23
23
12
9
Pulmonary consolidation
214
209
226
226
29
46
30
36
14
3
6
0
1
0
0
0
Ground glass opacity
236
248
235
256
14
8
18
5
8
2
9
1
0
0
0
0
Cysts or bullae
245
246
240
252
12
12
22
10
0
0
1
0
0
0
0
0
163
247
160
244
37
4
35
8
42
5
43
6
19
2
21
4
64
6
50
6
34
5
49
12
209
62
44
53
51
46
1
26
0
16
0
0
1
Air trapping extent If yes: Air trapping appearance Centrolobular micronodules
134
214
183
Platelike atelectasis
98
225
103
219
141
34
139
41
17
1
20
0
2
0
0
0
Emphysema extent
82
133
80
117
67
53
65
71
56
33
42
34
53
41
75
38
Pulmonary embolus
75
76
NA
NA
3
2
NA
NA
Pleural effusion
79
79
80
82
10
9
7
6
Mediastinal or hilar lymphadenopathy
65
75
83
85
24
13
4
3
Reticular pattern or honeycombing
86
88
84
80
3
2
3
6
Pulmonary mass or nodule
72
77
67
76
17
11
20
12
Note. Abbreviation: NA = not applicable.
CT examinations One patient had a left upper lobectomy, one had a left lower lobectomy, and one had both middle and right lower lobectomy. Our readers thus reviewed 520 lobes and 88 sides. The frequencies of a CT feature graded by each reader at exacerbation and at control are listed in Table 2. Almost all CT features were detected with various grades at both exacerbation and control, indicating that they could remain present after an exacerbation episode, even without any acute symptom. Reader 1 and 2, respectively, detected 3/39 (7.7%) and 2/39 (5.1%) of patients with PE, with five CT examinations at exacerbation where enhancement was missing or inappropriate for evaluating PE for both readers. Nevertheless, as control scans were unenhanced, we did not investigate the evolution of PE at control. All patients showed at least one significant change at CT between exacerbation and control. A comparison of the numbers of patients with worsening, improvement, or no change from exacerbation to control for each CT feature by both readers are shown in www.copdjournal.com
Table 3. The severity of bronchial wall thickening (Figure 2) and the presence of mediastinal or hilar lymphadenopathy (Figure 3) were graded significantly higher by both readers (p ranging from < 0.001 to 0.028), during exacerbation than at control. The proportion of patients with mediastinal or hilar lymphadenopathy present at exacerbation were 13/44 (29.5%) for reader 1 and 8/44 (18.2%) for reader 2. In patients with bronchial wall thickening present at both exacerbation and control, the proportion with increased severity at exacerbation were 14/27 (51.8%) for reader 1 and 12/27 (44.4%) for reader 2. In addition, other items, such as the presence of bronchial wall thickening, the central extent of bronchial wall thickening, the peripheral extent of bronchial wall thickening, and the extent of centrilobular micronodules were graded significantly higher at exacerbation than at control by only one of our readers (p ranging from < 0.001 to 0.039). Results of weighted kappa statistics are listed in Table 4. Agreement between readers was fair for the
41
42
Hackx et al.
Table 3. Comparisons of numbers of patients with improvement, worsening or no change from exacerbation to control Reader 1 Improvement
Worsening
No change
p-value
Improvement
Worsening
No change
p-value
14
16
14
.784
13
15
16
.777
Bronchiectasis largest size
0
2
6
.289
0
1
2
.617
Bronchiectasis average size
0
0
8
NA
0
0
3
NA
Bronchiectasis central extent
2
1
5
.773
1
0
2
.617
Bronchiectasis peripheral extent
1
2
5
.773
1
0
2
.617
17
9
18
.141
15
9
20
.262
Mucous plugging central extent
1
1
4
.724
3
0
0
.149
Mucous plugging peripheral extent
2
1
3
.773
3
0
0
.149
Bronchial wall thickening
15
1
28
