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Table 2 Histopathological evaluation of endobronchial biopsies before and after bronchial thermoplasty

From: Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes

[A]

All asthma patients

(N = 30)

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P Value*

Inflammation in the stroma**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 30

5 (16.7)

15 (50.0)

10 (33.3)

Ν = 27

5 (18.5)

13 (48.2)

9 (33.3)

Ν = 23

4 (17.4)

12 (52.2)

7 (30.4)

0.948

Tissue lymphocyte infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 30

7 (23.3)

12 (40.0)

11 (36.7)

Ν = 27

5 (18.5)

15 (55.5)

7 (25.9)

Ν = 23

4 (17.4)

14 (60.9)

5 (21.7)

0.814

Tissue eosinophil infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 30

14 (46.7)

7 (23.4)

9 (30.0)

Ν = 27

19 (70.3)

3 (11.1)

5 (18.5)

Ν = 23

14 (60.9)

7 (30.4)

2 (8.7)

0.149

Granulocytes in the stroma**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 30

19 (63.3)

11 (36.4)

0

Ν = 27

21 (77.8)

6 (22.2)

0

Ν = 23

18 (78.3)

4 (17.4)

1 (4.3)

0.408

BM thickening **

Normal, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 30

1 (3.3)

19 (63.3)

10 (33.3)

Ν = 25

5 (20.0)

15 (60.0)

5 (20.0)

Ν = 23

2 (8.7)

14 (60.9)

7 (30.4)

0.148

Average ASM mass (%)

Median [IQR]

Mean (SD)

Ν = 30

13.3 [4.8–31.2]

19.0 (17.5)

Ν = 26

4.2 [0.0–15.0]

10.8 (14.8)

N = 23

2.5 [0.0–18.0]

9.6 (16.4)

0.014

Distance BM-ASM

μm, Median [IQR]

Mean (SD)

Ν = 24

73.2 [36.7–117.3]

83.9 (56.1)

N = 11

56.5 [24.9–161.8]

95.0 (86.0)

N = 8

81.6 [35.5–126.4]

95.4 (77.5)

0.987

[B]

Asthma patients with blood eosinophils ≥ 300/μL

(N = 7)

Asthma patients with blood eosinophils < 300/μL

(N = 23)

Before

1st BT

At 2nd BT 1 month after

1st BT

At 3rd BT 1 month after

2nd BT

P value*

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P value*

Inflammation in the stroma**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 7

2 (28.6)

2 (28.6)

3 (42.8)

N = 5

1 (20.0)

2 (40.0)

2 (40.0)

N = 5

0

2 (40.0)

3 (60.0)

0.589

N = 23

3 (13.0)

13 (56.5)

7 (30.3)

N = 22

4 (18.2)

11 (50.0)

7 (31.7)

N = 18

4 (22.2)

9 (50.0)

5 (27.9)

0.665

Tissue lymphocyte infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 7

1 (14.3)

2 (28.6)

4 (57.1)

N = 5

1 (20.0)

3 (60.0)

1 (20.0)

N = 5

0

4 (80.0)

1 (20.0)

0.279

N = 23

6 (26.1)

10 (43.5)

7 (30.4)

N = 22

4 (18.2)

12 (54.5)

6 (27.1)

N = 18

4 (22.2)

10 (55.5)

4 (22.3)

0.836

Tissue eosinophil infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 7

4 (57.1)

1 (14.3)

2 (28.6)

N = 5

3 (60.0)

0

2 (40.0)

N = 5

2 (40.0)

3 (60.0)

0

0.980

N = 23

10 (43.5)

6 (26.0)

7 (30.4)

N = 22

16 (72.7)

3 (13.6)

3 (13.6)

N = 18

12 (66.7)

4 (22.2)

2 (11.2)

0.109

Granulocytes in the stroma**

Absence, n (%)

Mild-moderate n (%)

High, n (%)

N = 7

6 (85.7)

1 (14.3)

0

N = 5

4 (80.0)

1 (20.0)

0

N = 5

4 (80.0)

1 (20.0)

0

0.949

N = 23

13 (56.5)

10 (43.5)

0

N = 22

17 (77.3)

5 (22.7)

0

N = 18

14 (77.8)

3 (16.7)

1 (5.6)

0.280

BM thickening **

Normal, n (%)

Mild-moderate, n (%)

High, n (%)

N = 7

1 (14.3)

3 (42.8)

3 (42.8)

N = 5

1 (20.0)

2 (40.0)

2 (40.0)

N = 5

1 (20.0)

2 (40.0)

2 (40.0)

0.821

N = 23

1 (4.3)

15 (65.2)

7 (30.4)

N = 20

4 (20.0)

13 (65.0)

3 (15.0)

N = 18

1 (5.6)

12 (66.7)

5 (27.8)

0.126

Average ASM mass (%)

Median [IQR]

Mean (SD)

N = 7

43.3 [10.5–50.0]

33.3 (20.1)

N = 5

10.0 [5.0–12.5]

9.0 (5.5)

N = 5

1.0 [0.0–10.3]

4.3 (7.7)

0.009

N = 23

12.5 [1.3–20.0]

14.7 (14.4)

N = 21

2.5 [0.0–21.7]

11.2 (16.3)

N = 18

2.5 [0.0–20.0]

10.3 (17.2)

0.248

Distance BM-ASM μm

Median [IQR]

Mean (SD)

N = 7

67.7 [45.0–79.0]

63.7 (20.1)

N = 1

296.0

296.0

N = 1

114.3

114.3

ǂ

N = 17

76.0 [33.7–136.0]

92.2 (64.3)

N = 10

55.5 [23.7–123.9]

74.9 (57.3)

N = 7

75.8 [32.6–130.4]

92.7 (83.4)

0.770

[C]

Asthma patients with Atopy (N = 19)

Asthma patients without atopy (N = 11)

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P Value*

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P Value*

Inflammation in the stroma**

Absence, n (%)

Mild-moderate, n (%)

Severe, n (%)

N = 19

5 (26.3)

6 (31.6)

8 (42.2)

N = 17

4 (23.5)

7 (41.2)

6 (35.3)

N = 13

2 (15.4)

7 (53.9)

4 (30.8)

0.972

N = 11

0

9 (81.8)

2 (18.2)

N = 10

1 (10.0)

6 (60.0)

3 (30.0)

N = 10

2 (20.0)

5 (50.0)

3 (30.0)

0.942

Tissue lymphocyte infiltration**

Absence, n (%)

Mild-moderate, n (%)

Severe, n (%)

N = 19

4 (21.1)

6 (31.6)

9 (47.4)

N = 17

4 (23.5)

8 (47.1)

5 (29.5)

N = 13

2 (15.4)

8 (61.6)

3 (23.1)

0.516

N = 11

3 (27.3)

6 (54.5)

2 (18.2)

N = 10

1 (10.0)

7 (70.0)

2 (20.0)

N = 10

2 (20.0)

6 (60.0)

2 (20.0)

0.800

Tissue eosinophil infiltration**

Absence, n (%)

Mild-moderate, n (%)

Severe, n (%)

N = 19

10 (52.6)

3 (15.8)

6 (31.6)

N = 17

12 (70.6)

2 (11.8)

3 (17.7)

N = 13

6 (46.2)

6 (46.2)

1 (7.7)

0.420

N = 11

4 (36.4)

4 (36.4)

3 (27.3)

N = 10

7 (70.0)

1 (10.0)

2 (20.0)

N = 10

8 (80.0)

1 (10.0)

1 (10.0)

0.198

Granulocytes in the stroma**

Absence, n (%)

A few, n (%)

Many, n (%)

N = 19

13 (68.4)

6 (31.6)

0

N = 17

13 (76.5)

4 (23.5)

0

N = 13

10 (76.9)

3 (23.1)

0

0.783

N = 11

6 (54.5)

5 (45.5)

0

N = 10

8 (80.0)

2 (20.0)

0

N = 10

8 (80.0)

1 (10.0)

1 (10.0)

0.444

BM thickening **

Normal, n (%)

Mild-moderate, n (%)

Severe, n (%)

N = 19

1 (5.3)

12 (63.2)

6 (31.6)

N = 15

2 (13.3)

9 (60.0)

4 (26.7)

N = 13

8 (61.5)

0

5 (38.5)

0.522

N = 11

0

7 (63.6)

4 (36.4)

N = 10

3 (30.0)

6 (60.0)

1 (10.0)

N = 10

2 (20.0)

7 (70.0)

1 (10.0)

0.146

Average ASMC mass (%)

Median [IQR]

Mean (SD)

N = 19

13.3 [1.3–30.0]

18.5 (17.9)

N = 16

4.2 [0.0–11.9]

7.8 (9.8)

N = 13

0.0 [0.0–9.4]

4.8 (7.7)

0.012

N = 11

13.3 [5.0–35.0]

19.9 (17.4)

N = 10

6.3 [0.0–31.3]

15.5 (20.2)

N = 10

4.2 [0.9–25.6]

15.9 (22.4)

0.424

Distance BM-ASMC μm

Median [IQR]

Mean (SD)

N = 13

79.0 [54.4–119.8]

94.3 (64.7)

N = 5

111.3 [35.3–232.5]

129.4 (109.4)

N = 2

100.8

100.8 (18.9)

0.547

N = 11

71.5 [33.5–124.5]

71.6 (43.8)

N = 6

55.5 [20.5–110.4]

66.4 (55.3)

N = 6

59.9 [28.8–163.0]

93.5 (91.3)

0.896

[D]

Asthma patients with allergy (N = 16)

Asthma patients without allergy (N = 14)

Before

1st BT

At 2nd BT 1 month after

1st BT

At 3rd BT 1 month after 2nd BT

P value*

Before 1st BT

At 2nd BT 1 month after

1st BT

At 3rd BT 1 month after

2nd BT

P value*

Inflammation in the stroma**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 16

3 (18.8)

8 (50.0)

5 (31.2)

N = 14

2 (14.3)

5 (35.7)

7 (50.0)

N = 13

2 (15.4)

7 (53.8)

4 (30.8)

0.588

N = 14

2 (14.3)

7 (50.0)

5 (35.7)

N = 13

3 (23.1)

8 (61.5)

2 (15.4)

N = 10

2 (20.0)

5 (50.0)

3 (30.0)

0.410

Tissue lymphocyte infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 16

4 (25.0)

7 (43.7)

5 (31.3)

N = 14

2 (14.3)

7 (50.0)

5 (35.7)

N = 13

2 (15.4)

9 (69.2)

2 (15.4)

0.698

N = 14

3 (21.4)

5 (35.7)

6 (42.9)

N = 13

3 (23.1)

8 (61.5)

2 (15.4)

N = 10

2 (20.0)

5 (50.0)

3 (30.0)

0.488

Tissue eosinophil infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 16

7 (43.7)

4 (25.0)

5 (31.2)

N = 14

9 (64.3)

1 (7.1)

4 (28.6)

N = 13

7 (53.8)

5 (38.5)

1 (7.7)

0.536

N = 14

7 (50.0)

3 (21.4)

4 (28.6)

N = 13

10 (76.9)

2 (15.4)

1 (7.7)

N = 10

7 (70.0)

2 (20.0)

1(10.0)

0.245

Granulocytes in the stroma**

Absence, n (%)

Mild-moderate n (%)

High, n (%)

N = 16

10 (62.5)

6 (37.5)

0

N = 14

10 (71.4)

4 (28.6)

0

N = 13

9 (69.2)

3 (23.1)

1 (7.7)

0.862

N = 14

9 (64.3)

5 (35.7)

0

N = 13

11 (84.6)

2 (15.4)

0

N = 10

9 (90.0)

1 (10.0)

0

0.304

BM thickening **

Normal, n (%)

Mild-moderate, n (%)

High, n (%)

N = 16

0

10 (62.5)

6 (37.5)

N = 14

3 (21.4)

6 (42.9)

5 (35.7)

N = 13

2 (15.4)

8 (61.5)

3 (23.1)

0.216

N = 14

0

10 (71.4)

4 (28.6)

N = 11

1 (9.1)

9 (81.8)

1 (9.1)

N = 10

0)

6 (60.0)

4 (40.0)

0.274

Average ASM mass (%)

Median [IQR]

Mean (SD)

N = 16

20.0 [9.2–44.6]

25.1 (18.8)

N = 14

6.0 [0–15.0]

9.2 (11.2)

N = 13

0 [0–2.9]

4.0 (7.8)

0.001

N = 14

11.1 [1.2–17.1]

12.1 (13.3)

N = 12

4.2 [0–25.0]

12.6 (18.5)

N = 10

10.6 [2.0–20.0]

15.5 (20.9)

0.626

Distance BM-ASM μm

Median [IQR]

Mean (SD)

N = 12

69.6 [30.1–78.3]

67.4 (42.2)

N = 6

74.9 [23.7–195.4]

108.7 (105.6)

N = 2

46.6

46.6 (41.3)

0.667

N = 12

91.3 [48.5–129.4]

100.4 (64.9)

N = 5

54.5 [29.0–140.2]

78.5 (62.6)

N = 6

100.8 [41.3–163.0]

111.6 (82.5)

0.850

[E]

Asthma patients with relevant smoke exposure (N = 10)

Asthma patients without relevant smoke exposure (N = 20)

Before 1st BT

At 2nd BT 1 month after

1st BT

At 3rd BT 1 month after 2nd BT

P value*

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P value*

Inflammation in the stroma**

Absence, n (%)

Mild-Moderate, n (%)

High, n (%)

Ν = 10

1 (10.0)

6 (60.0)

3 (30.0)

Ν = 10

3 (30.0)

3 (30.0)

4 (40.0)

Ν = 7

1 (14.3)

6 (87.7)

0

0.593

Ν = 20

4 (20.0)

9 (45.0)

7 (35.0)

Ν = 17

2 (11.8)

10 (58.8)

5 (29.4)

Ν = 16

3 (18.8)

6 (37.5)

7 (43.7)

0.945

Tissue lymphocyte infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 10

3 (30.0)

4 (40.0)

3 (30.0)

Ν = 10

3 (30.0)

4 (40.0)

3 (30.0)

Ν = 7

1 (14.3)

6 (87.7)

0

0.915

Ν = 20

4 (20.0)

8 (40.0)

8 (40.0)

Ν = 17

2 (11.8)

11 (64.7)

4 (23.5)

Ν = 16

3 (18.8)

8 (50.0)

5 (31.2)

0.897

Tissue eosinophil infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 10

5 (50.0)

0

5 (50.0)

Ν = 10

8 (80.0)

0

2 (20.0)

Ν = 7

5 (71.4)

2 (28.6)

0

0.233

Ν = 20

9 (45.0)

7 (35.0)

4 (20.0)

Ν = 17

11 (64.7)

3 (17.6)

3 (17.6)

Ν = 16

9 (56.2)

5 (31.3)

2 (12.5)

0.544

Granulocytes in the stroma**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 10

7 (70.0)

3 (30.0)

0

Ν = 10

7 (70.0)

3 (30.0)

0

Ν = 7

5 (71.4)

2 (28.6)

0

0.981

Ν = 20

12 (60.0)

8(40.0)

0

Ν = 17

14 (82.3)

3(17.7)

0

Ν = 16

13 (81.2)

2 (12.5)

1 (6.3)

0.291

BM thickening **

Normal, n (%)

Mild-moderate, n (%)

High, n (%)

Ν = 10

0

7 (70.0)

3 (30.0)

Ν = 9

3 (33.3)

5 (55.6)

1 (11.1)

Ν = 7

0

7 (100.0)

0

0.162

Ν = 20

1 (5.0)

12 (60.0)

7 (35.0)

Ν = 16

2 (12.5)

10 (62.5)

4 (25.0)

Ν = 16

2 (12.5)

7 (43.8)

7 (43.8)

0.461

Average ASM mass (%)

Median [IQR]

Mean (SD)

Ν = 10

9.2 [1.2–22.5]

14.1 (16.8)

Ν = 10

7.5 [0.0–18.7]

13.5 (19.1)

Ν = 7

2.5 [0.0–16.2]

6.3 (8.3)

0.602

Ν = 20

17.2 [9.2–41.2]

21.5 (17.7)

Ν = 16

4.2 [0.1–10.0]

9.1 (11.7)

N = 16

2.5 [0.0–19.0]

11.1 (19.5)

0.019

Distance BM-ASM

μm, Median [IQR]

Mean (SD)

Ν = 8

80.7 [33.6–142.3]

100.8 (79.9)

Ν = 4

102.3 [28.7–249.8]

127.0 (121.5)

Ν = 3

87.4 [7.3–93.3]

78.4 (57.1)

0.864

Ν = 16

73.2 [48.5–94.2]

75.4 (40.4)

Ν = 7

54.5 [24.9–161.8]

76.7 (62.2)

Ν = 5

75.8 [38.4–187.6]

105.5 (92.5)

0.788

[F]

Asthma patients with T2 subtype I (N = 12)

Asthma patients with T2 subtype II (N = 9)

Asthma patients with T2 subtype III (N = 4)

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P value*

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P value*

Before 1st BT

At 2nd BT 1 month after 1st BT

At 3rd BT 1 month after 2nd BT

P value*

Inflammation in the stroma**

Absence, n (%)

Mild-Moderate, n (%)

High, n (%)

N = 12

2 (16.7)

6 (50.0)

4 (33.3)

Ν = 11

2 (18.2)

4 (36.4)

5 (45.4)

Ν = 8

2 (25.0)

2 (25.0)

4 (50.0)

0.806

Ν = 9

1 (11.1)

5 (55.6)

3 (33.3)

Ν = 8

1 (12.5)

5 (62.5)

2 (25.0)

Ν = 7

1 (14.3)

6 (85.7)

0

0.372

Ν = 4

2 (50.0)

0

2 (50.0)

Ν = 3

1 (33.3)

0

2 (66.7)

Ν = 3

0

1 (33.3)

2 (66.7)

0.344

Tissue lymphocyte infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 12

4 (33.3)

4 (33.3)

4 (33.3)

Ν = 11

2 (18.2)

5 (45.4)

4 (36.4)

Ν = 8

2 (25.0)

3 (37.5)

3 (37.5)

0.810

Ν = 9

1 (11.1)

4 (44.4)

4 (44.4)

Ν = 8

1 (12.5)

5 (62.5)

2 (25.0)

Ν = 7

1 (14.3)

6 (85.7)

0

0.288

Ν = 4

1 (25.0)

1 (25.0)

2 (50.0)

Ν = 3

1 (33.3)

1 (33.3)

1 (33.3)

Ν = 3

0

2 (66.7)

1 (33.3)

0.450

Tissue eosinophil infiltration**

Absence, n (%)

Mild-moderate, n (%)

High, n (%)

N = 12

3 (25.0)

4 (33.3)

5 (41.7)

Ν = 11

7 (63.6)

1 (9.1)

3 (27.3)

Ν = 8

4 (50.0)

2 (25.0)

2 (25.0)

0.316

Ν = 9

6 (66.7)

2 (22.2)

1 (11.1)

Ν = 8

7 (87.5)

1 (12.5)

0

Ν = 7

4 (57.1)

3 (42.9)

0

0.287

Ν = 4

2 (50.0)

0

2 (50.0)

Ν = 3

1 (33.3)

0

2 (66.7)

Ν = 3

1 (33.3)

2 (66.7)

0

0.787

Granulocytes in the stroma**

Absence, n (%)

Mild-moderate n (%)

High, n (%)

N = 12

8 (66.7)

4 (33.3)

0

Ν = 11

9 (81.8)

2 (18.2)

0

Ν = 8

7 (87.5)

0

1 (12.5)

0.614

Ν = 9

6 (66.7)

3 (33.3)

0

Ν = 8

6 (75.0)

2 (25.0)

0

Ν = 7

5 (71.4)

2 (28.6)

0

0.878

Ν = 4

3 (75.0)

1 (25.0)

0

Ν = 3

2 (66.7)

1 (33.3)

0

Ν = 3

2 (66.7)

1 (33.3)

0

0.945

BM thickening **

Normal, n (%)

Mild-moderate, n (%)

High, n (%)

N = 12

0

10 (83.3)

2 (16.7)

Ν = 9

2 (22.2)

5 (55.6)

2 (22.2)

Ν = 8

1 (12.5)

5 (62.5)

2 (25.0)

0.786

Ν = 9

1 (11.1)

6 (66.7)

2 (22.2)

Ν = 8

1 (12.5)

6 (75.0)

1 (12.5)

Ν = 7

1 (14.3)

5 (71.4)

1 (14.3)

0.872

Ν = 4

0

1 (25.0)

3 (75.0)

Ν = 3

1 (33.3)

0

2 (66.7)

Ν = 3

0

1 (33.3)

2 (66.7)

0.350

Average ASM mass (%)

Median [IQR]

Mean (SD)

N = 12

15.1 [7.8–26.4]

17.1 (14.6)

Ν = 10

4.1 [0.8–19.2]

10.0 (12.8)

Ν = 8

9.8 [2.2–18.9]

10.6 (10.0)

0.290

N = 9

20.0 [8.1–40.0]

24.1 (20.7)

Ν = 8

5.3 [-0.5–16.0]

7.7 (9.8)

Ν = 7

0 [-3.1–9.2]

3.1 (6.6)

0.049

N = 4

26.9 [-7.1–65.1]

29.0 (22.7)

Ν = 3

10.0 [-10.6–27.3]

8.3 (7.6)

Ν = 3

0 [-2.7–4.4]

0.8 (1.4)

0.082

Distance BM-ASM μm

Median [IQR]

Mean (SD)

Ν = 10

84.8 [51.0–153.8]

102.4 (71.8)

Ν = 7

93.3 [43.9–146.8]

95.3 (55.6)

Ν = 3

75.8 [-33.2–153.5]

60.2 (37.6)

0.639

Ν = 5

71.5 [14.3–132.5]

73.4 (47.6)

Ν = 1

19.9

Ν = 1

114.3

–

Ν = 4

65.7 [26.6–93.7]

60.1 (21.1)

Ν = 1

296.0

Ν = 0

–

  1. T2 subtype I: Patients with only one T2 positive marker (allergy, or atopy, or eosinophils ≥ 300/μL)
  2. T2 subtype II: Patients with any two of T2 positive markers
  3. T2 subtype III: Patients with any three of T2 positive markers
  4. ǂCannot be determined, only 1 observation in two time points
  5. *Comparisons between values before and after BT. For categorical values, the p value was calculated using mixed multinomial (ordinal) logistic regression models, where the factor patient was included as a random effect. For continuous values, the p value was calculated using rank mixed linear regression models, where the factor patient was included as a random effect
  6. **Qualitative evaluation, 0–3 scale: 0 to < 0.5 = absence/normal, 0.5 to < 1.50 = mild-moderate, 1.5–3 = high
  7. BT bronchial thermoplasty, BM basement membrane, ASM airway smooth muscle, IQR inter quartile range, SD standard deviation
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Respiratory Research

ISSN: 1465-993X

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