Online supplement Table a

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Online supplement

Table a Immunological abnormalities

Abnormality

Low IgG, IgM, IgG2, haemophilus antibody response

IgG and IgG1 low

IgG, IgG1 and IgG2 low

IgG, IgA and IgG2 low

IgG, IgG1, IgG2, haemophilus and pneumococcus antibody responses all low

IgG, IgG2 and IgG3 repeatedly low

IgG2 and haemophilus antibody responses low

Haemophilus and pneumococcus antibody responses

Low IgA, IgG, IgG2, IgG3

Repeatedly low IgG and IgG2

Ig,Immunoglobulin n Atopic status

1 Atopic

1 Atopic

1 Atopic

1 Atopic

1 Atopic

1 Non atopic

1 Non atopic

1 Non atopic

1 Non atopic

1 Non atopic

1

Table b High Resolution CT Results

CT change

Normal

Bronchial wall thickening

Small airways disease/air trapping

Bronchiectasis

Bronchial wall thickening & small airways disease

Other

Atopic

(n=39)

12/39 (31)

11/39 (28)

9/39 (23)

1/39 (3)

4/39 (10)

Non atopic

(n=8)

1/8 (13)

0/8 (0)

2/8(25)

2/8(25)

2/8(25)

Double aortic arch (n=1)

RML Collapse +BWT

(n=1)

1/8 (13)

- narrow trachea

Data represented as number positive/number who had test (%). BWT, bronchial wall thickening;

RML, right middle lobe

2

Table c Bacterial growth from bronchoalveolar lavage

Bacterial growth Number positive

(n=19)

Staphylococcus aureus

Streptoccous pneumoniae

Haemophilus influenzae ,

Pseudomonas influenzae and streptococcus pneumoniae

H influenzae, Streptococcus pneumoniae and

Branhamella Catarrhalis

Haemophilus influenzae and streptococcus pneumoniae

8/19

5/19

2/19

1/19

1/19

2/19

*5 patients did not have bronchoalveolar cytology performed

Concurrent neutrophilia in

BAL

(n=15)*

3/5

3/4

1/2

1/1

1/1

1/2

3

Table d Significant alternative diagnoses

Atopic status

Condition

Atopic Sinusitis

Atopic Bronchiectasis

Atopic Vascular ring

Atopic

Job’s syndrome

Non Bronchiectasis – Primary atopic ciliary dyskinesia

Intervention Dose inhaled corticosteroid

(1yr follow up)

Endoscopic sinus surgery Stopped

Physiotherapy, azithromycin Same dose

Corrective surgery Reduced by 75%

Regular septrin Same

Physiotherapy, azithromycin Reduced by 80%

4

Table e Significant co-morbidities diagnosed during protocol

Condition Intervention

Atopic

Non atopic

Non atopic

Vocal cord dysfunction

& large tonsils

Severe gastro-oesphageal reflux

Severe gastro-oesphageal reflux & immune abnormalities

Psychological interventions & breathing techniques, tonsillectomy

Anti reflux treatement

Optimised anti reflux treatment

Dose inhaled corticosteroid

(1yr follow up)

Weaned by 50% at 2 yr follow up

Stopped

Reduced by 50%

5

Table f Comparison of children with symptom response vs non response

Atopy

Male

Smokers at home

History intubation

Pets present at home

Age (mean, SD, range)

Median IgE (range)

Mean % predicted FEV

1

(SD)

Baseline

Post steroid trial

FEV

1

abnormal

Baseline

Post steroid trial

Median % BDR (range)

Baseline

Post steroid trial

BDR present at

Baseline (number)

Post steroid trial

FeNO abnormal

Baseline

Post steroid trial

BAL eosinophilia

BAL neutrophilia

EB eosinophilia

EB neutrophilia

EB reticular basement membrane thickening

Steroid trial group

(n=81)

74/81 (91)

48/81 (51)

31/79 (39)

29/81 (36)

10/81 (12)

11.8 (2.6) (6-19)

654 (8-11355)

65.4 (19)

77.25 (18.3)

57/78 (73)

40/75 (53)

19.5 (0-130)

10 (0-82)

48/68 (71)

28/64 (44)

33/65 (51)

17/68 (25)

22/53 (42)

23/53 (43)

28/54 (52)

27/54 (50)

32/41 (78)

*Symptom response

(n=37)

33/37 (89)

25/37 (68)

10/36 (28)

5/36 (14)

14/37 (38)

11.2 (2.4)(7-16)

819 (31-11355)

64.7 (19.2)

80.5 (17.4)

25/35 (71)

16/35 (46)

19 (0-130)

8 (0-65)

24/31 (77)

10/29 (34)

16/31 (52)

5/31 (16)

9/25 (36)

14/25 (56)

12/26 (46)

17/26 (65)

16/21 (76)

Symptom non response

(n=38)

36/38 (95)

2/38 (5)

19/37 (51)

4/38 (11)

11/38 (29)

11.9 (2.7)(6-17)

623 (17-5014)

65.4 (19.2)

73.2 (19.1)

29/38 (76)

24/37 (65)

15 (0-79)

12 (0-82)

21/34 (62)

18/33 (55)

15/31 (48)

10/34 (29)

10/24 (42)

8/24 (33)

15/24 (63)

9/24 (38)

15/19 (79) p value

NS

NS

0.04

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

0.05

NS

Data represented as number positive/number who had test (%). BAL: bronchoalveolar lavage; BDR: % bronchodilator reversibility; EB: endobronchial biopsy; FeNO: fractional exhaled nitric oxide; FEV

1

: Forced expiratory volume in 1 second expressed as % predicted for height; IgE: immunoglobulin E; SD: standard deviation. *Defined as symptomatic improvement or resolution at the end of trial, data available in 75 patients only.

6

Table g Comparison of children with FEV

1

response vs non response

Atopy

Male

Smokers at home

Pet present at home

History intubation

Mean age (years, SD, range)

Median IgE (IU/ml, range)

Mean FEV

1

(SD)

Baseline

Post steroid trial

Baseline FEV

1

normal

Median % BDR (range)

Baseline

Post steroid trial

BDR present at

Baseline

Post steroid trial

FeNO abnormal

Baseline

Post steroid trial

Symptoms better

BAL eosinophilia

BAL neutrophilia

EB eosinophilia

EB neutrophilia

EB reticular basement membrane thickening

Steroid trial group

(n=81)

74/81 (91)

48/81 (59)

31/79 (39)

29/81 (36)

10/81 (12)

11.8 (2.6) (6-19)

654 (8-11355)

65.4 (19)

77.25 (18.3)

21/78 (27)

19.5 (0-130)

10 (0-82)

47/67 (70)

28/64 (44)

32/65 (49)

17/68 (25)

37/75 (49)

22/53 (42)

23/53 (43)

28/54 (52)

27/54 (50)

32/41 (78)

*FEV

1

response

(n=35)

32/35 (91)

19/35 (54)

16/35 (46)

14/35 (40)

4/35 (11)

11.3 (2.7)(6-17)

686.5 (26-11355)

74.2 (17.8)

92.9 (9.3)

14/34 (41)

19.9 (0-57)

5 (0-16)

23/30 (77)

5/27 (19)

13/26 (50)

8/28 (29)

19/32 (59)

11/20 (55)

9/20 (45)

14/24 (58)

14/25 (56)

13/17 (76)

FEV

1

non response

(n=40)

36/40 (90)

25/40 (63)

14/38 (37)

12/30 (40)

5/39 (13)

12 (2.2)(6-16)

700 (17-5680)

55 (16)

63.5(12)

4/39 (10)

24 (0-130)

13.5 (0-82)

24/37 (65)

23/37 (62)

17/35 (49)

8/37 (22)

16/40 (40)

9/28 (32)

13/28 (46)

14/27 (52)

14/27 (52)

17/21 (81) p value

NS

NS

NS

NS

NS

NS

NS

0.000

0.000

0.002

NS

0.000

NS

0.001

NS

NS

NS

NS

NS

NS

NS

NS

Data represented as number positive/number who had test (%). BAL: bronchoalveolar lavage; BDR: % bronchodilator reversibility; EB: endobronchial biopsy; FeNO: fractional exhaled nitric oxide; FEV

1

: Forced expiratory volume in 1 second expressed as % predicted for height; IgE: immunoglobulin E; SD: standard deviation. *Defined as FEV

1

≥80% predicted at the end of trial, 75 patients had pre/post data.

7

Table h Comparison of children with BDR response vs non response

Atopy

Male

Smokers at home

History intubation

Pet present

Mean age (SD, range)

Median IgE (range)

Mean % predicted FEV

1

(SD)

Baseline

Post steroid trial

FEV

1

abnormal

Baseline

Post steroid trial

Median % baseline BDR (range)

BDR present at baseline

FeNO abnormal

Baseline

Post steroid trial

Symptoms better

BAL eosinophilia

BAL neutrophilia

EB eosinophilia

EB neutrophilia

EB reticular basement membrane thickening

Steroid trial group

(n=81)

74/81 (91)

48/81 (59)

31/79 (39)

29/81 (36)

10/81 (12)

11.8 (2.6) (6-19)

654 (8-11355)

65.4 (19)

77.25 (18.3)

57/78 (73)

40/75 (53)

19.5 (0-130)

48/68 (71)

32/65 (49)

17/68 (25)

37/75 (49)

22/53 (42)

23/53 (43)

28/54 (52)

27/54 (50)

32/41 (78)

*BDR response

(n=36)

34/36 (94)

21/36 (58)

17/35 (35)

7/35 (20)

12/36 (33)

11.5 (2.5)(6-17)

690.5(26-5518)

66.4 (17.9)

84 (14.5)

28/35 (80)

14/36 (39)

22.9 (0-130)

25/35 (71)

14/29 (48)

5/30 (17)

19/34 (56)

11/24 (46)

12/24 (50)

13/26 (50)

15/26 (58)

15/19 (79)

BDR non response

(n=28)

25/28 (89)

18/28 (64)

10/27 (37)

2/28 (7)

10/28 (36)

11.5(2.7)(6-16)

852 (17-11355)

62.8 (20.4)

65.3 (16.7)

20/27 (74)

23/28 (82)

18 (0-79)

17/25 (68)

13/24 (54)

9/26 (35)

10/28 (36)

7/18 (39)

7/18 (39)

10/18 (50)

10/18 (56)

12/14 (86) p value

NS

NS

NS

NS

NS

NS

NS

NS

0.000

NS

0.001

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

Data represented as number positive/number who had test (%). BAL: bronchoalveolar lavage; BDR: % bronchodilator reversibility; EB: endobronchial biopsy; FeNO: fractional exhaled nitric oxide; FEV

1

: Forced expiratory volume in 1 second expressed as % predicted for height; IgE: immunoglobulin E; SD: standard deviation. *Defined as negative BDR test at end of trial, 64 patients had BDR pre/post corticosteroid trial.

8

Table I Comparison of children with FeNO response vs non response

Atopy

Male

Smokers at home

History intubation

Pet present

Age (mean, SD, range)

Median IgE (range)

Mean % predicted FEV

1

(SD)

Baseline

Post steroid trial

FEV

1

abnormal

Baseline

Post steroid trial

Median BDR (%)

Baseline

Post steroid trial

BDR present at

Baseline (number)

Post steroid trial

Symptoms better

FeNO normal at baseline

BAL eosinophilia

BAL neutrophilia

EB eosinophilia

EB neutrophilia

EB reticular basement membrane thickening

Steroid trial group

(n=81)

74/81 (91)

48/81 (51)

31/79 (39)

29/81 (36)

10/81 (12)

11.8 (2.6) (6-19)

654 (8-11355)

65.4 (19)

77.25 (18.3)

57/78 (73)

40/75 (53)

19.5 (0-130)

10 (0-82)

48/68 (71)

28/64 (44)

37/75 (49)

33/65 (51)

22/53 (42)

23/53 (43)

28/54 (52)

27/54 (50)

32/41 (78)

FeNO response*

(n=53)

47/53 (89)

32/53 (60)

22/51 (43)

6/52 (12)

19/53 (36)

11.7 (2.6)(6-17)

623 (17-5680)

64.5 (18.9)

76.3 (19.4)

39/52 (75)

30/51 (59)

18.3 (0-130)

10 (0-82)

29/45 (64)

18/44 (41)

26/52 (50)

28/47 (60)

12/32 (38)

13/32 (41)

17/35 (49)

18/35 (51)

21/27 (78)

FeNO non response

(n=17)

17/17 (100)

11/17 (65)

5/17 (29)

1/17 (6)

5/12 (41)

13(2.3) (9-19)

1044 (8-11355)

69.4 (18.2)

77.8 (16)

13/17 (76)

8/16 (50)

24 (5.7-79)

13.5 (0-35)

12/15 (80)

9/14 (64)

5/15 (33)

2/14 (14)

8/13 (62)

5/13 (38)

10/13 (77)

8/13 (62)

10/12 (83)

p value

NS

NS

NS

NS

NS

0.003

NS

NS

0.07

NS

NS

NS

NS

NS

NS

0.086

NS

NS

NS

NS

NS

NS

Data represented as number positive/number who had test (%). BAL: bronchoalveolar lavage; BDR: % bronchodilator reversibility; EB: endobronchial biopsy; FeNO: fractional exhaled nitric oxide; FEV

1

: Forced expiratory volume in 1 second expressed as % predicted for height; IgE: immunoglobulin E; SD: standard deviation. *Defined as normal FENO at the end of trial, 70 patients had FeNO performed pre/post corticosteroid trial.

9

Table j Persistent airflow limitation

Atopy

Male

Smokers at home

History intubation

Pets present

Age (mean, SD, range)

Median IgE (range)

Baseline mean % predicted FEV

1

Baseline FEV

1

abnormal

Baseline median % BDR

Baseline number with BDR present

FeNO abnormal

Baseline

Post steroid trial

Symptoms better

BAL eosinophilia

BAL neutrophilia

EB eosinophilia

EB neutrophilia

EB reticular basement membrane thickening

Steroid trial group

(n=81)

74/81 (91)

48/81 (59)

31/79 (39)

29/81 (36)

10/81 (12)

11.8 (2.6) (6-19)

654 (8-11355)

65.4 (19)

57/78 (73)

19.5 (0-130)

48/68 (71)

32/65 (51)

17/70 (24)

37/75 (49)

22/53 (42)

23/53 (43)

28/54 (52)

27/54 (50)

32/41 (78)

No persistent airflow limitation

(n=59)

54/57 (95)

36/59 (61)

22/58 (38)

7/58 (121)

26/59 (44)

(2.4) (6-17)

(26-11355)

(17.8)

35/56 (63)

18.6 (0-130)

36/50 (72)

23/47 (49)

12/49 (24)

30/53 (57)

15/36 (42)

15/36 (41)

20/40 (50)

18/40 (20)

24/31 (77)

*Persistent airflow limitation

(n=17)

15/17 (88)

9/17 (53)

8/16 (50)

3/17 (18)

2/17 (12)

13 (1.9) (9-16)

640.5 (17-5518)

50 (13.4)

17/17 (100)

27.5 (1.6-79)

10/15 (75)

7/15 (47)

4/15 (27)

6/17 (35)

6/13 (46)

7/13 (54)

7/11 (64)

7/11 (64)

6/8 (75) p value

NS

NS

NS

NS

0.02

NS

NS

<0.001

0.039

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

Data represented as number positive/number who had test (%). BAL: bronchoalveolar lavage; BDR: % bronchodilator reversibility; EB: endobronchial biopsy; FeNO: fractional exhaled nitric oxide; FEV

1

: Forced expiratory volume in 1 second expressed as % predicted for height; IgE: immunoglobulin E; SD: standard deviation *Defined as FEV

1

<80% predicted post bronchodilator & post corticosteroid trial

10

Analysis of children on systemic corticosteroids at baseline

Table k Comparison of corticosteroid response

Steroid response

Complete

Not on systemic corticosteroids

(n=51)

8/51 (16)

Partial

Non

36/51 (71)

7/51 (14)

On systemic corticosteroids

(n=30)

1/30 (3)

29/30 (97)

0/30 (0)

Table l Each parameter analysis

Parameter

Symptomatic response

Not on systemic steroids

26/49 (53%)

On systemic steroids

11/27 (41%)

FEV

1

(% pred)

BDR (%) pre

70

(32-102)

20 post

79

(49-125)

10 change

11

(-24-88)

-12 pre post

61 77

(27-109)

19

(37-106)

9.4 change

10

(-41-58)

-3

FeNO z score

FeNO

50

(ppb)

(0-130)

0.03

(-3.5-4)

(0-82)

-1.05

(-4.2-2)

(-126-19)

-1.16

(-4.3-1.1)

(0-55)

-1.33

(-3-2.6)

(0-42)

-1.38

(-4.9-1.4)

(-44-42)

-0.7

(-5.3-3.8)

25

(6-257)

13

(2-79)

-13.6

(-234-33)

12.7

(7-113)

12

(2-58)

-8

(-56-9)

Numerical values show the median and range. The symptomatic response data shows the number over the number tested and percentage in brackets .

BDR: bronchodilator reversibility; FeNO: Fractional exhaled nitric oxide; FeNO

50

: Fractional exhaled nitric oxide at flow rate 50ml/second; FEV

1: forced expiratory volume in 1 second p

NS (0.3)

NS (0.5)

NS(0.5)

NS (0.4)

NS (0.3)

11

Comparison of type of systemic steroid used in corticosteroid trial

Table m Comparison of corticosteroid response and route of steroid administration used

Steroid response Oral prednisolone

(n=65)

IM triamcinolone

(n=16)

Complete 8/65 (12) 1/16 (6)

Partial

Non

Parameter

Symptomatic response

50/65 (77)

7/65 (11)

15/16 (94)

0/16 (0)

Table n Comparison of response in each parameter and route of steroid administration used

Prednisolone

26/61 (43)

IM Triamcinolone

11/15

*

(73)

FEV

1

BDR

(% pred)

(%) pre

57

(27-109)

18

(0-130) post

79

(37-125)

11

(0-82)

Change

10

(-41-81)

-10

(-126-42) pre Post

61 77

(36-102)

24

(2-53)

(53-104)

10

(0-35) change

16

(-17-54)

-14

(-48-13)

FeNO z score -0.4

(-3.5-2.9)

-1.6

(-4.9-2)

1.1

(-5.3-1.8)

1.1

(-2.7-4)

-0.1

(-3.1-1.5)

-0.9

(-4.1-0.8)

FeNO

50

(ppb) 19 11 -7 48 24 -22

(6-113) (2-79) (-89-33) (21-257) (3-58) (-234-5)

Numerical values show the median and range. The symptomatic response data shows the number over the number tested and percentage in brackets .* Note that there is some missing data on symptomatic response therefore n=15 had triamcinolone and symptom data. BDR: bronchodilator reversibility;

FeNO: Fractional exhaled nitric oxide; FeNO

50

: Fractional exhaled nitric oxide at flow rate

50ml/second; FEV

1: forced expiratory volume in 1 second p

0.03

NS (0.7)

NS (0.7)

NS (0.9)

0.01

12

Table o Comparison between single and multiple allergies and each parameter response

Parameter Single allergy

(n=7)

Multiple allergies

(n=67)

Symptomatic response

FEV

1

(% pred)

BDR (%) pre

82

(45-88)

11

1/7 (14) post

74

(44-99)

13 change

13

(-41-21)

6

Pre

65

(27-109)

24

32/63 (51)

post

80

(38-106)

9 change

11

(-24-58)

-14

FeNO z score

FeNO

50

(ppb)

(0-25)

-0.6

(-1.9-4)

(11-20)

-0.6

(-1.9 to-0.9)

(-13-14)

-0.47

(-4-1.2)

(2-130)

-0.15

(-3.5-2.9)

(0-82)

-1.1

(-4.9-2)

(-126-23)

-1.2

(-5.3-1.1)

19

(8-257)

17

(8-23)

-7

(-234-9)

23

(6-123)

13

(2-79)

-11

(-89-33)

Numerical values show the median and range. The symptomatic response data shows the number over the number tested and percentage in brackets .

BDR: bronchodilator reversibility; FeNO: Fractional exhaled nitric oxide; FeNO

50

: Fractional exhaled nitric oxide at flow rate 50ml/second; FEV

1: forced expiratory volume in 1 second p

0.07

NS (0.6)

0.018

NS (0.4)

NS (0.7)

13

Graph a Log Fractional exhaled nitric oxide at flow rate 50ml/second pre and post triamcinolone

1000

100

10

1 pre post

Graph b Fractional exhaled nitric oxide at flow rate 250ml/second pre and post triamcinolone

30

20

10

0 pre post

14

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