Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Goyal V, Grimwood K, Byrnes CA, et al. Amoxicillin clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial. Lancet 2018; published online Sept 18.

2 Amoxicillin-clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): A multi-centre, double-blind, non-inferiority randomised controlled trial- web supplement Vikas Goyal FRACP, Department of Respiratory and Sleep Medicine, Lady Cilento Children s Hospital, Brisbane, Queensland, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Centre for Children's Health Research, Queensland University of Technology, Brisbane, Queensland, Australia. Professor Keith Grimwood MD, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia; Departments of Infectious Diseases and Paediatrics, Gold Coast Health, Gold Coast, Queensland, Australia. Catherine A Byrnes MD, Department of Paediatrics, University of Auckland, Auckland, New Zealand; Respiratory Department, Starship Children s Hospital, Auckland, New Zealand. Professor Peter S Morris PhD, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia; Department of Paediatrics, Royal Darwin Hospital, Darwin, Northern Territory, Australia. I Brent Masters PhD, Department of Respiratory and Sleep Medicine, Lady Cilento Children s Hospital, Brisbane, Queensland, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland, Australia. Professor Robert S Ware PhD, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia. Gabrielle B McCallum PhD, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. Michael J Binks PhD, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. Julie M Marchant PhD, Department of Respiratory and Sleep Medicine, Lady Cilento Children s Hospital, Brisbane, Queensland, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Centre for Children's Health Research, Queensland University of Technology, Brisbane, Queensland, Australia. Professor Peter van Asperen MD, Department of Respiratory Medicine, The Children s Hospital at Westmead, Sydney, New South Wales, Australia. Kerry-Ann F O Grady PhD, Centre for Children's Health Research, Queensland University of Technology, Brisbane, Queensland, Australia. Anita Champion BPharm, Pharmacy Department, Lady Cilento Children s Hospital, Brisbane, Queensland, Australia. Helen M Buntain PhD, Department of Respiratory and Sleep Medicine, Lady Cilento Children s Hospital, Brisbane, Queensland, Australia. Helen Petsky PhD, School of Nursing and Midwifery, Griffith University, Brisbane, Queensland, Australia; Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia. Professor Paul J Torzillo FRACP, Central Clinical School, University of Sydney, Sydney, New South Wales, Australia; Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. Professor Anne B Chang, PhD Department of Respiratory and Sleep Medicine, Lady Cilento Children s Hospital, Brisbane, Queensland, Australia; Centre for Children's Health Research, Queensland University of Technology, Brisbane, Queensland, Australia; Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. 1 Corresponding author: Dr. Vikas Goyal Department of Respiratory and Sleep Medicine, Lady Cilento Children s Hospital 501 Stanley Street, South Brisbane, Qld 4101 Australia drvikasgoyal@gmail.com Tel:

3 2 Sensitivity analysis Long-term macrolide use Data from various adult and paediatric randomised controlled trials on long-term macrolides in bronchiectasis show that macrolides significantly reduce exacerbation frequency. 1,2 A subgroup of children in our study were receiving long-term macrolide antibiotics. We therefore a-priori planned a subgroup analysis excluding children who were taking macrolide antibiotics. This subgroup analysis was included in the statistical analysis plan approved by the data safety monitoring committee. In the Bronchiectasis Exacerbation Study, BEST-2, there were 97 children taking long-term antibiotics at baseline. Of these, 30 were receiving co-trimoxazole and the remaining 67 were taking one of the macrolides at baseline. Of these 67 children, 45 were identified as receiving long-term (>4-weeks) macrolide antibiotics when they were randomised at the beginning of an exacerbation. These children were excluded and the analyses for primary and secondary outcomes were repeated in the remaining 134 children (Supplement Figure 1) using similar statistical methods as described in the main manuscript. By day-21, 58 (75 3%) participants randomised to the amoxicillin-clavulanate study arm and not taking long-term macrolides returned to their baseline state compared to 44 (77 1%) in the azithromycin arm who also were not receiving these antibiotics long-term. The risk difference (RD) for resolution in the azithromycin compared to the amoxicillinclavulanate group was 0 8% in the per-protocol (PP) population (n=121) (95% confidence interval (CI) -1 5, 14 2), thereby falling within the a-priori calculated 20% non-inferiority margin, (Supplement Figure 2) and reaffirmed by the intention-to-treat (ITT) analysis (n=134) 1 8% (95%CI -12 6, 16 4). The median time-to-resolution of the exacerbation was also shorter (i.e. better) in the amoxicillin-clavulanate group compared to azithromycin (10 vs 14-days, p=0 03) in the PP as well as ITT analyses. There was no difference in median time-to-the next exacerbation between the two groups (Supplement Table 1). There were no significant between-group differences in alterations to the parent cough-specific quality-of-life score, inflammatory markers and spirometry parameters in the children where these data were available on day-1 and day-21 in either the PP or ITT analyses. (Supplement Table 2). Similarly, the azithromycin resistance in nasopharyngeal Staphylococcus aureus isolates cultured from children, where paired NS were available was similar in both groups on day-1 and day-21. Of note though, all S. aureus isolates tested from the children receiving long-term macrolide antibiotics, regardless of the intervention group were resistant to azithromycin on day-1 and remained resistant by day-21 (Supplement Table 3). Identification of a virus at the start of an exacerbation Post-hoc subgroup analyses (restricted to ITT) were undertaken based the presence or absence of a virus at the beginning of an exacerbation for the primary (proportion of children whose exacerbation resolved within the 21-day treatment period) and three secondary outcomes (change in PC-QoL, length of exacerbation [days] and time-to-the next exacerbation [days]). Among the children where a virus was not detected at the beginning of exacerbation, the resolution rate by day-21 was 81 4% in the amoxicillin-clavulanate group compared to 70 6% in those receiving azithromycin (RD -10 8, 95% CI -30, 8 4), falling outside our a priori defined non-inferiority margin. In the presence of a detectable virus, the primary outcome results were also outside our non-inferiority margin; the resolution rate was 81 1% and 84 9 % for amoxicillin-clavulanate and azithromycin respectively (RD 3 8, 95%CI -13 8, 21 3). The main secondary outcomes are presented in Supplement table 4. Among children with a respiratory virus identified at the start of an exacerbation, as for the total group, we found that those receiving azithromycin had a significantly longer duration of symptoms compared to the amoxicillin-clavulanate group. However, the difference between the groups was larger (median difference of 7-days) compared with the overall cohort (median difference of 4-days). Age We also undertook post-hoc subgroup analyses based on age ( 5-years or >5-years) for the primary outcome and three secondary outcomes (PC-QoL, length of exacerbation and time-to-next exacerbation [days]). Among children aged 5-years, the resolution rate was 68 6% and 72 4 % for amoxicillin-clavulanate and azithromycin respectively (RD 3 8, 95%CI -18 5, 26 2), which is outside our non-inferiority margin. The acute exacerbation resolved in 82 3% of children >5-years of age in the amoxicillin-clavulanate group and 79 3% in the azithromycin group (RD -3 1, 95%CI -17 5, 11 4). The main secondary outcomes are presented in Supplement table 4a. Children aged >5-years who received azithromycin took significantly longer to resolve than those treated with amoxicillin-clavulanate (14 versus 10-days respectively). No significant differences between groups in change in PC-QoL scores were found irrespective of detection of virus at the beginning of exacerbation or age of the child (Supplement table 4b). Supplementary tables and figures Supplement figure 3 represents Kaplan Meier curve for median time-to-next exacerbation (days) with azithromycin compared to amoxicillin-clavulanate.

4 We have presented table 1 from main manuscript with continuous data presented as means and SD in the supplement, for the interest of readers, and to aid researchers who might include this data in future meta-analyses where means and SDs are analysed (Supplement table 5). Comparison of clinical characteristics of two treatment groups at the beginning of exacerbation is presented in Supplement table 6 and 7 for the interest of readers and any future meta-analyses. Comparison of adverse symptoms between two groups is presented in Supplement table 8. 3

5 4 Supplement Figure 1: Trial profile for children not taking long-term (>4-weeks) macrolide antibiotics BEST-2= Bronchiectasis Exacerbation Study. ITT= intention to treat population- included all children who were randomised to the respective group and took at least one dose of study medication. PP= per-protocol population, summation of children completing treatment course, including those who were hospitalised, but excluding one child who discontinued therapy because of P. aeruginosa isolation.

6 Supplement Figure 2: Risk difference of resolution in children not receiving long-term (>4-weeks) macrolide 5

7 Supplement Figure 3: Time-to-next exacerbation with azithromycin compared to amoxicillin-clavulanate 6

8 7 Supplement table 1: Comparison of days-to-resolution of exacerbation and days-to-next exacerbation in children not taking long-term macrolides Per-protocol analyses Amoxicillin-clavulanate (n=77) Azithromycin (n= 57) p value Time-to-resolution, days 10 (6, 15) 14 (8, 16) p=0 03 Time-to-next exacerbation, days 88 (34, 180) 105 (46 5, 180 ) p=0 6 Intention-to-treat analyses Time-to-resolution, days 10 (6, 15) 14 (8, 16) p=0 03 Time-to-next exacerbation, days 88 (30, 180) 105 (46 5, 180 ) p=0 52 *Data presented are medians (25 th -75 th percentile), days. Data were censored at 180-days. Supplement table 2: Laboratory and FEV 1 %predicted results, and PC-QoL scores on Days-1 and 21 in children not taking long-term macrolides Amoxicillin-clavulanate Azithromycin Difference between Day-1 Day-21 Day-1 Day-21 change in groups (95%CI) Per-protocol analyses WBC (n=26) 8 9 (7 5, 10 5) 7 7 (6 7, 9 9) 9 6 (6 9, 10 6) 7 7 (6 3, 10 3) -0 9 (-4 2, 2 4) CRP (n=26) * 2 9 (2, 7 4) 2 0 (2, 2) 4 2 (2, 11) 2 0 (2, 2) 3 6 (-1 4, 8 6) FEV 1 % pred (n=30) (70, 89) PC-QoL ( n=106) 4 1 (3 2, 5 1) Intention-to-treat analyses WBC (n=27) 8 6 (71, 96) 6 1 (5 0, 6 8) (66, 89) 4 4 (3 3, 5 4) (72, 99) 6 0 (4 6, 6 9) (-5 9, 9 9) -0 3 (-1 1, 0 6) (7 3, 10 4) 7 4 (6 7, 9 2) 9 6 (6 9, 10 6) 7 7 (6 3, 10 3) -0 6 (-3 8, 2 6) CRP (n=28) * 2 6 (2, 6 3) 2 (2, 2) 4 2 (2, 11) 2 (2, 2) 3 6 (-1 4, 8 6) FEV 1 % pred (n=30) 80 (66, 89) 83 (71, 96) 73 5 (66,89) 86 (72, 99) 2 (-5 9, 9 9) PC-QoL (n=110) 4 2 (3 3, 5 2) 6 1 (5 0, 6 8) 4 3 (3 2, 5 5) 6 0 (4 6, 6 9) -0 4 (-1 1, 0 4) * Data are presented as medians (25 th -75 th percentile). To compare difference between groups, median regression with 95% CIs are reported. Abbreviations: CI, confidence interval; CRP, C-reactive protein; FEV 1 %, forced expiratory volume in one-second percent; PC-QoL, parent coughspecific quality-of-life; WBC, white blood cell count.

9 8. Supplement Table 3: Staphylococcus aureus and azithromycin resistance by prior long-term macrolide exposure S. aureus in the nasal swab Start of exacerbation End of exacerbation Amox-clav Azithro Amox-clav Azithro S. aureus isolation in subgroup not taking macrolides (n=134) 7/77 (9%) 5/57 (9%) 7/77 (9%) 2/57 (4%) Azithromycin resistance 3 (43%) 2 (40%) 2 (29%) 2 (100%) S. aureus isolation in subgroup taking macrolides (n=45) 1/20 (5%) 4/45 (9%) 2/20 (10%) 4/45 (9%) Azithromycin resistance 1 (100%) 4 (100%) 2 (100%) 4 (100%) Amox-clav: Amoxycillin-clavulanate, Azithro: Azithromycin Supplement Table 4a: Comparison of days-to-resolution of exacerbation and days-to-next exacerbation based on presence or absence of virus at the beginning of exacerbation and age (post-hoc analyses) Amoxicillin-clavulanate Azithromycin Virus detected (n=58) Time-to-resolution, days 7 5 (6, 12) 14 5 (6 5, 17) p=0 009 Time-to-next exacerbation, days 85 5 (22, 180) 99 5 (55 5, 180) p=0 6 Virus not detected (n=59) Time-to-resolution, days 11 (6, 15) 14 (5 5, 15) p=0 21 Time-to-next exacerbation, days 60 (25, 142) 85 (19, 180) p=0 48 Age <5-years (n=45) Time-to-resolution, days 10 (6, 14 5) 13 (8, 16) p=0 42 Time-to-next exacerbation, days 47 (20 5, 88 5) 87 5 (38, 130) p=0 07 Age >5-years (n=93) Time-to-resolution, days 10 (6, 15) 14 (6, 17) p=0 04 Time-to-next exacerbation, days 92 (36, 180) 92 (36, 180) p=0 98 *Data are presented as medians (25 th -75 th percentile), days. Data were censored at 180-days. Supplement Table 4b: Comparison of PC-QoL based on presence or absence of virus at the beginning of exacerbation and age (post-hoc analyses) Amoxicillin-clavulanate Azithromycin Difference between change in groups (95%CI) Day1 Day 21 Day 1 Day21 Virus detected (n=66) Virus not detected (n=65) Age <5-years (n=45) 4 1 (3 3, 5 3) 4 3 (3 5, 5 4) 4 0 (3 4, 4 8) 6 5 (5 5, 7) 6 2 (5 0, 6 8) 6 2 (5 8, 6 8) 4 2 (3 1, 5 4) 5 0 (4 1, 5 8) 4 1 (2 9, 5 8) 6 0 (4 9, 6 8) 6 0 (4 8, 6 9) 6 0 (4 4, 6 8) -0 7 (-1 7, 0 3) -0 5 (-1 6, 0 5) -0 7 (-1 7, 0 4) Age >5-years (n=93) 4 4 (3 5, 5 4) 6 3 (5 2, 7) 4 5 (3 7, 5 6) 5 9 (4 9, 6 9) -0 7 (-1 5, 0 1) * Data are presented as medians (25 th -75 th percentile). To compare difference between groups, median regression with 95% CIs are reported.

10 9 Supplement Table 5: Baseline characteristics of participants by treatment group* Characteristics Amoxicillin-clavulanate (n=97) Azithromycin (n=82) Sociodemographic Age, years 7 4 (4 0) 7 1 (3 8) Male 55 (56 7%) 40 (48 8%) Indigenous ethnicity 37 (38 1%) 33 (40 2%) Medical history History of preterm birth (<37-weeks) (n=169) 22/90 (24 4%) 21/79 (26 6%) Breastfeeding (ever in infancy) 69 (71 1%) 61 (74 4%) Tobacco smoke exposure 29 (29 9%) 26 (31 7%) Age at diagnosis of bronchiectasis, years 5 0 (3 3) 4 5 (3 0) Number of lobes affected 3 0 (1 2) 2 9 (1 3) Non-hospitalised exacerbations in last 12-months (n=173) Hospitalisations in last 2-years for bronchiectasis exacerbations (n=178) 3 6 (3 1) 3 6 (2 7) 1 3 (1 7) 1 4 (1 9) Long-term (>4-weeks) antibiotics 54 (55 7%) 43 (52 4%) Long-term macrolides 35 (36 1%) 32 (39 0%) Underlying aetiology Post-infectious 57 (58 8%) 47 (57 3%) Idiopathic 19 (19 6%) 12 (14 6%) Immunodeficiency 5 (5 2%) 3 (3 7%) Aspiration 8 (8 2%) 8 (9 8%) Primary ciliary dyskinesia 3 (3 1%) 3 (3 7%) Other 3 (3 1%) 6 (7 3%) Comorbidities Tracheomalacia 13 (13 4%) 6 (7 3%) Syndromic (e.g. Trisomy 21) 4 (4 1%) 8 (9 8%) Asthma 19 (19 6%) 10 (12 2%) Examination findings Weight at enrolment, kilograms 28 4 (15 2) 28 3 (15 9) Oxygen saturation (n=163) 98 5 (1 5) 98 4 (1 2) Cough score 3 (n=177) 0 9 (1 1) 0 9 (1 0) Digital Clubbing (n=178) 22/96 (22 9%) 11/82 (13 4%) Chest wall deformity 24 (24 7%) 19 (23 2%) Wheeze at baseline 2 (2 1%) 2 (2 4%) Crackles at baseline 8 (8 2%) 2 (2 4%) FEV 1 %predicted (n=99) 86 5 (21 5) 84 3 (15 8) PC-QoL score 4 (n=175) 5 7 (1 4) 5 6 (1 6) Serum biomarkers WBC (n=92) x 10 9 per litre 8 3 (2 4) 10 6 (12 4)

11 10 CRP (n=94) milligram per litre 2 4 (2 0) 2 1 (1 4) *Data are presented as means (standard deviation) or proportions expressed as percentages. The only other long-term antibiotic used in these children was co-trimoxazole, n=19 in the amoxicillin-clavulanate arm and n=11 in the azithromycin arm. Abbreviations: CRP, C-reactive protein; FEV 1 %, forced expiratory volume in one-second percent; PC-QoL, parent cough-specific quality-of-life; WBC, white blood cell count. Supplement Table 6: Clinical characteristics at the beginning of the exacerbation* Amoxicillin-clavulanate (n=97) Azithromycin (n=82) Cough score (0 9) 3 1 (1 1) Long-term (>4-weeks) macrolides 20 (20.6%) 25 (30.5%) Days between onset of symptoms and starting study medication 4 (3, 6) 4 (3, 7) Weight, kilograms 31 7 (18 9) 29 7 (17 5) Fever present 15 (15%) 12 (15%) Oxygen saturation percentage 98 2 (1 9) 97 6 (1 5) Respiratory rate per min 23 8 (6 3) 23 2 (4 2) Wheeze present (n=139) 10/76 (13 2%) 5/63 (7 9%) Auscultatory crackles (n=139) 30/76 (39 5%) 24/63 (38 1%) Abnormal ENT examination (n=139) 52/76 (68 4%) 41/63 (65 1%) WBC (n=62) x 10 9 per litre 9 0 (3 3) 8 9 (2 3) CRP (n=63) milligram per litre 2 0 (2, 5 1) 2 0 (2, 9 9) FEV 1 % predicted (n=61) 78 3 (16 5) 75 1 (17 1) PC-QoL score (1 3) 4 4 (1 4) Respiratory virus detected (n=147) 37 (46 2%) 33 (49 3%) Atypical pathogen 1 (1 3%) 1 (1 5%) *Data are presented as means (standard deviation) or proportions expressed as percentages except for days between onset of symptoms and starting study medications and CRP which are median (25 th -75 th percentile). not all children were seen by a study doctor on treatment day-1of their exacerbation or provided complete information, including nasal swab samples or being able to perform spirometry. Mycoplasma pneumoniae, Chlamydiales pneumoniae. Abbreviations: CRP, C-reactive protein; ENT, ears, nose and throat; FEV 1 %, forced expiratory volume in one-second percent; PC-QoL, parent cough-specific quality of life; WBC, white blood cell count.

12 11 Supplement Table 7: Clinical characteristics at the beginning of the exacerbation* Amoxicillin-clavulanate (n=97)* Azithromycin (n=82)* Cough score 17 3 (2, 4) 3 (2, 4) Taking long-term (>4-weeks) macrolides 20 (21%) 25 (31%) Days between onset of symptoms and starting study medications 4 (3, 6) 4 (3, 7) Weight, kilograms 24 8 (17, 42 6) 22 1 (17, 38 4) Fever present# 15 (15%) 12 (15%) Oxygen saturation percentage 99 (97, 100) 98 (97, 98 5) Respiratory rate per min 23 5 (20, 26) 23 5 (20, 26) Wheeze present (n=139) 10/76 (13%) 5/63 (8%) Auscultatory crackles (n=139) 30/76 (40%) 24/63 (38%) Abnormal ENT examination (n=139) 52/76 (68%) 41/63 (65%) WBC (n=62) x 10 9 per litre 8 8 (7, 10 5) 8 8 (7 2, 10 6) CRP (n=63) milligram per litre 2 0 (2, 5 1) 2 0 (2, 9 9) FEV 1 % predicted (n=61) 81 (68 5, 90) 73 5 (66, 89) PC-QoL score (3 4, 5 3) 4 5 (3 5, 5 7) Respiratory virus detected (n=147) 37 (46%) 33 (49%) Atypical pathogens 1 (1%) 1 (1%) *Data are presented as medians (25 th -75 th percentile) for continuous data or proportions expressed as percentages for categorical data. not all children were seen by a study doctor on treatment day-1of their exacerbation or provided complete information, including nasal swab samples or able to perform spirometry, hence (n) represents the number of children where data were available. # Fever reported by parents on day-1. Mycoplasma pneumoniae, Chlamydiales pneumoniae. Abbreviations: CRP, C-reactive protein; ENT, ears, nose and throat; FEV 1 %, forced expiratory volume in one-second percent; PC-QoL, parent cough-specific quality-of-life; WBC, white blood cell count. Supplement Table 8: Paired nasal swab culture and antibiotic susceptibility results Day-1 Day-21 Amox-clav Azithro Amox-clav Azithro Number of swab pairs, (%) Haemophilus influenzae 8 (13 1%) 8 (15 4%) 1 (1 6%) 4 (7 7%) Azithromycin-resistant 1 (12 5%) 1 (12 5%) 0 2 (50 0%) Ampicillin-resistant 2 (25 0%) 2 (25 0%) 0 1 (25 0%) Streptococcus pneumoniae 9 (14 7%) 4 (7 7%) 1 (1 6%) 0 (0) Azithromycin-resistant 2 (22 2%) 0 (0) 0 (0) 0 (0) Penicillin-resistant 1 (11 1%) 0 (0) 0 (0) 0 (0) Moraxella catarrhalis* 14 (23 0%) 14 (26 9%) 3 (4 9%) 1 (1 9%) Beta-lactamase positive 14 (100%) 12 (85 7%) 3 (100%) 1 (100%) Staphylococcus aureus 8 (13 1%) 9 (17 3%) 9 (14 7%) 6 (11 5%) Azithromycin-resistant 4 (50 0%) 6 (66 7%) 4 (44 4%) 6 (100%) Methicillin-resistant 2 (25 0%) 1 (11 1%) 1 (11 1%) 2 (33 3%) Any of the above pathogens present 28 (45 9%) 27 (51 9%) 14 (23 0%) 10 (19 2%) Azithromycin-resistant 7 (25 0%) 6 (22 2%) 4 (28 5%) 8 (80 0%) pathogens (any)

13 12 *Azithromycin-resistance not tested in Moraxella catarrhalis isolates. Abbreviations. Amox-clav, amoxicillin-clavulanate; Azithro: azithromycin References 1. Valery PC, Morris PS, Byrnes CA, et al. Long term azithromycin for Indigenous children with noncystic fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double blind, randomised controlled trial. Lancet Respir Med 2013; 1: Kelly C, Chalmers JD, Crossingham I, et al. Macrolide antibiotics for bronchiectasis. Cochrane Database Syst Rev 2018; 3: CD Chang AB, Newman RG, Carlin JB, Phelan PD, Robertson CF. Subjective scoring of cough in children: parent completed vs child completed diary cards vs an objective method. Eur Respir J 1998; 11: Newcombe PA, Sheffield JK, Chang AB. Minimally important change in a Parent Proxy Quality of Life questionnaire for pediatric chronic cough. Chest 2011; 139: