WG Minutes REG Summit 2018

1. Child Health Working Group
Meeting
CHAIR: Nikos Papadopoulos
DATE: Thursday 22nd March 2018
TIME: 14.00–15.00
VENUE: Park Plaza Hotel, Amsterdam Airport

2. Agenda
1) Update on current project
‘Evaluation the comparative effectiveness of adding antibiotics to usual
care (oral steroids) for the management of asthma exacerbations.’
2) Discussion of future projects
a) Bronchiolitis and asthma risk (marker of future asthma or cause of
future asthma) in paediatrics
b) Adherence project
c) Severe asthma in paediatrics
3) Any new project ideas?

3. Evaluation the comparative effectiveness of adding
antibiotics to usual care (oral steroids) for the
management of asthma exacerbations.
1) Update on current project

4. Background
• Asthma exacerbations are major contributors to asthma morbidity and mortality
(and related costs), and their management presents a major clinical need that is
not adequately met by current approaches.
• Atypical bacterial infections (e.g. Mycoplasma pneumonia and Chlamydophila)
may contribute to exacerbation severity.1
• Standard management of asthma exacerbations is the use of bronchodilators
and systemic steroids,2 but macrolide antibiotics and the ketolide antibiotic,
telithromycin, may have an effect on asthma exacerbations through their
antibacterial and/or anti-inflammatory properties.1
• A RCT in adults (n=278) with acute asthma exacerbations found patients
receiving add-on telithromycin had a significant reduction in asthma symptoms
compared with placebo.3
• In children (n=40) with acute asthma clarithromycin used as add-on therapy
gave a benefit over standard exacerbation treatment alone.4
1) Johnston SL. J Allergy Clin Immunol. 2006;117:1233-6. 2) Global Initiative for Asthma (GINA). Pocket
Guide for Asthma Management and Prevention. April 2015. http://www.ginasthma.org/documents/1/Pocket-
Guide-for-Asthma-Management-and-Prevention. 3) Johnston SL et al. N Engl J Med. 2006;354:1589-600.
4) Koutsoubari I, et al. Pediatr Allergy Immunol. 2012;23:385-90.

5. Aims
1) Evaluate the comparative effectiveness of managing asthma exacerbations
with oral steroids alone (i.e. usual care) versus combination antibiotics and
oral steroids in pediatric and adult asthma populations.
2) Explore the differential usage and associated outcomes of different classes
of antibiotics in asthma management.

6. Approach- Phase II
Comparative Outcomes
Inclusion criteria:
• Age: 2–65 years at IPD.
• >=3 episodes of wheeze or asthma
ever.
• Patients ≥5 years: physician-
diagnosed asthma
Patients <5 years: ≥1 asthma or
wheeze episode during baseline
• Received ≥1 ICS or LTRA
prescription during baseline.
• ≥52 weeks continuous records
Exclusion criteria:
• Are on chronic antibiotics
• Other chronic respiratory conditions
• Received an oral steroid during the baseline period
• 19-65 yrs with a diagnosis of COPD
Primary outcome period: 12 wks
Secondary outcome periods: 2, 6, and 26 wks
26 wk baseline
characterisation period

7. Outcomes
Survival time analysis has been carried out for each outcome Primary care
consultations for asthma / wheeze
a. Primary care consultations for asthma / wheeze resulting in an oral steroid
prescription with or without an antibiotic
b. Primary care consultations coded for asthma / wheeze resulting in a
prescription for a short-acting bronchodilator (SABA)
c. Hospitalisations for lower respiratory complaints
d. Accident & Emergency (A&E) attendance for lower respiratory complaints
Primary outcome period: 12 weeks
Secondary outcome periods: 2, 6, and 26 weeks

8. Prescribing of
antibiotics was not
a random event
Table 3. UNMATCHED Patient Demographics in 19-65 yr olds, by treatment type at IPD.
Treatment at Index Prescription Date
Total
No. 70,118
OCS
No. 35,336
OCS + Antibiotic
No. 34,782
P-value
Age, yrs (mean±SD)
Mean (SD) 45.5 (±12.3) 44.7 (±12.4) 46.3 (±12.1) < 0.001
Age, yrs (n(%))
19-25 5,294 (7.6%) 2,992 (8.5%) 2,302 (6.6%) < 0.001
26-35 10,596 (15.1%) 5,757 (16.3%) 4,839 (13.9%)
36-45 17,475 (24.9%) 9,085 (25.7%) 8,390 (24.1%)
46-55 18,596 (26.5%) 9,060 (25.6%) 9,536 (27.4%)
56-65 18,157 (25.9%) 8,442 (23.9%) 9,715 (27.9%)
Gender (n(%))
Female 47,210 (67.3%) 23,990 (67.9%) 23,220 (66.8%) 0.001
Male 22,908 (32.7%) 11,346 (32.1%) 11,562 (33.2%)
BMI, kg/m2
(mean±SD)
Underweight 1,132 (1.6%) 601 (1.7%) 531 (1.5%) < 0.001
Normal 17,941 (25.6%) 9,429 (26.7%) 8,512 (24.5%)
Overweight 21,573 (30.8%) 10,977 (31.1%) 10,596 (30.5%)
Obese 28,178 (40.2%) 13,657 (38.6%) 14,521 (41.7%)
Missing 1,294 (1.8%) 672 (1.9%) 622 (1.8%)
Smoking status (n(%))
Current Smoker 15,355 (21.9%) 6,688 (18.9%) 8,667 (24.9%) < 0.001
Ex-Smoker 18,048 (25.7%) 9,085 (25.7%) 8,963 (25.8%)
Non-Smoker 35,438 (50.5%) 18,901 (53.5%) 16,537 (47.5%)
Missing 1,277 (1.8%) 662 (1.9%) 615 (1.8%)
GINA category (n(%))
Step 2 16,110 (23.0%) 8,254 (23.4%) 7,856 (22.6%) < 0.001
Step 3 17,899 (25.5%) 9,339 (26.4%) 8,560 (24.6%)
Step 4 36,109 (51.5%) 17,743 (50.2%) 18,366 (52.8%)
Eosinophil Count (n(%))
≥0.0 <0.2 16,694 (23.8%) 8,400 (23.8%) 8,294 (23.8%) < 0.001
≥0.2 <0.4 21,204 (30.2%) 10,276 (29.1%) 10,928 (31.4%)
≥0.4 <0.6 8,204 (11.7%) 4,096 (11.6%) 4,108 (11.8%)
≥0.6 <0.8 2,867 (4.1%) 1,511 (4.3%) 1,356 (3.9%)
≥0.8 <1.0 1,079 (1.5%) 597 (1.7%) 482 (1.4%)
≥1.0 999 (1.4%) 521 (1.5%) 478 (1.4%)
Missing 19,071 (27.2%) 9,935 (28.1%) 9,136 (26.3%)
Season of IPD (n(%))
Autumn 19,057 (27.18%) 9,393 (26.58%) 9,664 (27.78%) < 0.001
Spring 15,119 (21.56%) 7,795 (22.06%) 7,324 (21.06%)
Summer 13,859 (19.77%) 8,039 (22.75%) 5,820 (16.73%)
Winter 22,083 (31.49%) 10,109 (28.61%) 11,974 (34.43%)

9. Prescribing of
antibiotics was not
a random event
Table 5. UNMATCHED Patient baseline consultations in 19-65 yr olds, by treatment type at IPD.
Treatment at Index Prescription Date
Total
No. 70,118
OCS
No. 35,336
OCS + Antibiotic
No. 34,782
P-value
No. of asthma/wheeze consults (n(%))
0 36,428 (51.95%) 17,973 (50.86%) 18,455 (53.06%) < 0.001
1-5 32,759 (46.72%) 16,903 (47.84%) 15,856 (45.59%)
6-10 808 (1.15%) 398 (1.13%) 410 (1.18%)
11-15 97 (0.14%) 50 (0.14%) 47 (0.14%)
16-20 21 (0.03%) 10 (0.03%) 11 (0.03%)
21-25 1 (0.00%) 0 (0.00%) 1 (0.00%)
26-30 4 (0.01%) 2 (0.01%) 2 (0.01%)
No. of asthma/wheeze consults for SABA (n(%))
0 36,428 (51.95%) 17,973 (50.86%) 18,455 (53.06%) < 0.001
1 29,028 (41.40%) 14,857 (42.04%) 14,171 (40.74%)
2 4,662 (6.65%) 2,506 (7.09%) 2,156 (6.20%)
No. of asthma/wheeze consults for antibiotics (n(%))
0 65,211 (93.00%) 32,808 (92.85%) 32,403 (93.16%) 0.14
1 4,466 (6.37%) 2,294 (6.49%) 2,172 (6.24%)
2 380 (0.54%) 195 (0.55%) 185 (0.53%)
3 45 (0.06%) 27 (0.08%) 18 (0.05%)
4 13 (0.02%) 9 (0.03%) 4 (0.01%)
5 3 (0.00%) 3 (0.01%) 0 (0.00%)

10. Table 2. Demographics and clinical characteristics for 19-65 yr olds, by treatment type at IPD.
Treatment at Index Prescription Date
Total
No. 61,168
OCS
No. 30,584
OCS + Antibiotic
No. 30,584
P-value
Age, yrs (mean (± SD)) 45.6 (±12.3) 44.7 (±12.4) 46.4 (±12.2) < 0.001
Age, yrs (n(%))
19-25 4,596 (7.5%) 2,566 (8.4%) 2,030 (6.6%) < 0.001
26-35 9,152 (15.0%) 4,975 (16.3%) 4,177 (13.7%)
36-45 15,298 (25.0%) 7,955 (26.0%) 7,343 (24.0%)
46-55 16,211 (26.5%) 7,873 (25.7%) 8,338 (27.3%)
56-65 15,911 (26.0%) 7,215 (23.6%) 8,696 (28.4%)
Gender (n(%))
Female 41,242 (67.4%) 20,785 (68.0%) 20,457 (66.9%) 0.005
Male 19,926 (32.6%) 9,799 (32.0%) 10,127 (33.1%)
BMI, kg/m2
(mean (± SD))
Underweight 970 (1.6%) 516 (1.7%) 454 (1.5%) < 0.001
Normal 15,595 (25.5%) 8,156 (26.7%) 7,439 (24.3%)
Overweight 18,821 (30.8%) 9,483 (31.0%) 9,338 (30.5%)
Obese 24,739 (40.4%) 11,891 (38.9%) 12,848 (42.0%)
Missing 1,043 (1.7%) 538 (1.8%) 505 (1.7%)
Smoking status (n(%))
Current Smoker 13,056 (21.3%) 6,528 (21.3%) 6,528 (21.3%) 1.0
Ex-Smoker 16,190 (26.5%) 8,095 (26.5%) 8,095 (26.5%)
Non-Smoker 31,922 (52.2%) 15,961 (52.2%) 15,961 (52.2%)
GINA category (n(%))
Step 2 14,164 (23.2%) 7,082 (23.2%) 7,082 (23.2%) 1.0
Step 3 15,426 (25.2%) 7,713 (25.2%) 7,713 (25.2%)
Step 4 31,578 (51.6%) 15,789 (51.6%) 15,789 (51.6%)
Eosinophil Count (n (%))
≥0.0 <0.2 14,703 (24.0%) 7,343 (24.0%) 7,360 (24.1%) 0.002
≥0.2 <0.4 18,343 (30.0%) 8,927 (29.2%) 9,416 (30.8%)
≥0.4 <0.6 7,054 (11.5%) 3,446 (11.3%) 3,608 (11.8%)
≥0.6 <0.8 2,522 (4.1%) 1,310 (4.3%) 1,212 (4.0%)
≥0.8 <1.0 953 (1.6%) 510 (1.7%) 443 (1.4%)
≥1.0 887 (1.5%) 447 (1.5%) 440 (1.4%)
Missing 16,706 (27.3%) 8,601 (28.1%) 8,105 (26.5%)
Season of IPD (n(%))
Autumn 16,750 (27.38%) 8,375 (27.38%) 8,375 (27.38%) 1.0
Spring 13,526 (22.11%) 6,763 (22.11%) 6,763 (22.11%)
Summer 11,276 (18.43%) 5,638 (18.43%) 5,638 (18.43%)
Winter 19,616 (32.07%) 9,808 (32.07%) 9,808 (32.07%)
Data sets matched on:
• GINA step
• Smoking status
• Season of IPD
• Number of asthma/
wheeze consults in
baseline period

11. Data sets matched on:
• GINA step
• Smoking status
• Season of IPD
• Number of asthma/
wheeze consults in
baseline period
Table 4. Patient baseline consultations in 19-65 yr olds, by treatment type at IPD.
Treatment at Index Prescription Date
Total
No. 61,168
OCS
No. 30,584
OCS + Antibiotic
No. 30,584
P-value
No. of asthma/wheeze consults (n(%))
0 31,946 (52.23%) 15,973 (52.23%) 15,973 (52.23%) 1.0
1-5 28,634 (46.81%) 14,317 (46.81%) 14,317 (46.81%)
6-10 544 (0.89%) 272 (0.89%) 272 (0.89%)
11-15 38 (0.06%) 19 (0.06%) 19 (0.06%)
16-20 6 (0.01%) 3 (0.01%) 3 (0.01%)
No. of asthma/wheeze consults for SABA (n(%))
0 31,946 (52.23%) 15,973 (52.23%) 15,973 (52.23%) 0.97
1 25,495 (41.68%) 12,741 (41.66%) 12,754 (41.70%)
2 3,727 (6.09%) 1,870 (6.11%) 1,857 (6.07%)
No. of asthma/wheeze consults for antibiotics (n(%))
0 56,954 (93.11%) 28,508 (93.21%) 28,446 (93.01%) 0.25
1 3,864 (6.32%) 1,902 (6.22%) 1,962 (6.42%)
2 309 (0.51%) 148 (0.48%) 161 (0.53%)
3 32 (0.05%) 19 (0.06%) 13 (0.04%)
4 9 (0.01%) 7 (0.02%) 2 (0.01%)

12. Time to first consultation for asthma/wheeze
Figure 1. Survival analysis to 1st primary care consultation for asthma/wheeze following IPD.
A) 2-5 years B) 6-12 years
C) 13-18 years D) 19-65 years

13. Figure 5. Survival analysis to 1st primary care consultation for asthma/wheeze resulting in a
prescription for oral steroids with or without antibiotics following IPD.
A) 2-5 years B) 6-12 years
C) 13-18 years D) 19-65 years
Time to first consultation for asthma/wheeze
resulting in a prescription for oral steroids ± antibiotics

14. Summary
Effectiveness of OCS vs OCS + antibiotics at IPD
• In adults the time until 1st asthma/wheeze consultation was increased by
addition of an antibiotic.
Similar results for 6-12 yr olds and 13-18 yr olds only at 2 wks post IPD.
• In adults the time until 1st asthma/wheeze consultation that resulted in an
OCS ± antibiotic was decreased by the addition of an antibiotic.
Similar results for 6-12 yr olds only at 26 wks and 13-18 yr olds only at 12
and 26 wks post IPD.
• No difference the time to 1st consultation resulting in a SABA prescription,
hospitalisation or A&E attendance for a lower respiratory complaint.

15. Next steps
• Amend exclusion criteria so we only require a 3 month baseline free from
OCS prescriptions, so we exclude less of the frequent exacerbators
• Review the Read code lists to ensure we are including all acute events, and
removing as many routine/planned consultations as possible.
• Include year of IPD in matching criteria
• Focus on the 2 and 6 week outcome periods

16. Time to first consultation for asthma/
wheeze by ICS type (6-65 yr olds combined)
Figure 26. Survival analysis to 1st primary care consultation for asthma/wheeze following IPD
A) Beclometasone B) Fluticasone
C) Budesonide D) No ICS
Baseline ICS Hazard ratio 95% CI
Beclometasone 0.88 0.85, 0.92
Fluticasone 0.94 0.91, 0.97
Budesonide 0.92 0.87, 0.97

17. Time to first consultation for asthma/
wheeze: macrolides vs penicillinsFigure 21. Survival analysis to 1st primary care consultation for asthma/wheeze following IPD
A) 2-5 years B) 6-12 years
C) 13-18 years D) 19-65 years
Table 18. Type of antibiotic at IPD, by age.
Treatment at Index Prescription Date
Total 19-65 yrs 13-18 yrs 6-12 yrs 2-5 yrs
Macrolides 7,279 6,558 357 304 60
Penicillins 28,716 24,150 1,801 2,283 482

18. Summary
Sub-analysis: effect of OCS vs OCS + antibiotics, by type of ICS
With the addition of antibiotics
- Time to 1st asthma/wheeze consultation increased to similar extend in those taking
beclometasone, fluticasone and budesonide, but not in those not taking an ICS.
- Time to 1st consultation resulting in an OCS ± an antibiotic decreased (and to a
similar extent) only in those taking fluticasone and budesonide.
- Time to 1st hospitalisation/A&E attendance for a lower respiratory complaint
decreased only in those taking beclomethasone.
Sub-analysis: effect of antibiotic type
No consistent differences in the effectiveness of penicillins vs macrolides in any age
group.

19. Bronchiolitis and asthma risk (marker of
future asthma or cause of future asthma)
in paediatrics
2) Future projects

20. Bronchiolitis and asthma risk in
paediatrics
Aims:
1) Evaluate the risk of asthma at different ages (3-4 yrs, 6-7 yrs, 9-10 yrs, 13-14
yrs) that can be attributed to respiratory syncytial virus (RSV) bronchiolitis, in
a UK primary care population.
2) Evaluate the overall risk of bronchiolitis on asthma diagnosis and activity
(medication prescription, healthcare utilisation), on overall health, interaction
with other risk factors (gender, age, prematurity, tobacco exposure, allergic
diseases) and long-term bronchiolitis burden.
Next step is to write a full protocol
There is literature on this area, but it is not completely clear.
OPCRD gives the chance to assess real-life situations and future respiratory
morbidity.
This would be timely given there are new drugs coming out at present for RSV.

21. Adherence in paediatrics (PI Steve Turner)
• Does adherence change with age?
• What predicts a year-on-year change in adherence?
• What outcomes are associated with different adherence phenotypes?
• Is there a seasonality to adherence?
Need to consider how to assess adherence from the database.
Severe asthma in paediatrics (PI’s Theresa Guilbert & Nikos Papadopoulos).
• Investigate the definition of severe asthma and breakdown of mild, moderate and
severe asthma
• How many have severe asthma? And are still treated in primary care?
• Natural history of the disease and is it influenced by referral?
• Investigate exacerbations to determine if medication is a valid method of
categorising asthma severity. Symptoms vs risk, for classifying severe asthma.
Future projects to be developed

22. Paediatric consensus statement
• Objectives:
o Define the limits of the existing International Consensus (ICON)
o Widen the scope of existing ICON
o Create a wide scope “paediatric consensus statement” using a
pragmatic approach, and highlighting the need for precision in
paediatrics
• Methods:
o Literature review → Systematic review → Delphi → ?
• Funding:
o To cover researcher time, branding, manuscript development
and IT support
• Publication approach:
o One comprehensive guide or shorter separate publications?

23. 3) Any new project ideas