1. Chronic cough and management of paediatric bronchiectasis involves early diagnosis, treatment of exacerbations, and long term management to prevent progression of the disease. 2. Key aspects of treatment include airway clearance therapy, mucoactive agents, antibiotics to treat exacerbations and for prophylaxis, and asthma-type therapies although evidence for many treatments is limited. 3. Potential new therapies are being studied including anti-inflammatory agents, vaccines, and drugs targeting neutrophilic inflammation but more research is still needed in paediatric populations.

1. Chronic cough and management of
paediatric bronchiectasis
Vikas Goyal
Queensland children’s Hospital

2. 2

3. Chronic cough
• Cough is a large burden
• Chronic cough in children is defined as cough > 4 weeks
• Most children with chronic wet cough have BAL evidence
of infection and secretions
(Chang et al, Respir Res. 2005)
16/08/2022

4. Chronic cough
• More than 80% of children have >= 5 doctor visits and 53%
have > 10 visits in previous 12 months
• The median duration of cough in children before they
present to the respiratory specialist is 12 months
Marchant et al 2008
16/08/2022

5. 5

6. Who develops chronic cough
• Data from ED cough study
• Out of 2569 children screened 876 enrolled
• 171 (20%) were still coughing at 28 days and were
followed up in respiratory clinics
• Multi-centre study across Australia
16/08/2022
O’Grady et al 2017
Chang et al 2012

7. • Presence of continuous chronic (>4 weeks’ duration) wet or productive
cough;
• Absence of symptoms or signs (i.e. specific cough pointers) ; and
• Cough resolved following a 2– 4-week course of an appropriate oral
antibiotic.
PBB
7
ERS statement on protracted bacterial bronchitis
in children 2017

8. 8

9. Wet cough
• Wet cough is reliably reported by parents when compared to
clinician's assessment and bronchoscopic findings.
• Neutrophilic inflammation of the lower airways.
Chang et al 2005, Marchant et al 2008
16/08/2022

10. Wet Cough
• Chronic wet cough which does not respond to treatment
should be investigated further
• Coren’s study showed 43% of children with chronic wet
cough (6 months) had bronchiectasis
• (BTS guidelines 2010, TSANZ guidelines 2006, Coren et al 1998)
16/08/2022

11. Response to antibiotics
• Antibiotics reduce the proportion of children not cured at
follow-up in children with chronic wet cough
• Chronic wet cough due to PBB resolves with two weeks of
appropriate antibiotics
(Marchant et al, Cochrane 2005, Marchant et al, Thorax 2012)
16/08/2022

12. 12

13. Spectrum?
Progression of disease process
(at least in a some)

14. Why Bother
16/08/2022

15. 16/08/2022

16. • R.T.H. Laennec
16

17. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
17

18. Chang et al. Expert Opin Emerg Drugs 2015

19. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
19

20. 1. Early diagnosis
2. Identifying underlying causes and associated conditions
3. Diagnosis, treatment and prevention of acute exacerbations
4. Improving quality of life
5. Prevent lung function decline and complications of bronchiectasis
Management principles
Goyal et al. Paed Pulm 2016

21. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
21

22. • Early diagnosis is important
– progressive, long term morbidity
– early bronchiectasis in paediatrics can be reversible
• When to consider investigating for BE
– chronic wet cough in children
– red flag signs
• Investigations
Diagnosis
Gaillard et al. Radiol 2003
Haidopoulou et al. Pediatr Pulmonol 2009
TSANZ Guidelines 2015
Chang et al. Paediatrics 2015
Goyal et al. Arch Dis Child 2015

23. • Bronchial wall dilation is the characteristic
feature of bronchiectasis.
• The BA ratio
– increases with age in adults
– lower threshold is recommended in
children
Radiology
BTS guidelines Thorax 2010
Kapur et al. Chest 2011
Kuo et al. Chest 2017

24. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
24

25. • Haemophilus influenzae 40%
• Streptococcus pneumoniae 20%
• Staphylococcus aureus 7.6%
• Moraxella catarrhalis 8.5%
• Pseudomonas aeruginosa 7.9%
Microbiology
Pizzutto et al. Front. Paediatrics 2017

26. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
26

27. • Important
– Independent risk factor for lung function decline
– Huge economic burden
– Associated with poor quality of life
• Definition
– New wet cough for more than 3 days
– Increase in sputum volume
– Change in sputum colour
Exacerbations
Kapur et al. Pediatr Pulmonol 2012
Kapur et al Chest 2012

28. • Respiratory viruses were identified in 48% of exacerbations in 69
Queensland children with bronchiectasis
• Detected in the BAL of 44% of 68 clinically stable children
• Rhinovirus most common
Viruses
Pizzutto et al. Plos one 2015
Kapur et al. Arch Dis Child. 2014
Goyal et al lancet 2018

29. • Antibiotics
• Airway clearance therapy
• Muco-active agents
• Asthma therapies
– Steroids/ bronchodilators- combinations
Treatment Options

30. • A Cochrane review found that there are no RCTs for short term oral or
IV antibiotics in bronchiectasis
• Two antibiotics trials
– Placebo controlled RCT of 2 weeks of antibiotics
– Non inferiority trial of amox- clav vs azithromycin for 3 weeks
• If oral antibiotics used, clinical review required
Antibiotics
Wurzel et al. Cochrane database 2011
Chang et al Trials 2012
Chang et al Trials 2013

31. BEST -2 Study
31

32. 32

33. 33

34. BEST 1
34

35. Results: Primary Outcome
Placebo 29/67 (43%)
Amox-clav 41/63 (65%)
RR=1.50 (95%CI 1.08-2.09), p=0.02
NNT-B=5 (95%CI 3-20)
Azithro 41/67 (61%)
RR=1.41 (95%CI 1.01-1.97), p=0.04
NNT-B =6 (95%CI 3-79)

36. Duration of exacerbation
•Duration to resolution (median)
–Placebo =10 days
–Amox-clav =7 days, p=0.018
–Azithro =8 days, p=0.24

37. 0.00
0.25
0.50
0.75
1.00
0 50 100 150 200
Analysis time in days
azithromycin
amoxicillin-clavulanate
placebo
Kaplan-Meier survival estimates

38. Point prevalence of viruses
•Deep nasal swab n=153
•82 (53%) virus +ve
•Rhinovirus common (n=53, 65%)
–Amox-clav n =31/49 (63 %)
–Azithro n =31/51 (61%)
–Placebo n =20/54 (37%)

39. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
39

40. • Airway clearance therapy
• Muco-active agents
• Prophylactic antibiotics
• Asthma type therapy
• Nutrition
• Vaccines
Treatment Options

41. • Cochrane review identified 7 studies, 105 subjects
• One study in children (n=9)
– oscillatory positive expiratory pressure 3 times a day
– lung function measured after a 3-month period
– exacerbation was not an outcome
Airway clearance

42. • Airway clearance therapy
• Muco-active agents
• Prophylactic antibiotics
• Asthma type therapy
• Nutrition
• Vaccines
Treatment Options

43. • Multiple agents available
• The exact mechanism of action of most mucolytics is unclear
• No pediatric trials
• RhDNase is not recommended
Muco-active agents
O’Donnell et al. Chest 1999

44. • 6% hypertonic vs isotonic saline for 12 months in 40 adult patients
– exacerbation rate similar
– significant improvements in QOL in both groups
• 7% HS in 28 adult patients for 3 months
– improved FEV1, QOL,
– decreased annualised antibiotic
• Dry powder mannitol vs placebo in 461 adult patients for 12 months
– No difference in number of exacerbations
Hyperosmolar agents
Kellet et al. Respir Med. 2011
Nicolson et al. Respir Med. 2012
Bilton et al. Thorax 2014

45. • No paediatric studies
• Many patients are wrongly diagnosed as asthma before a diagnosis of
bronchiectasis is made
• Wheeze can be a feature of bronchiectasis exacerbation
• In the absence of a confirmed diagnosis of asthma, not recommended
Bronchodilators

46. • Airway clearance therapy
• Muco-active agents
• Prophylactic antibiotics
• Asthma type therapy
• Nutrition
• Vaccines
Treatment Options

47. • No paediatric studies
• Oxytetracycline for 1 year superior to penicillin and placebo
– physician-assessed clinical improvement,
– reduced 24-h sputum volumes and
– fewer days confined to bed
• High-dose amoxicillin for 32 weeks
– amoxicillin group achieved and
– greater reductions in sputum volumes.
Non macrolide antibiotics for maintenance therapy
Currie QJM 1990

48. • In the Australian study 89 children were randomized to receive either azithromycin
(30 mg/kg once-a-week) or placebo for up to 24 months.
• Azithromycin group
– lower exacerbation rates (incidence rate ratio 0.50; 95% CI 0.35, 0.71) .
– better weight z scores
– increased macrolide resistance
BIS trial
Valery et al. Lancet Resp. Med 2013
Wong et al Lancet 2012

49. • Nil consistency in managing Pseudomonas aeruginosa
• 14-day IV ceftazidime & tobramycin, followed by nebulised tobramycin or placebo
for 3 months
– 54.5 % free of P. aeruginosa at 12 months vs 29.4% placebo.
• Retrospective studies:
– 64 patients who had additional 3 months of colistin
– eradication rate at 6 months was 52% (n=33), and 70% (n=23) at 12 months
– chronic P. aeruginosa infection- addition of neb tobramycin to high-dose oral
ciprofloxacin for 14 days –better microbial clearance at day 14
Pseudomonas eradication
Orriols et al Respiration. 2015
Vallières et al. ERJ 2017
Bilton et al. Chest 2006

50. • Airway clearance therapy
• Muco-active agents
• Prophylactic antibiotics
• Asthma type therapy
• Nutrition
• Vaccines
Treatment Options

51. • Nil studies in paediatric bronchiectasis
• A Cochrane review found no significant difference between groups in all outcomes
examined when only placebo-controlled studies were included-update
• Nil evidence for use of ICS + LABA
• Increase in bronchial hyper-reactivity after ceasing ICS, decrease in neutrophilic
apoptosis in induced sputum but no change in sputum inflammatory markers or
exacerbations
Asthma type therapies
Kapur et al. Cochrane database 2018
Goyal et al. Cochrane database 2013

52. • Airway clearance therapy
• Muco-active agents
• Prophylactic antibiotics
• Asthma type therapy
• Nutrition
• Vaccines
Treatment Options

53. • Maintaining optimal nutrition is important
• Low level of vitamin D associated with increased exacerbations in
adults
• Meta- analysis of 7 RCT of vitamin D
Nutrition and Vitamin D
Xiao et al. Br Jr Nutr 2015

54. • Role of Influenza and Pneumococcal vaccines have not been
systematically studied
• Potential vaccines
– PsA vaccine
– NTHi vaccine
– 10-valent pneumococcal-H.influenzae protein D conjugate vaccine in
children with chronic suppurative lung disease and bronchiectasis
oreduction in antibiotic treated exacerbations
Vaccines

55. • Management principles
• Diagnosis
• Microbiology
• Treatment of exacerbations
• Long term management
• Potential therapies
Overview
55

56. • Atorvastatin
• Long term NAC
• CXCR2 antagonist AZD5069
• Neutrophil elastase inhibitor
– AZD9668 improved lung function and sputum inflammatory biomarkers although
there was no change in sputum neutrophil count
– BAY85-8501 trial finished in June 2014
• HYBRID study
Potential therapies
Desoyza et al. ERJ 2015

57. • Some evidence of benefit in children with CF
• A Cochrane review found no eligible studies for use of inhaled or oral NSAIDs in
bronchiectasis in children
Non-steroidal anti-inflammatory agents

58. 1. Early diagnosis
2. Identifying underlying causes and associated conditions
3. Diagnosis, treatment and prevention of acute exacerbations
4. Improving quality of life
5. Prevent lung function decline and complications of bronchiectasis
Management principles
Goyal et al. Paed Pulm 2016

59. • Clinical review
• Lung function
• Microbiology
• Severity scores
– FACED score and BSI both adult based scoring system
– Limited use in children
• Individualized management plans
• Multidisciplinary approach
Monitoring and on-going care

60. Treatments successful in CF patients:
inhaled rhDNase- proven to be harmful
tobramycin, aztreonam, and colistin did not show similar benefit
Is it safe to use CF experience in bronchiectasis?
O’Donnell et al
Barker A et al. Eur Respir J. 2013

61. • American bronchiectasis registry
• EMBARC
• NZ bronchiectasis registry
• Australian Bronchiectasis registry
Registries

62. 62

63. • RCT 10-valent pneumococcal-H. influenzae protein D conjugate vaccine -
children who received the 10vPHiD-CV were less likely to have respiratory
symptoms in each fortnight of surveillance.
• Cochrane review -open label study in 167 adults 23-valent pneumococcal
vaccine as routine management in adults with bronchiectasis.
• (O'grady et al., 2018 Chang et al., 2009)
Vaccines
63

64. • With good management of children with bronchiectasis lung function stabilizes.
• Pediatric bronchiectasis in its early stages can be stabilized and even reversed.,
• 131 indigenous children at a single follow-up visit (median 9 years after first visit)
with increasing age, rates of acute lower respiratory infections declined and median
FEV1 was 90% predicted
(Bastardo et al., 2009, Kapur et al., 2010 Mccallum et al., 2020, Gaillard et al., 2003, Haidopoulou et al., 2009)
Long Term Outcomes
64

65. 65