Non-Cystic Fibrosis Bronchiectasis in

Children

Nitin Kapur

Bachelor of Medicine and Bachelor of Surgery (M.B.B.S.)

Doctorate of Medicine (M.D.)

A thesis submitted for the degree of Doctor of Philosophy at

The Charles Darwin University in September 2011

Institute of Advanced Studies

II

Declaration by author

I hereby declare that the work herein, now submitted as a thesis for the degree of Doctor of

Philosophy of the Charles Darwin University, is the result of my own investigations, and all

references to ideas and work of other researchers have been specifically acknowledged. I

herby certify that the work embodied in this thesis has not already been accepted in substance

for any degree, and is not being cunently submitted in candidature for another degree.

Nitin Kapur

ll1

Statement of contributions to jointly authored works contained in the thesis

1. Kapur N, Karadag B. Differences and similarities in non-cystic fibrosis

bronchiectasis between developing and affluent countries. Paediatdc Respiratory

Reviews. 2011 Jun;12(2):91-6.

Drs Kapur and Karadag contributed to review outline and concept. Dr Kapur contributed

by undertaking literature search. Drs Kapur and Karadag contributed to the drafting of

the atiicle.

2. Kapur N, Masel J, Watson D, Masters IB, Chang AB. Bronchoarterial ratio on

High Resolution CT scan of the chest in children without pulmona1-y pathology-

Need to redefine bronchial dilatation. Chest. 2011 Jun;139(6):1445-50.

Drs. Kapur, Masters, Masel and Chang contributed to the study concept and design. Ms

Watson contributed by performing HRCT reconstruction from raw data. Drs. Kapur and

Masel performed bronchial and atierial diameter measurements. Drs Kapur and Chang

contributed to the analysis and interpretation of the data. Drs. Kapur, Masters, Chang,

Masel and Ms Watson contributed to the drafting of the article.

3. Kapm· N, Masters IB, Newcombe P, Chang AB. The burden of disease in

paediatric non-cystic fibrosis bronchiectasis. Chest. 2011 Sep 1. (Accepted for

publication and published online)

Drs. Kapur, Masters and Chang contributed to the study concept and design. Dr Kapur

collected all the data. Drs Kapur and Newcombe contributed to the analysis and

interpretation of the data. Drs. Kapur, Newcombe, Masters and Chang contributed to the

drafting of the article.

IV

4. Kapur N, Masters IB, Chang AB. Longitudinal growth and lung function in

pediatric non-CF bronchiectasis - what influences lung function stability? Chest.

2010;138:158-164

Drs. Kapur, Masters and Chang contributed to the study concept and design. Dr Kapur

collected all the data. Drs Kapur and Chang contributed to the analysis and

interpretation of the data. Drs. Kapur, Masters and Chang contributed to the drafting of

the article.

5. Kapur N, Grimwood K, Masters IB, Morris PS, Chang AB. Lower airway

microbiology and cellularity in children with newly diagnosed non-CF

bronchiectasis. Pediatr Pulmonol. 2011 Sep 7. doi: 10.1002/ppul.21550.

Drs. Kapur, Grimwood, Masters and Chang contributed to the study concept and

design. Dr Kapur collected all the data. Drs Kapur and Grimwood contributed to the

analysis and interpretation of the data. Drs. Kapur, Grimwood, Masters, Morris and

Chang contributed to the drafting of the article.

6. Kapur N, Masters IB, Chang AB. Exacerbations in noncystic fibrosis

bl"Onchiectasis: Clinical features and investigations. Respir Med. 2009; 103:1681-

1687.

Drs. Kapur, Masters and Chang contributed to the study concept and design. Dr Kapur

collected all the data. Drs Kapur and Chang contributed to the analysis and

interpretation of the data. Drs. Kapur, Masters and Chang contributed to the drafting of

the article.

v

7. Kapur N, Masters IB, Morris PS, Galligan J, Ware R, Chang AB. Defining

Pulmonm-y Exacerbation in Children with Non-Cystic Fibrosis B1·onchiectasis.

Pediat1· Pulmonol. 2011 Aug 9. doi: 10.1002/ppul.21518.

Drs. Kapur, Masters, Morris and Chang contributed to the study concept and design.

Mr. Galligan contributed in serum IL6, precalcitonin and amyloid A measurements. Drs

Kapur, Masters and Chang contributed to data collection. Dr. Kapur, Dr. Chang and

Mr. Ware contributed to the analysis and interpretation of the data. Drs. Kapur,

Masters, Chang, Morris and Mr. Ware and Mr. Galligan contributed to the drafting of

the article.

8. Kapur N, Mackay IM, Sloots TP, Masters IB, Chang AB. Role of Respirato1-y

Viruses in Exacerbations of Non-Cystic Fibrosis Bronchiectasis in Child1·en.

Thorax 2011, awaiting editorial decision.

Drs. Kapur, Masters and Chang contributed to the study concept and design. Dr Mackay

contributed in nasopharyngeal aspirate polymerase chain reaction (PCR) for respiratory

viruses. Dr Kapur collected all the data. Drs Kapur and Chang contributed to the

analysis and interpretation of the data. Drs. Kapur, Masters, Sloots, Mackay and Chang

contributed to the drafting of the article. This work has been submitted to Thorax and

awaits editorial decision.

9. Kapur N, Bell S, Kolbe J, Chang AB. Inhaled steroids for bronchiectasis.

Cochrane Database Syst Rev. 2009 Jan2l;(l):CD000996.

Dr Chang was responsible for independent review of studies identified, independent

data extraction and assessment of quality of studies independently. Dr Kapur was also

responsible for independent review of studies identified, independent data extraction and

assessment of quality of studies independently as well as the meta-analysis, literature

vi

review and writing of manuscript. Drs Bell and Kolbe were responsible for reviewing

the manuscript and the statistics.

10. Kapur N, Chang AB. Oral non-steroid anti-inflammatol'ies for children and adults

with bronchiectasis. Cochrane Database Syst Rev. 2007; (4):CD006427.

Dr Chang was responsible for independent review of studies identified and assessment

of quality of studies independently. Dr Kapur was also responsible for independent

review of studies identified and assessment of quality of studies independently as well

as the literature review and writing of manuscript.

vii

List of Publications relevant to the Thesis

1. Kapur N, Karadag B. Differences and similarities in non-cystic fibrosis bronchiectasis

between developing and affluent countries. Paediatric Respiratory Reviews. 2011

Jun;12(2):91-6. (Incorporated as chapter 1B)

2. Kapur N, Masel J, Watson D, Masters IB, Chang AB. Bronchoarterial ratio on High

Resolution CT scan of the chest in children without pulmonary pathology- Need to

redefine bronchial dilatation. Chest. 2011 Jun;l39(6):1445-50. (!nc01porated in chapter

2 as section 2.1)

3. Kapur N, Masters IB, Newcombe P, Chang AB. The burden of disease in paediatric

non-cystic fibrosis bronchiectasis. Chest. 20 II Sep 1. (Accepted for publication and

published online). (Jnc01porated in chapter 3 as section 3.1)

4. Kapur N, Masters IB, Chang AB. Longitudinal growth and lung function in pediatric

non-CF bronchiectasis- what influences lung function stability? Chest. 2010;138:158-

164. (Inc01porated in chapter 4 as section4.1)

5. Kapur N, Grimwood K, Masters IB, Morris PS, Chang AB. Lower airway microbiology

and cellularity in children with newly diagnosed non-CF bronchiectasis. Pediatr

Pulmonol. 20 II Sep 7. doi: I 0.1 002/ppul.21550. (Inc01porated in chapter 5 as section

5.1)

viii

6. Kapur N, Masters IB, Chang AB. Exacerbations in noncystic fibrosis bronchiectasis:

Clinical features and investigations. Respir Med. 2009;103:1681-1687. (Incorporated

in chapter 6 as section 6.1)

7. Kapur N, Masters IB, Morris PS, Galligan J, Ware R, Chang AB. Defining Pulmonary

Exacerbation in Children with Non-Cystic Fibrosis Bronchiectasis. Pediatr Pulmonol.

2011 Aug 9. doi: 10.1002/ppul.21518. (Incorporated in chapter 7 as section 7.1)

8. Kapur N, Mackay IM, Sloots TP, Masters IB, Chang AB. Role ofRespiratmy Vimses

in Exacerbations of Non-Cystic Fibrosis Bronchiectasis in Children. Thorax 2011,

awaiting editorial decision. (Incorporated in chapter 8 as section 8.1)

9. Kapur N, Bell S, Kolbe J, Chang AB. Inhaled steroids for bronchiectasis. Cochrane

Database Syst Rev. 2009 Jan 2l;(l):CD000996. (Incorporated in chapter 9 as section

9.1)

10. Kapur N, Chang AB. Oral non-steroid anti-inflammatories for children and adults with

bronchiectasis. Coclll'ane Database Syst Rev. 2007; (4):CD006427. (Incorporated in

chapter 9 as section 9.2)

IX

Presentation by the candidate relevant to the thesis

1. Presenting at the 2011 Queensland Royal Australian College of Physicians (RACP)

Paediatric Advanced Trainee Presentations, Brisbane Powerhouse, breakfast session

in October 20 I I; Oral Presentation on Defining Exacerbations in Non- Cystic Fibrosis

Bronchiectasis.

2. Presented at the Queensland Children's Medical Research Institute's (QCMRI)

Annual Student Expo in August 20 II and was awarded the "Best Oral Presentation"

award as well as the "Student Researcher of the Year" award.

3. Oral presentation at the Australian Society of Medical Research (ASMR)

Postgraduate Student Conference, Brisbane 2011; Oral presentation: Defining

Exacerbations in Non- Cystic Fibrosis Bronchiectasis.

4. Presented at the Thoracic Society of Australia and New Zealand (TSANZ) Annual

Scientific Meeting (ASM), Perth 2011 for the Ann Woolcock Young Investigator

Award: Defining Pulmonary Exacerbation in Children with Non-Cystic Fibrosis

Bronchiectasis.

5. Presented at the TSANZ ASM, Perth 2011; Oral presentation: Lower airway

microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis.

6. To present at the TSANZ ASM, Perth 20 II; Poster presentation: Role of Respiratory

Viruses in Exacerbations of Non-Cystic Fibrosis Bronchiectasis in Children.

7. Asia-Pacific Society of Respirology (APSR) ASM, Manila 2010; Oral presentation:

Lower airway microbiology and cellularity in children with newly diagnosed non-CF

bronchiectasis.

8. APSR ASM, Manila 2010; Oral presentation: Bronchoarterial ratio on High

Resolution CT scan of the chest in children without pulmonary pathology- Need to

redefine bronchial dilatation.

X

9. TSANZ ASM, Brisbane 201 0; Oral presentation: Longitudinal growth and lung

function in pediatric non-CF bronchiectasis - what influences lung function stability?

APSR ASM, Seoul 2009; Oral presentation: Exacerbations in non-cystic fibrosis

bronchiectasis: Clinical features and investigations.

10. TSANZ ASM, Darwin 2009; Poster presentation: Exacerbations in non-cystic fibrosis

bronchiectasis: Clinical features and investigations.

XI

Acknowledgement

There are many people who deserve acknowledgement for the work presented here but the

one whom I want to profusely thank and express my gratitude to is Professor Anne Chang.

She has been my inspiration and my mentor in every sense of the word. Her tireless

dedication, constant suppoti, encouragement and understanding have made this long journey

fruitful. She is untiring in her dedication to her students and gives of her time endlessly and

unquestioningly. I cmmot put to words my most sincere thanks to her.

I am also deeply indebted to my associate supervisors. To Associate Professor Dr Brent

Masters, for his constant guidance, wonderful ideas and showing complete faith in me. He

has also shaped to a great extent the way I approach clinical research, and kept my moral up

throughout the last three years. Without his support and the innumerable cups of coffee with

him, this thesis would not have been possible. I will always be grateful to him. To Associate

Professor Dr Peter Morris for his support, encouragement and ideas.

The doctors and staff of the Respiratory Department at the Royal Children's Hospital,

Brisbane cannot all be mentioned but have been a wonderful suppoti. In particular I wish to

thank Barry Dean and Margaret McElrae for their assistance in the laboratory and that too

always with a smile. I would also like to thank Dr Paul Francis, Dr Claire Wainwright and Dr

Helen Buntain for their help and support with patient emolment and follow-up. Helen Petsky

and Carol Willis for help with data-collection and dataset formulation. Special thanks to

Danielle Wurzel, who constantly encouraged me to keep going, especially towards the final

part of this PhD. We have a wonderful team and I feel privileged to be part of it.

xii

I must also thank Dr Ian Mackay and John Galligan for their willingness to support this

project and providing laboratory support for viral assays and serum inflammatory markers.

This research was only made possible by funding from the Endeavour Asia Award who

fnnded this research for I year and the ANZ Trustees scholarship that funded it for two years.

Without bodies, such as these, it would be very difficult to attract clinicians into research.

Sincere thanks also to the children and their parents who so willingly gave of their time to

participate in this research for without their support this clinical research would have been

impossible. They have helped me to always remember why I embarked on this journey.

I would also like to thank my parents, who in spite of being miles away in physical distance,

were a constant source of guidance and support to me.

But the biggest thanks should go to my wife Shveta and my daughters Nysha and Savaana. I

thank you for your patience Shveta and supporting me at all times. This thesis would not have

been possible if you were not besides me eve1y second of the way. I know you have

sacrificed a lot to be with me here in Australia, away from your parents, but all I can say is I

feel extremely lucky to have you Jaan, and I look forward to celebrate with you! This one is

for you, Shveta!

xiii

Abstract

Introduction

Non Cystic-Fibrosis (CF) bronchiectasis is recognised as an important cause of chronic

respiratory morbidity in developing countries and in Indigenous people of affluent countries.

Over the last decade, it is also increasingly diagnosed and recognised as an important cause

of respiratory illness in the non-Indigenous populations of affluent countries. Yet it is a

neglected condition with gaps in knowledge in m1ijor clinical issues pe1iaining to its

diagnosis, management and outcome, especially in regard to pulmonary exacerbations.

Aims

The specific aims of this thesis were:

I. To determine the range of bronchial to accompanying arterial diameter ratio in

children undergoing multi-detector Computed Tomography (MDCT) of the chest for

non-pulmonary conditions.

2. To examine the burden of disease and psychological influences (anxiety, depression,

stress) in parents of children with bronchiectasis and to assess the magnitude of

changes in these parameters with pulmonary exacerbations.

3. To study the determinants of changes in the lung fi.mction and growth parameters in

children with bronchiectasis over a three and five year period.

4. To describe the microbiologic and cellular constituents of BAL fluid at the time of

diagnosing bronchiectasis.

5. To ascertain the clinical and investigational features of pulmonary exacerbations in

bronchiectasis.

6. To formulate a robust, clinically relevant, repeatable and easy to use definition of

pulmonary exacerbation in children with bronchiectasis.

xiv

7. To identify and determine the point prevalence of respiratory viruses associated with

pulmonary exacerbations in children with bronchiectasis.

8. To perfonn systematic reviews using Coc!U'ane methodology to evaluate the efficacy

of inhaled corticosteroids (ICS) and non-steroid anti inflammatory drugs (NSAIDs) in

children and adults with bronchiectasis.

Methods

Broncho-arterial ratio study

Children undergoing MDCT chest for non-pulmonary conditions were prospectively

identified. Airway and vessel diameters were measured in the upper and lower lobes of both

lungs. Mean broncho-arterial (BA) ratio was calculated and its conelation with age assessed.

Prospective bronchiectasis cohort study

A coho1t of 69 children with non-CF bronchiectasis was prospectively followed for 900

child-months. The changes in clinical, systemic and lung function parameters with

exacerbations were statistically evaluated to formulate a definition of a pulmonary

exacerbation. The parents completed two questiollllaires [parent-proxy cough-specific QOL

(PC-QOL) and Depression, Anxiety and Stress scale (DASS)] in stable and exacerbation

states. Polymerase chain reaction (PCR) for respiratory viruses was performed on

nasopharyngeal-aspirates collected during exacerbations.

Longitudinal lung function study

Children with ::>:3-years oflung function data were retrospectively reviewed. Changes in

atmual antlll'opometry and spirometry at year-3 and year-5 from baseline were analysed. The

impact of gender, age, aetiology, baseline FEVt, exacerbation frequency, extent of

radiological changes, socio-economic status, environmental tobacco smoke exposure and

period of diagnosis was evaluated.

Bronchoalveolar lavage (BAL) fluid study

XV

Microbiology and cellularity of BAL fluid was analysed retrospectively at diagnosis of

bronchiectasis.

Results

The mean (SD) BA ratio on HRCT chest of children with non-pulmonary conditions was

0.626 (0.068), significantly lower than that in adults. Pulmonary exacerbations caused

significant worsening in the burden of disease and parental depression, anxiety and stress in

children with non-CF bronchiectasis. In this group, wet cough and cough severity (score 2:2)

over 72-hours were the best predictors of an exacerbation with area under the curve (AUC) of

0.85 (95% CI 0.79-0.92) and 0.84 (95% CI 0.77-0.91) respectively. Sputum colour, chest

pain, dyspnoea, haemoptysis and chest signs were significant though minor criteria. Inclusion

of serum C-reactive protein, amyloid-A and IL-6 to the definition improved its specificity.

Respiratory viruses were associated with 48% of exacerbations, with human rhinovirus being

the most common virus implicated. Lung function and antl!l'opometric parameters remained

stable over a 3 and 5 year follow-up period once appropriate therapy was initiated. At

diagnosis, 68% children had positive BAL fluid cultures for respiratory bacterial pathogens

with Haemophilus injluenzae being the most common. In contrast, Pseudomonas aeruginosa

was rare, while mycobacterial and fungal species were absent.

Conclusions

In the paediatric age-group, the airway is significantly smaller than the adjoining vessel.

Using the radiological criteria of BA ratio greater than one to define bronchial dilatation, as is

done in adults, would under estimate the presence and extent of bronchiectasis leading to

delayed and missed diagnosis. There is a significant burden of disease on parents of children

with bronchiectasis that gets worse with exacerbations. Pulmonary exacerbation in children

with non-CF bronchiectasis can be validly predicted using a standardised assessment of

clinical features, with additional systemic markers improving predictive values. Respiratory

xvi

viruses are commonly found during pulmonary exacerbations of children with bronchiectasis.

Spirometric and anthropometric parameters in children with non-CF bronchiectasis remain

stable over a 3-5 year follow-up. BAL fluid microbiology of children with bronchiectasis

differs from adults with rates of P. aeruginosa, mycobacterial and fungal species being

substantially lower.

Keywords:

Biomarkers, bronchoalveolar lavage, bronchiectasis, bronchoarterial ratio, burden, definition,

exacerbation, HRCT chest, quality of life, viruses, microbiology, spirometry

xvii

Table of Contents

Declm·ation by author .......................•.........•................•................•....... iii

Statement of Contributions ..........•.........•............................................•... iv

List of publications relevant to the thesis .................................................. viii

Presentation by the candidate relevant to the thesis •....................................•. x

Abstract ............................................................................................ :xiv

List of Figures ................................................................................... xxii

List of Tables .................................................................................... xxiv

List of Abbreviations ...•......................................•................•.............. xxvi

1 Introduction and Litemture Review .......•............................................•.... 1

1.1 Overview of bronchiectasis .................................................................... 1

1.2 Burden of disease ............................................................................... 2

1.2.1 Epidemiology and prevalence .................................................. 00 .. 2

1.2.2 Pulmonary morbidity in bronchiectasis ............... 00 ........ 00 ............ 00 .5

1.2.3 Bronchiectasis and nutrition ....................................................... 8

1.2.4 Psychological burden of disease in bronchiectasis .............................. 9

1.2.5 Cardiac and other co-morbidities in bronchiectasis ........................ 00.11

1.3 Pathology and Pathophysiology of bronchiectasis .................................... oo.l2

1.3.1 Pathology and Pathophysiology ................................................. 12

1.3.2 Aetiological risk factors ......................................................... 15

1.4 Diagnosis of bronchiectasis ................................................................ 16

1.4.1 What is the history of bronchiectasis diagnosis? .. oooo ................................ 16

1.4.2 Radiological diagnosis ........................................................... 17

1.4.3 Clinical features ofbronchiectasis ............................................. 19

xviii

1.5 Respiratory exacerbations of bronchiectasis ............................................. 20

1.5.1 Clinical features of exacerbation in bronchiectasis ......................... 21

1.5.2 What is the definition of exacerbation in paediatric bronchiectasis? ...... 22

1.5.2.a Potential Biomarkers of exacerbation .............................. 23

1.5.2.b Lung function parameters during exacerbations .................. 24

1.5.3 Pathogenesis of acute pulmonary exacerbation in bronchiectasis ......... 24

1.5 .4 What precipitates an exacerbation in bronchiectasis? ............................. 26

1.5.5 How does acute pulmonary exacerbation affect the burden of

disease in bronchiectasis? ....................................................................... 27

1.6 Why is this thesis about bronchiectasis in children? ............................................... 28

1.6.1 Hypothesis and aims ............................................................. 28

1.7 Thesis Design ................................................................................. 30

1.8 Summary of Chapter 1 ...................................................................... 32

lB Publication on: Differences and similarities in non-cystic fibrosis

bronchiectasis between developing and affluent countries ....................... 33

2 Bronchoarterialratio on High Resolution CT scan of the chest in children

without pulmonary pathology- Need to redefine bronchial dilatation ........... .40

2.1 Journal article ...................................................................... .41

2.2 Summary of chapter 2 ............................................................. 50

3 The burden of disease in paediatric non-cystic fibrosis bronchiectasis .......... 51

3.1 Journal article ...................................................................... 52

XIX

3.2 Supplementary material. ......................................................... 80

3.3 Parent-proxy cough-specific QOL (PC-QOL) ................................ 83

3.4 DASS-21 questionnaire .......................................................... 87

3.5 Summary of chapter 3 ............................................................ 88

4 Longitudinal growth and lung function in paediatric non-CF bronchiectasis

-what influences lung function stability? ............................................................ 89

4.1 Journal article ..................................................................... 90

4.2 Supplementary material.. ....................................................... 97

4.3 Summary of chapter 4 .......................................................... 105

5 Lower airway mic1·obiology and cellularity in children with newly diagnosed

non-CF broncltiectasis ................................................................... 106

5.1 Journal article ..................................................................... 107

5.2 Summary of chapter 5 ........................................................... 115

6 Exacerbations inn on cystic fibrosis bronchiectasis:

Clinical features and investigations ................................................... 116

6.1 Journal article ..................................................................... 117

6.2 Summary of chapter 6 ............................................................ 124

7 Defining Pulmonary Exacerbation in Children with Non-Cystic

Fibrosis Bronchiectasis .................................................................. 125

7.1 Journal article ..................................................................... 126

7.2 Supplementary material. ........................................................ 134

XX

7.3 Summary of chapter 7 ............................................................ 143

8 Role of Respiratory Viruses in Exacerbations of Non-Cystic Fibrosis

Bronchiectasis in Children ...........•.....................•............................. 144

8.1 Journal article ..................................................................... .145

8.2 Supplementary material .......................................................... 172

8.3 Summary of chapter 8 ............................................................ 181

9 Role of preventer anti-inflammatory therapy in bronchiectasis .................. 182

9.1 Cochrane review on inhaled steroids for bronchiectasis ..................... 183

9.2 Cochrane review on oral non steroid anti-inflammatory drugs for

children and adults with bronchiectasis ....................................... 221

9.3 Cochrane update .................................................................. 234

9.4 Summary of chapter 9 ............................................................ 234

10 Conclusion .................................................................................. 236

10.1 Discussion ........................................................................ 236

10.2 Limitations of the thesis ......................................................... 243

10.3 Conclusions ...................................................................... 244

10.4 Future projects and further research work .................................... 245

10.5 Summary ......................................................................... 248

References (Introduction & Discussion) ................................................. 249

xxi

List of Figures

2.1 CT image showing electronic calliper markings and measurements of bronchus and

adjoining vessel. ................................................................................. .43

2.2 Two way scatter plot depicting relationship between age and bronchomierial ratio .... .44

3.1 Comparative analysis showing effect ofpnlmonary exacerbation on PC-QOL total and

sub-component scores ........................................................................... 78

3.2 Comparative analysis showing effect of pulmonary exacerbation on DASS-21 total and

sub-component scores ............................................................................ 79

4.1 Longitudinal FEV,% predicted over 3 years. Normal vs. low baseline FEV1 •............ 93

4.2 Longitudinal mean FEV1% predicted over 3 years .......................................... .101

4.3 Longitudinal mean FEV,% predicted over 5 years .......................................... 101

4.4 Longitudinal mean FVC %predicted over 3 years .......................................... 1 02

4.5 Longitudinal mean FVC% predicted over 5 years ........................................... .102

4.6 Longitudinal mean Height z scores over 3 years ............................................. 103

4.7 Longitudinal mean Height z scores over 5 years .............................................. 103

4.8 Longitudinal mean BMI z scores over 3 years ................................................ 104

4.9 Longitudinal mean BMI z scores over 5 years ................................................ 104

9.1 Analysis 1.1: Stable State Bronchiectasis (6 months or less), Clinical severity indices.207

9.2 Analysis 1.2: Stable State Bronchiectasis (6 months or less), Lung function indices ... 209

9.3 Analysis 1.3: Stable State Bronchiectasis (6months or less), Average number of

exacerbations per subject. ....................................................................... 213

9.4 Analysis 1.4: Stable State Bronchiectasis (6 months or less), Sputum and biomarkers

Characteristic ..................................................................................... 214

9.5 Analysis 2.1: Stable State Bronchiectasis(> 6 months), Lung fimction indices...... 215

9.6 Analysis 2.2: Stable State Bronchiectasis(> 6 months), Average number of exacerbations

XXIl

per subject. ........................................................................................ 217

9.7 Analysis 2.3: Stable State Bronchiectasis(> 6 months), Sputum and biomarkers

characteristic .................................................................................... 217

xxiii

List of Tables

1.1 Demographic profile of various paediatric cohorts with bronchiectasis ................... .35

1.2 Aetiological distribution of various paediatric cohmis with bronchiectasis ............... 37

1.3 Lung function parameters ........................................................................ 3 7

2.1 Indications of MDCT chest in the BA ratio study ............................................ 48

2.2 Mean BA ratio per lobe .......................................................................... 49

3.1 General patient characteristics of the prospective bronchiectasis cohort. ................. 62

3.2 Factors associated with Total PC-QOL and Total DASS-21 scores during stable-state.64

3.3 Comparison ofDASS-21 scores between stable and exacerbation state .................. 66

3.4 Point prevalence of respiratory viruses during an exacerbation of bronchiectasis ....... 81

4.1 Anthropometric and Lung Function Data during follow-up period ........................ 92

4.2 Baseline Characteristics of subjects included in 5 year analysis ............................ 93

4.3 Baseline characteristics of the study group based on cause of bronchiectasis ............ 93

4.4 Comparison based on FEV 1 abnormality ...................................................... 93

4.5 Baseline characteristics of past and current coho1is .......................................... 94

5.1 Bacterial loads in the BAL fluid cultures from children with bronchiectasis ............ 110

5.2 Clinical, radiographic and bronchoalveolar lavage findings of the children with

Pseudomonas aeruginosa infection ........................................................... .111

5.3 BAL fluid total and differential cell counts at the time of diagnosing bronchiectasis .. 112

5.4 Risk factors associated with lower airway infection in children with newly

diagnosed bronchiectasis ....................................................................... 113

6.1 Underlying aetiology of non-CF bronchiectasis in the retrospective cohort. ............ 119

6.2 Clinical features of exacerbation in the retrospective cohort ............................... 119

6.3 Appendix I: Definitions used for data extraction ............................................ 122

7.1 Underlying Etiology of Bronchiectasis ....................................................... .127

xxiv

7.2 Univariate logistic regression for factors predicting exacerbation ........................ 129

7.3 Receiver operating characteristic analysis of individual variables ........................ 129

7.4 Sputum microbiology during stable state and exacerbation state ......................... 134

7.5 Change in clinical and investigational parameters with treatment of exacerbation ..... l39

8.1 Comparison offeatures during 'stable state' phase in children grouped by

PCR virus-positive and negative exacerbations ............................................. 155

8.2 Point Prevalence of viruses detected by PCR ................................................ 156

8.3 Univariate Logistic regression for factors associated with Virus-positive exacerbation I 58

8.4 Multiple Logistic regression for clinical and investigational models ..................... 160

8.5 HCo V Primer and probe sequence ............................................................. 175

8.6 Underlying Etiology of Bronchiectasis ........................................................ 178

9.1 Search strategies for Cochrane review on inhaled corticosteroids in bronchiectasis .... 188

9.2 Characteristics of studies included in Coclu·ane review on inhaled steroids in

bronchiectasis .................................................................................... 198

9.3 Characteristics of studies excluded from Coclu·ane review on inhaled steroids in

bronchiectasis .................................................................................... 205

9.4 Search strategies for Coclu·ane review on NSAID's in bronchiectasis .................... 226

9.5 Characteristics of studies excluded from Cochrane review on oral NSAID's in

bronchiectasis .................................................................................... 230

XXV

List of Abbreviations

AUC Area under the curve

BA Broncho-arterial

BAL Bronchoalveolar Lavage

BE Bronchiectasis

BMI Body Mass Index

BO Bronchiolitis obliterans

CF Cystic Fibrosis

CFU Colony Forming Units

CI Confidence Interval

COPD Clll'onic Obstructive Pulmonary Disease

CRP C-reactive protein

CT Computerised Tomography

CXR Chest x-ray

DASS Depression Anxiety and Stress

DLCO Diffusing capacity of the lung for carbon monoxide

ETS Enviromnental Tobacco Smoke

FEFzs-?s Forced expiratory flow midexpiratory phase

FEVt Forced expiratory volume in the first second

FTT Failure to tlll'ive

FVC Forced Vital Capacity

HBo V Human boca virus

HCoV Human coronavirus

HEV Human enterovirus

hMPV Human Metapneumovirus

xxvi

HPIV Human parainfluenza virus

HRCT High Resolution computerised tomography

HRQOL Health related quality of life

HRV Human rhinovirus

hs-CRP High sensitivity C-reactive protein

ICS Inhaled Corticosteroids

IL Interleukin

lOS Impulse Oscillometry System

IQR Interquartile range

IV Intravenous

MDCT Multi-detector computerised tomography

MMP Matrix metalloproteinase

MPI Myocardial Perforniance Index

NP A Nasopharyngeal aspirate

NPV Negative predictive value

NSAID Non Steroidal Anti-Inflammatory Drug

NTM Non-tuberculous Mycobacterium

NZ New Zealand

OR Odd's Ratio

PCD Primary Ciliary Dyskinesia

PC-QOL Parent proxy cough specific quality of life

PCR Polymerase Chain Reaction

PCT Procalcitonin

PPV Positive predictive value

xxvii

QOL

RCT

ROC

RSV

SAA

SD

SGRQ

TCC

TNF

VIP

URTI

USD

wee

Quality of life

Randomised Controlled Trial

Receiver Operating Characteristic

Respiratory Syncytial virus

Serum Amyloid A

Standard Deviation

St George's Respiratory Questionnaire

Total cell count

Tumour Necrosis factor

Usual Interstitial Pneumonitis

Upper respiratory tract infection

United States dollar

White Cell Count

xxviii

1

Introduction and Literature Review

1.1 An overview of bronchiectasis

Bronchiectasis is a pathological state of the conducting airways manifested by

radiological evidence of bronchial dilatation and clinically by cln·onic productive

cough. 1•2 The hallmarks of bronchiectasis are stasis of infected airway secretions;

reduced airway mucus clearance; and regional or diffuse airway wall dilatation,

thickening and destruction with loss of airway structural integrity.3-5 Such damage is

the result of a vicious cycle of inflannnation and infection arising from a number of

causes either inherited or acquired. 6 Bronchiectasis is associated with a prolonged

neutrophilic inflammatory and secretory response within the airways, producing a

"wet" sounding cough in young children7 and mucopurulent sputum expectoration in

older children. When bronchiectasis is localised, it can produce recurrent cough and

infectious exacerbations, or it may be diffuse, resulting in additional generalised

1

airway obstruction and destruction that may eventually lead to respiratory failure. 1

Though pathological changes of bronchiectasis are usually considered irreversible,

recent data suggests that there is a potential for reversibility of radiological changes in

some children if appropriate treatment is offered in a timely manner.8•9

Bronchiectasis is diagnosed by characteristic airway features seen on high-resolution

computerised tomographic (HRCT) scans of the chest. 10'12 The most imp01iant cause

of clinically significant bronchiectasis in North America, Europe and Australia is

Cystic Fibrosis (CF). 1 Other causes of bronchiectasis, unrelated to CF, constitute a

diverse and important yet neglected group of disorders that come under the umbrella

of non-CF bronchiectasis. The focus of this dissertation is non-CF bronchiectasis and

all references to bronchiectasis imply non-CF bronchiectasis, unless otherwise

specified.

1.2 Burden of disease

1.2.1 Epidemiology and Prevalence

Improved hygiene and nutrition, better vaccine coverage and early institution of

antibiotic therapy have all been instrumental in the decline of bronchiectasis

prevalence in the developed countries, making it an "orphan disease". 13•14 It continues

to be an imp01iant cause of respiratory morbidity in developing countries15'22 and

Indigenous and socially disadvantaged populations of the affluent countries.8•23

'26 In

the last decade though, there has been renewed clinical and research interest8•27

•28 and

increasing incidence29•30 of this ignored condition in the developed world as well.

2

In the later part of last century, the prevalence of bronchiectasis was reported to be

declining in the affluent world with a reported decline in incidence from 48/10,000

people in 1940 to 10/10,000 people in 1960.31 Similarly, in a longitudinal report from

Finland,32 Saynajakangas and colleagues reported a decline in bronchiectasis treated

in hospital from 143 admissions per million inhabitants in 1972 to 87 admissions per

million inhabitants in 1992. The admissions, new occurrences and the days in hospital

all decreased, at a1111ual rates of 1.3, 4.2 and 5.7%, respectively. Thus, where the

number of new occurrences was 50 per million persons in1977, it was 27 per million

in 1992. These trends have been attributed to effective treatment of pulmonary

infections, vaccination against measles and the reduction in tuberculosis.

More recently though, the rate of bronchiectasis-associated hospitalisation29 and

mortality30 in adults has been increasing. The bronchiectasis hospitalisation data from

12 states in the United States from 1993 to 200629 suggested that the age-adjusted rate

increased significantly, with an average a1111ual percentage increase of 2.4% among

men and 3.0% among women. The median cost for inpatient care was US$ 7,827

(range, US$ 13-543,914). Fmther, between 2001 and 2007, 5745 bronchiectasis

related deaths were registered in England and Wales. 30 When standardised to the 2007

population, this showed an increase in absolute numbers from 797 (200 1) to 908

(2007), a rise in mortality of3% per year. In a recent study from Japan,33 of the 1,409

adults (aged 23-86 years) on whom CT chest was performed as pmt of a health­

screening program at a single health promotion centre, 129 (9.1 %) were diagnosed

with bronchiectasis. It has been estimated that there are at least 110,000 adults in the

United States with this condition.34 In addition, there is overlap with chronic

3

obstructive pulmonary disease (COPD), with two studies reporting an incidence of

bronchiectasis in COPD as being 29%35 and 50%/6 respectively.

Longitudinal data on prevalence of bronchiectasis in children is limited to single-point

estimates of paediatric prevalence fi·om the affluent countries. These range from 1 in

6000 in the Auckland paediatric population25 to 1 in 5 800 in the British paediatric

population.8 The incidence of bronchiectasis has been repotied to be 3.7/100,000 per

year in under 15 years old children in the New Zealand cohort with calculated

prevalence of 1 in 3000 children overall (twice that of CF) and 1 in 625 in children of

Pacific Island etlmicity.26 The same study repotied the incidence of bronchiectasis to

be tln·ee times higher in Maori and twelve times higher in Pacific children compared

with those of European etlmicity. Similarly, the Indigenous children from Central

Australia have a much higher reported prevalence of 4.9 per 1000,24 which is similar

to the rates reported from the Alaska paediatric population. 23 Singleton and

colleagues23 also repotied that the prevalence of bronchiectasis in Alaska native

children had been relatively stable for those born between the 1940s and 1980s, with a

prevalence of approximately 11.0 per 1,000 persons among those born during the

1940s and 1950s, to 20.5 per 1,000 persons among persons born during the 1960s.

Although similar data on incidence and prevalence is not available from the

developing world, data from Indigenous and socially deprived population of the

affluent world may be used as proxy. Even if we use the somewhat moderate estimate

of prevalence such as 1 in 3000 children in the developing world, the burden of

disease is potentially substantial.

4

In spite of the high prevalence of bronchiectasis in children and adults as described

above, it remains a neglected condition. Further, it is likely that even these estimates

are falsely low since a significant number of these children with chronic cough are

misdiagnosed as "astluna" and do not reach a diagnostic conclusion either due to lack

of facilities for CT scan of the chest in the non-affluent world, or just delay in referral

of these "cln·onic coughers" to a respiratory specialist. This is reflected by

demographic data suggesting that the age at diagnosis of bronchiectasis is

significantly later than the age at initiation of symptoms. In a cohort of 105 children

with bronchiectasis from Italy,28 the median age at diagnosis was 7 years though the

children were symptomatic from the median age of 6 months. Similar delay in

diagnosis have been reported in the British cohort of 93 children8 who were

symptomatic from the first year of life but the diagnosis was made at more than 7

years of age. Epidemiological studies are needed to determine the incidence and

prevalence of paediatric bronchiectasis in these regions. Also, data pe1iaining to the

health related cost of managing children with bronchiectasis is needed. Further, there

is no bronchiectasis related paediatric mortality data available from the affluent or

developing world. The epidemiology of bronchiectasis is discussed in greater detail in

Chapter lB.

1.2.2 Pulmonary morbidity in bronchiectasis

Bronchiectasis is predominantly a disease of the lungs with pulmonary

symptomatology constituting the m[\jor p011ion of disease burden, though it may have

non -pulmonary co-morbidities associated with it. When the disease is localised to a

single or few lobes, infectious exacerbations and recurrent cough are the m[\jor

features and cause significant morbidity. Exacerbations may require hospitalisation37

5

resulting in increased health care cost and worsen the pulmonary morbidity. As the

pulmonary involvement becomes more diffuse and severe, additional features of

airflow limitation may develop. This may result in increasing symptoms, exercise

I. . . d II h . . "' 'I II · 15 18 I umtatwn an eventua y ypercapnetc respiratory .m ure. - aemoptysts, · c 1est

deformitl8 and chronic respiratory failure19•20 have all been conm1only rep01ted in

some cohmts of children with bronchiectasis. The clinical features of bronchiectasis

are discussed in detail in section 1.4.3 and chapter IB; and the role of pulmonary

exacerbation in worsening pulmonary morbidity in section 1.5.

While the best monitoring tool for pulmonary disease in bronchiectasis is yet

undetermined, pulmonary function measurements and HRCT are the most objective

parameters.3 While HRCT may be useful tool in following disease progression,39 the

radiation (and reported increased cancer risk)40•41 associated with repeat scmming

limits its use in children. As we considered it unethical to subject children to

additional radiation for research purposes, repeated HRCT scans was not performed

in studies within this thesis and will not be discussed as a tool for monitoring disease

progression. However, the use of HRCT as a diagnostic tool in bronchiectasis is

discussed in section 1.4.2.

Spirometry is generally considered insensitive in detecting early structural lung

damage and disease progression42 though it still one of the most objective tools for

monitoring the severity of bronchiectasis and is a commonly used measure in

interventional trials.43•44 Moreover, low forced expiratory volume in the first second

(FEV I) is one of the important predictor of poor quality of life in adults with

bronchiectasis.45 Spirometric values may be normal in children with bronchiectasis,

6

but when an abnormality is present, it is classically obstructive in the earlier stages

and later becomes a mixed obstructive and restrictive process. Banjar20 in a Saudi

Arabian cohort reported lung function abnormality in 88% of the children with

bronchiectasis (22% obstructed, 18% restrictive & 48% both). Similarly, the mean

FEY 1 in a Turkish cohore5 was 63.3% of predicted and 68% of predicted in a

Tunisian cohort. 19 Among those with obstructive changes on spirometry, 45% to 70%

have some component of airway reversibility with bronchodilators.46 Lung fi.mction

abnormalities have been less prominent in cohotis from the affluent world. In a study

of 105 children with bronchiectasis from Italy, Santamaria and colleagues repotied

the median FEY1 to be 95% ofpredicted.28 Similarly, Twiss et al.26 reported a nearly

normal lung function indices in 65 children with bronchiectasis from New Zealand.

The use of conventional lung fi.mction measurements while non-invasive, is limited

by their inability to achieve meaningful results in younger/uncooperative children.

Respiratory impedance measurements by impulse oscillometry system (lOS) can

potentially be used as a lung function parameter in younger children due to it being a

simpler technique along with tidal breathing measurements, 47 though there use is still

limited to research settings.

In spite of its potential significance, paediatric data on longitudinal lung function is

minimal with no information on factors that predict change in lung function over time.

In 61 adults with bronchiectasis, King et al48 have recently repotied a progressive

decline in FEY 1 and diffusing capacity of the lung for carbon monoxide (DLCO) over

a 7 year follow-up. Adult data suggests49 that with early and intensive treatment,

FEY 1 decline can be prevented. Other reported predictors of FEV 1 decline in adults

with bronchiectasis are chronic colonization with Pseudomonas aeruginosa,50

frequency of severe exacerbations and systemic inflammatory markers. 51

7

Prior to commencement of studies in this thesis, there were no paediatric papers on

the longitudinal pattern of FEV 1 in children with bronchiectasis. Hence a study was

undertaken to evaluate the determinants of changes in the lung function and growth

parameters in children with bronchiectasis over a tlu·ee and five year period. The 2

papers that were published before paper 4.1 reported contradictory results and neither

examined for multiple factors associated with respiratory function change. The British

study (59 children over 2-yrs, 31 children over 4-yrs) found that with intensive

treatment, lung function improves but does not necessary normalise. 52 In contrast, the

New Zealand study of 44 children over 4.5-yrs found that FEV 1 declined at 1.9% per

annum.Z6 Further, no information was available on the factors that govern nutritional

and/or lung function decline, if any, in children with bronchiectasis. Specifically, the

impact of modern pulmonary treatment regimens, which are largely based on CF

regimens, has not been well established on lung function parameters in childhood

bronchiectasis.

Since paper 4.1 was published, a further study from the same group in New Zealand

reported a mean FEV 1 decline of 1.6% predicted per year in 66 children with

bronchiectasis, with reduced lung function associated with male gender, chronic

Haemophilus influenzae infection, longevity of disease, and Maori and Pacific Island

ethnicity.53

1.2.3 Bronchiectasis and nutrition

In 1949, Field suggested that "Good nutrition and home conditions probably give the

child a better chance of more complete recove1y fi'om lung damaging disease."54 Poor

nutrition (both macro and micro-nutrient) is known to effect childhood morbidity and

mortalit/5 by affecting the innate and adaptive immune function56 and leads to the

8

malnutrition-infection-malnutrition cycle. 57 Appropriate nutrition is important for

both reduction of acute respiratory infections58•59 as well as maintaining good lung

function in chronic suppurative lung disease60•61 though data on malnutrition

specifically preceding bronchiectasis are limited and inconsistent. In bronchiectasis

related to CF, optimal nutrition is impot1ant for reducing pulmonary decline.60•61 Low

Body Mass Index (BMI) is known to increase long term mortality in adults with

bronchiectasis,62 though its role in predicting the clinical course in paediatric disease

is uncmtain. Bronchiectasis itself predisposes to malnutrition as a result of chronic

pulmonary infection causing diminished appetite and reduced caloric intake, and it is

a common feature in bronchiectasis cohorts from under-privileged populations.

Failure to thrive (FTT) was repotted in 46% of the 204 children with bronchiectasis in

the Turkish cohort,21 and 75% of the 65 children with bronchiectasis in the Indigenous

population. 24 In central Australia, children with bronchiectasis were three times more

likely to have had malnutrition in early childhood before the diagnosis of

bronchiectasis.63 In the 1960's, Clark reported similar prevalence of malnutrition in

bronchiectasis with nearly half the children below the 10111 centile for height and

weight.64 In contrast, malnutrition has been reported less frequently from the Alaskan

cohott,23 and more recently from the affluent countries. 52•65 High prevalence of breast

feeding among the Alaskan native mothers66 and early detection and management

among the affluent countries could be one of the reasons for this trend. A British

study published before paper 4.1 reported normal antlu·opometric parameters in their

cohort of 59 children with bronchiectasis.52 The growth was also normal over the

follow-up period of 4 years.

1.2.4 Psychological burden of disease in bronchiectasis

9

Outcomes of children with bronchiectasis have traditionally been assessed with

parameters such as pulmonary function and radiological extene though their

correlation with clinical severity may be poor.24•67 Moreover, even the clinical

measurements of disease do not always convey the true burden of illness for the child

and family. 68 Juniper therefore stated that "assessment of health-related quality of life

should be an essential component of all clinical evaluations".68 In paediatric cohmts

with chronic respiratory illness (asthma, CF, chronic cough), upper airway disease

such as sinusitis/ otitis,69 recunent doctor visits70 and high frequency of cough71 all

serve to increase the burden of disease. Though bronchiectasis specific data from

paediatric cohorts are missing, factors that govern quality of life (QOL) in adults with

bronchiectasis include Pseudomonas aeruginosa infection,72 dyspnoea, sputum

production 45 and fi·equency of exacerbation. 73 Since cln·onic cough is an important

and common feature of bronchiectasis, cough specific QOL parameters have been

used in bronchiectasis cohorts?4 Factors such as exacerbations that make the cough

worse are therefore likely to increase the burden of disease though there is no direct

data available. Given the lack of data, a study (chapter 3, aim 2 of thesis) was

undertaken to address this gap.

In addition to affecting the child, the family, and pmticularly the primary caregiver

may face considerable burden due to the chronic illness/0•75 causing stress, anxiety

and depression. 76 These are impmtant since maternal depression is an important factor

in non-adherence to therapy and morbidity.77•78 In adults with bronchiectasis, elevated

scores for anxiety and/or depression have been described in up to a third ofpatients.79

Knowledge of the issues of burden of illness and psycho-morbidity are important for

holistic patient/ family centred care which looks beyond treatment of the primary

illness to maximize favourable outcomes. Addressing these psychological aspects are

10

likely to improve health, function and minimise the burden of illness. 80 The lack of

data on the burden of disease in bronchiectasis in children is an important gap in

clinical knowledge on bronchiectasis.

1.2.5 Cardiac and other co-morbidities in bronchiectasis

Besides causing significant pulmonary morbidity, bronchiectasis has considerable

non-pulmonary co-morbidities as well. The effect on growth and the psychological

effects have already been addressed in section I .2.3 and section I .2.4.

Cardiac dysfunction, though uncommon in children with bronchiectasis, 1s an

important cause of morbidity especially in adults with severe lung disease. In 15

adults with bronchiectasis, HRCT scores were strongly correlated with pulmonary

artery pressure (regression R = 0.59, P value= 0.001),81 with nearly a third rep01iing

echocardiographic features of pulmonary hypeliension. Further, in 25 adults with

bronchiectasis, the myocardial performance index (MPI), a sensitive parameter of

both systolic and diastolic ventricular function, was significantly lower than age

matched controls signifying early cardiac dysfunction in this cohort. 82 The effect on

children is more subtle with study on 21 children with bronchiectasis reporting normal

left ventricular systemic function on echocardiography though some children had

abnormal diastolic function that correlated with clinical disease severity. 83 In addition,

exercise capacity was decreased in most children.

Hypertrophic osteomilu·opathy (clubbing, periostosis and arthritis-like features) is a

common feature of bronchiectasis15•17•18•20 with reported incidence ranging from 5% to

50%. It has also shown to correlate with the radiological severity of the disease.38

Systemic amyloidosis has also been reported as a complication of bronchiectasis84'86

II

causing renal failure in a few cases. Other reported co-morbid conditions associated

with bronchiectasis are scoliosis, chronic middle ear disease, gastroesophageal reflux,

social problems and developmental delay .1

1.3 Pathology and Pathophysiology of bronchiectasis

1.3.1 Pathology and pathophysiology

Bronchiectasis is the end result of chronic airway inflammation and infection with

resultant anatomical distortion and dilatation of the bronchi. The pathological

features include neutrophilic inflammation, intra-luminal accumulations of secretions

and obliteration of distal airway all causing alterations in sub-segmental bronchial

structures.2 There are additional changes ranging from peribronchial inflammation

and fibrosis, distal atelectasis and pleural adhesions. 1 The initial trigger for the

bronchiectasis process is unknown, though based on animal models, inadequate

mucus clearance and persistent infection are considered necessary prerequisites. 87 It is

well known that the lung is continuously exposed to inhaled pathogens and

enviromnental pollutants. Persistence of microorganisms in the airways because of

impaired mucus clearance or other host defence mechanisms may lead to a vicious

circle of umelenting inflannnatory reaction and progressive lung damage. 6 Cole

proposed that an environmental insult often on a background of genetic susceptibility

and impaired mucociliary clearance results in persistence of microbes in the sino­

bronchial tree and microbial colonisation. The microbial infection causes chronic

inflammation resulting in tissue damage and impaired mucociliary motility. In turn

this leads to more infection with a cycle of inflammation causing progressive lung

damage.

12

The current view is that the two factors required for the initiation and progression of

bronchiectasis are persistent infection and a defect in host defence. This is supported

by evidence of increased neutrophils and pro-inflammatory mediators in the airways

and endobronchial biopsy of adults with bronchiectasis.88 Their bronchoalveolar

lavage (BAL) fluid contains increased levels of inflammatory mediators such as

neutrophil elastase, myeloperoxidase, tumour necrosis factor (TNF) a and interleukin

8 (IL-8).89 Dilatation of the bronchus is believed to result from a combination of

factors including atelectasis induced negative intrapleural pressure on the wall of the

bronchus already weakened by these lytic enzymes.14•90

This inflanunatory cycle is not only triggered but also sustained by concomitant

infection with bacterial and viral agents. Pseudomonas aeruginosa infection in

particular is associated with increased morbidity in adult cohmis/1•91 though it is less

prevalent in paediatric cohmis. More recently, non-tuberculous mycobacterium

(NTM) and aspergillus related lung disease have been implicated in the pathogenesis

of bronchiectasis in adults though there is no published data on the prevalence and

significance of NTM in paediatric bronchiectasis. 10•91

•92 Data in adults with

bronchiectasis reported high prevalence of NTM from the sputum of screened

patients. 93"95 One British cohort of 100 adults with bronchiectasis repmied the

prevalence ofNTM to be 2%,94 and another cohort of 98 adults from a different centre

in United Kingdom repotied a prevalence of 10%.93 In 91 adults with bronchiectasis

seen over 6 years in Hong Kong,95 a positive mycobacteria culture was obtained in 12

( 13%) cases. NTM infection in bronchiectasis has also been reported to be associated

with aspergillus-related lung disease in adults.92

13

Despite the central role of infection and inflammation in the pathogenesis of

bronchiectasis, there are few published paediatric studies on the lower airway

microbiology and cellularity in bronchiectasis and on the organisms implicated in

early disease progression. Most data are from older children with well established

disease capable of providing sputum .. Cross-sectional studies conducted in outpatient

clinics or during an exacerbation report 40-67% of children with bronchiectasis have

respiratory bacterial pathogens in their sputum and that Haemophilus injluenzae and

Streptococcus pneumoniae are the most commonly identified bacteria. 15•20

•22

•25 As

contamination of respiratory specimens by oropharyngeal flora is a concern,96 BAL

fluid samples are the gold standard for evaluating lower airway microorganisms and

inflammation in adults as well as in young children unable to expectorate sputum.97

The few available studies using BAL techniques to collect lower airway specimens

from children with bronchiectasis have important limitations. Specifically, they have

either been conducted in special populations, such as Indigenous children from remote

communities in northern Australia where results may not be applicable to other

bronchiectasis patients24•98 or BAL culture results have been combined with those

from sputum cultures rather than being presented separately.8•27

•53 Given the lack of

data, a study (chapter 5, aim 4 of thesis) was undertaken to address this gap. Knowing

the type of airway infection and inflammation in early bronchiectasis would not only

help in the understanding of the pathogenesis of this chronic condition but would also

have important management implications by facilitating appropriate anti­

inflammatory and antibiotic therapy.43 Isolation of these micro-organisms from the

lower airways early in the disease does not directly implicate them as the "disease

initiator" but may link them to disease progression, specially since presence of certain

organisms such as Pseudomonas aeruginosa predict higher morbidity in

14

bronchiectasis.51•91

•99 Moreover, those with more severe bronchiectasis (earlier

diagnosis, lower FEV 1 and varicose-cystic bronchiectasis) are more likely to be

colonised with pathogens100 and have more intense inflammation than those not

colonised. 89 In this section, the pathophysiology of bronchiectasis has only been

briefly described since this was not one of the main objectives of this thesis.

1.3.2 Aetiological risl{ factors of bronchiectasis

Bronchiectasis is the end result of a variety of airway insults and predisposing

conditions that culminate in airway injury, recurrent or persistent airway infection and

destruction. 101 Many paediatric case series, from both the affluent and the developing

countries, have described in detail the underlying aetiology of bronchiectasis. As

most patients are usually diagnosed with bronchiectasis after several years of

symptoms, it is often difficult to prove causality in development of this condition. 14 A

common feature of most patients is the impaired local and/or systemic host defences

• "' · 102 103 I I I d" I . f f"' . . to mtect!On. · n t 1e non- n tgenous popu at10ns o a uuent countnes, pnmary

immunodeficiency remains the most common cause accounting for 20% to 40% of the

paediatric bronchiectasis.8•27.28.1°4 Nikolaizik and Warner104 reported 27% of the 41

children with bronchiectasis had underlying innnunodeficiency. Post-infectious

causes are more common in the Indigenous populations with up to 90% of

bronchiectasis being attributed to previous infections.23•24 Similarly, in non-affluent

countries, bronchiectasis consequent to previous infections are more connnon,

causing 17%17 to 30%15•18 of cases. Karadag et al. 15 reported significant past infection

in 30% of their cohort, of which 8% had measles, 3% had varicella and 2% had

tuberculosis. Primary ciliary dyskinesia (PCD) is also commonly reported as the

predominant underlying cause of bronchiectasis in the affluent countries (15% to

15

24%),27•28

•104 though it is rare in the developing countries and Indigenous populations

(0% to 10%).15•18

•20

•22 In addition to the known causes of bronchiectasis, nearly a 30-

50% have no apparent underlying cause found. Knowing the underlying aetiology in

bronchiectasis is also important since it guides appropriate management27 and could

facilitate improved outcomes. The aetiological risk factors for bronchiectasis are

discussed in greater details in chapter lB.

1.4 Diagnosis of bronchiectasis

1.4.1 What is the history of bronchiectasis diagnosis?

The histopathology of bronchiectasis was first described by Laetmec in 1819105

though most studies on pathology of bronchiectasis were reported between 1930 and

1960 due to access to significant quantities of lung specimens at this time. Whitwell106

studied 200 consecutive operative lung specimens with bronchiectasis and

demonstrated marked inflammation of the bronchial wall, principally in the smaller

airways. Bronchial dilatation was characterised by deficiency/ loss of elastin and more

advanced disease by destruction of muscle and cartilage. There was variable bronchial

wall fibrosis, atelectasis and peri bronchial pneumonic change. The diagnosis of

bronchiectasis continued to be made based on pathology till Jean Athnanse introduced

contrast bronchography in 1922, which allowed for images of the destructive changes

seen in bronchiectasis. In the 1950's, Lynne Reid linked bronchography with

pathologic specimens. 107 Reid categorised bronchiectasis as having three main

phenotypes: I) tubular characterised by smooth dilation of the bronchi; 2) varicose

where the bronchi are dilated with multiple indentations; and 3) cystic in which

dilated bronchi terminate in blind ending sacs. 108 Currently the gold standard of

16

diagnosing bronchiectasis is through data obtained from HRCT scan of the chest10"12

as discussed in the next section.

1.4.2 Radiological diagnosis

Plain chest radiographs are relatively insensitive in diagnosing bronchiectasis. In a

study of 27 patients by CuiTie et a!., the diagnosis of bronchiectasis by chest

radiograph was present in only 40% of those with proven bronchographic

bronchiectasis. 109 HRCT of the chest is now the gold standard for diagnosing

bronchiectasis in which one of the key markers in increased bronchoatterial (BA)

ratio. 1•5 Other radiological features of bronchiectasis include peribronchial thickening,

mucus plugging, failure of airway to taper normally while progressing to lung

periphery, air trapping and sacculations. 12•10

•111 HRCT does not distinguish the

aetiologies of bronchiectasis112 though adult studies have repo1ted certain

characteristic features in CF, allergic bronchopulmonary aspergillosis, and atypical

mycobacteria infection."3 The advent of multi-detector CT (MDCT) scan has further

enhanced this imaging capability by providing more comprehensive and precise

· "' • 114 115 H I d' I . I d fi . . f . d'I . d m,ormatton. ' owever, t te ra 10 og1ca e m1tton o atrway 1 atatton an

bronchiectasis in children has substantial limitations 7 since most criteria are still adult

based.9 Since HRCT features in adults may not necessarily be equivalent to those in

children as lung morphology changes with aging, 116•117 the lack of paediatric criteria is

an important knowledge gap in this area. Moreover, the adult criteria have been

predominantly based on a study on 6 adults by Naidich and colleagues4 with

bronchiectasis nearly three decades ago, whereby airways were considered dilated if

their internal diameter was larger than the outer diameter of the adjacent pulmonary

vessel i.e. the BA ratio of more than I. 5 However numerous subsequent studies on

17

asymptomatic adults have reported a much lower BA ratio, especially in younger

adults.ll8-I20 As BA ratio has been shown to increase with age, 118 application of adult

definitions to paediatric cohorts could underestimate the presence and extent of

bronchiectasis. This issue has previously been raised by Eastham and colleagues8 who

suggested that there is a group of children with chronic suppurative lung disease who

do not have radiological features of bronchiectasis. This has impotiant implications in

terms of late and/or missed diagnosis of clinical syndrome of bronchiectasis in

children, resulting in delayed initiation of treatment and increased morbidity. Another

issue with CT diagnosis of bronchiectasis includes the need of two HRCT scans to

truly fulfil the criteria of "irreversible dilatation", something that may be unethical in

children if done purely for diagnostic purposes, considering the increased risk of

cancer due to the radiation.41 Also, CT scans performed in different clinical states

such as in exacerbation may yield different results when compared with a so called

"stable state", both of which are difficult to define. This concern was raised by

Gaillard et a!} who suggested that early bronchial dilatation might be reversible once

appropriate treatment is initiated. In the Liverpool group,9 bronchial dilatation

resolved completely in 6 of the 21 children with bronchiectasis post-medical

treatment. Early diagnosis is important to a better clinical outcome in chronic

respiratory disease such as CF121 and COPD. 122 Ellerman and Bisgaard123 showed, in

their cohort of people with primary ciliary dyskinesia, that adults who were diagnosed

later had significantly worse lung function. Though direct evidence of such

correlation in bronchiectasis is missing, establishtneiit ofappt'opriate thet'<ljlfhas been

shown to stabilise lung function in children with bronchiectasis. 52•65 Also, data

suggests that radiological bronchiectasis can resolve with treatment,8•9 making timely

diagnosis even more significant. A paediatric radiological definition of bronchiectasis

18

is therefore highly relevant in the context of detecting early changes on HRCT in

children where changes may be subtle and often missed by using adult-based criteria.

This issue is addressed in chapter 2 (Aim 1 of thesis).

1.4.3 Clinical features of bronchiectasis

The clinical case definition of bronchiectasis is imprecise and diagnosis based solely

on clinical features may be inaccurate. Diagnosis of bronchiectasis should be

suspected when a child has a chronic moist-sounding cough, exertional dyspnoea,

recurrent wheezing and chest infections, haemoptysis, growth failure, digital

clubbing, and/or chest wall deformity.' Children with bronchiectasis typically have a

preceding history of recmTent pulmonary infections and cluonic cough. 1•2

•103 The

cough associated with bronchiectasis is chronic in nature, is "wet" in character7 and

may be associated with expectoration of purulent sputum in older children. 124 The

significance of sputum colour stems from the adult data suggesting high conelation

between sputum colour and bacterial colonisation (5% in mucoid sputum; 43.5% in

mucopurulent sputum; 86.4% in purulent sputum; p<O.OOOl) as well as severe

radiological bronchiectasis and worse lung function parameters. 125 Li et al.27 repmted

recurrent chest infection in 77% and chronic cough in 35% of their cohort. Clubbing,

chest deformity and FTT are usually rare in cohorts from the affluent world, with less

than 5% children showing features of FTT in the British cohort.27 Karadag et al. 15

reported cough (81%), dyspnoea (49%), and wheeze (47%) as the most common

presenting feature in their Turkish cohmt, with clubbing present in 41% of the

population. Similar features have been reported from Korea,22 Saudi Arabia,20

Tunisia19 and New Zealand25 though none of the studies have tried to differentiate the

clinical features as baseline or in exacerbation. Digital clubbing and chest deformities,

19

markers of disease severity,38 are common in the underprivileged population with

21%18 to 52%25 children reported to have clubbing. Haemoptysis (10% to 40%)15•18

and chronic respiratory failure (21% in Tunisian cohort19 and 23% in Saudi Arabian

cohort20) were a connnon features in this population, though they have been relatively

uncommon in the affluent populations. The clinical features of bronchiectasis are

discussed in greater detail in chapter lB.

As in other chronic pulmonary conditions such as asthma, CF and chronic obstructive

pulmonary disease (COPD), children and adults with bronchiectasis have recurrent

acute pulmonary exacerbations that impact the short and long term

morbidity.37•65

•73

•123 Acute pulmonary exacerbations in bronchiectasis is discussed in

detail under the following section.

1.5 Respiratory exacerbations of bronchiectasis

The importance of exacerbations (clinically and for research) is accepted for chronic

respiratory disease such as asthma/26'128 CF129

•130 and COPD.l3l-l35 Recurrent acute

pulmonary exacerbations form part of the disease progression in most children with

bronchiectasis resulting in increased morbidity, hospital achnission,37 health care cost

and the burden of disease. Recurrent exacerbations may lead to progressive

deterioration of lung function123 and is also one of the strongest predictors of poor

quality of life in adults with bronchiectasis. 73 Moreover, frequency of pulmonary

exacerbations is being increasingly used as an outcome measure in many therapeutic

trials on bronchiectasis and is a good clinical marker of disease severity and

control.44•136 Despite its known significance, there are significant gaps in the

knowledge and research pertaining to exacerbations in bronchiectasis. This includes

20

the lack of a standardised definition; minimal data on clinical features, effect on lung

function, precipitants and the effect on the burden of disease.

1.5.1 Clinical features of an exacerbation in bronchiectasis

Though data on the overall clinical features of bronchiectasis is available from large

case series, none of the published studies have carefully determined the clinical

features associated with respiratory exacerbations of bronchiectasis in children. A

significant contributory factor to this systematic lack of data is due to there being no

standard definition of an exacerbation, as discussed in section 1.5.2. Increase in

cough, sputum volume, increased sputum purulence, increased dyspnoea,

deterioration in spirometry or chest signs have all been reported in adult studies as

features of exacerbation.43•137

'139 However, adult features of bronchiectasis differ

significantly from paediatric cohorts since young children usually do not expectorate.

None of the adult studies have considered cough character, specially a "wet" cough,

as a feature of bronchiectasis exacerbation, a factor of immense significance in

paediatric chronic suppurative lung disease.7 Presence of wet cough indicates

presence of excessive airway mucus7 and therefore may be a proxy indicator of

ongoing lower airway inflammation in the non-expectorating paediatric population.

Moreover, whereas adult bronchiectasis is considered a disease of chronic cough and

sputum production, clinical experience had suggested that children with

bronchiectasis may be minimally symptomatic once stabilised on appropriate

management, though at the time of stmting this thesis, direct evidence to this was

missing. Further, no information is available on clinical features that may predict

exacerbation severity, treatment success or failure with oral or intravenous antibiotics

or factors precipitating an exacerbation

21

1.5.2 What is the definition of exacerbation in paediatric

bronchiectasis?

Despite the significance of exacerbations in bronchiectasis, there is a lack of a

standardised definition140 in the paediatric and adult literature with varying definitions

across studies including in CF as highlighted by Mogayzel et al. 141 In the current

literature, definitions of exacerbations include changes in sputum and selected

potential biomarkers and hospitalisations. As symptoms of bronchiectasis share

features, and often co-exist, with COPD/5•36 the definition of exacerbation in COPD

in adults by Anthonisen et al. 131 has been extrapolated to bronchiectasis studies. 43• 137

These features included increased dyspnoea, sputum purulence and sputum volume.

Anthonisen futiher graded these exacerbations into type 1 (all three cardinal

symptoms), type 2 (two cardinal symptoms) and type 3 (one cardinal symptom plus

one of the following: an upper respiratory tract infection in the past 5 days, fever

without other cause, increased wheezing or cough, or an increase in heart rate or

respiratory rate by 20% compared with baseline readings). Despite the fact that this is

a non-validated definition, this definition has come into common use in COPD and

even bronchiectasis. Moreover, extrapolation of an adult COPD definition on to

paediatric bronchiectasis is even more inappropriate considering the notable

differences the clinical and pathophysiological features in the two populations. 142

Sputum-based criterial3l,IJS used in adults, as in the Anthonisen's criteria, have low

sensitivity and limited applicability in paediatrics non-expectorating population.7

Clinical scores alone (such as those used in CF) lack specificity. 143 The need for

therapeutic interventions and/or hospitalisation is arguably variable (as it is

subjective) and limited to severe exacerbations. There are no studies on sputum or

plasma biomarkers of exacerbation in children with bronchiectasis.

22

1.5.2.a Potential biomarkers of exacerbation

The fact that exacerbation in bronchiectasis remains a clinical diagnosis and the

difficulties inherent in assessing airway inflammatory markers in clinical practice

have led to the idea that systemic biomarkers (blood and/or lung function parameters)

may have clinical utility in diagnosis of an exacerbation of bronchiectasis, akin to

COPD exacerbation. 134•144

"147 In adults, serum procalcitonin (PCT)148 and amyloid A

(SAA/49 show promise. PCT is a more specific and sensitive marker of bacterial

infections that has been increasingly used in clinical practice. 150 In the absence of

infection, PCT, a precursor peptide from the hormone calcitonin, is restricted to

predominantly the C-cells of the thyroid, where it is cleaved to fonn calcitonin and

stored in secretory granules. In contrast, bacterial infection leads to a constitutive

release of PCT from all parenchymal tissues of the body, causing increased serum

levels. This up regulated calcitonin gene expression is thought to be mediated by the

microbial toxins themselves, or via the cytokines of the cell mediated or antibody host

response. Its sensitivity for defining a bacterial infection is further increased by the

down regulation of calcitonin gene expression by cytokines related to a viral

infection. 151 Data from adult cohorts with bronchiectasis52 suggests that in spite of

some correlation of severity of exacerbation with PCT, overall it has not been a useful

marker of exacerbation when compared to CRP and is generally low in

bronchiectasis.

SAA is an acute-phase protein induced by inflammatory mediators, including IL-6,

IL-l~. and TNF-u. SAA is secreted from the liver as the predominant apolipoprotein

associated with plasma high-density lipoprotein cholesterol. The human SAA gene

family is comprised of four members: SAAl and SAA2 are induced during

inflammation or in response to tissue injury; SAA3 is a pseudogene; and SAA4 is

23

constitutively expressed. 152•153 SAA has been found to be more sensitive than C­

reactive protein (CRP) in acute exacerbation of COPD in adults152 with SAA levels of

7.7mg/L in stable state compared to 57.6 mg/L during an acute exacerbation; p<O.Ol.

1.5.2.b Spiromeh'Y during exacerbations

Acute fall in lung function parameters, especially FEV ~, have long been clinically

assumed to reflect deterioration in clinical state such as exacerbation, though direct

data proving this in lacking in paediatric bronchiectasis. Fmiher, its use in defining an

exacerbation is limited in paediatric cohorts due to the reasons discussed in section

1.2.2. In COPD, FEV1 declines with an acute exacerbation132•154

-156 and improves with

its treatment. Because in published literature, none of the systemic biomarkers and/or

lung function parameters clearly distinguish an exacerbation from the stable state in

bronchiectasis, it is imperative that a definition of exacerbation be a combination of

clinical and investigational parameters. The usefulness of combining clinical and

investigational parameters has been well established in COPD exacerbations, 146 a

condition much better researched. A standardised definition of pulmonary

exacerbation is clinically impmiant for treatment and as outcome for research studies.

This would improve the quality of individual intervention trials and enhance

comparison of results between studies and meta-analyses. An easy to use definition

with both clinical and objective markers will advance the field of bronchiectasis, a

relatively under-researched area. 103

1.5.3 Pathogenesis of acute pulmonary exacerbation in bronchiectasis

Bronchiectasis is considered a result of inflmmnatory and infectious damage to the

airways. Acceleration of the same inflammatory and infectious process by various

triggers is thought to be the underlying feature of an exacerbation. 140•157 There are

24

multiple factors stepping up this inflammatory cascade, all of which can lead to

further airway destruction and progression of disease, akin to the "Cole's vicious

circle hypothesis" described for the pathogenesis of bronchiectasis itself. Factors that

can trigger these changes are discussed in the section 1.5.4. Inflammatory surges seen

in exacerbation, play a role in clinical deterioration as well as lung function decline,

though this has been well studied and described only in COPD. 157 Sputum purulence,

a surrogate marker of level of airway infection and inflammation, 125.158 increases

during exacerbations and decreases with treatment. 159 Those with less purulent

sputum in the non-acute state have a longer period before their next exacerbation. 159

Several groups have shown an alteration in inflammatory profile after treatment of an

exacerbation, indirectly demonstrating the role of inflammation in the pathogenesis of

an exacerbation. Cominey et al. 139 in 18 adults with bronchiectasis reported that

sputum cell count, IL-8, neutrophil elastase and IL-l 0 all reduced with treatment of an

exacerbation. Ip and colleagues reported increased sputum neutrophil chemotactic

activity and elastolytic activity during an exacerbation of bronchiectasis. 160 Watt and

colleagues161 also showed that concentrations of TNF a, IL-8 and neutrophil elastase

in sputum supernatant were significantly reduced at day 14 of antibiotic therapy

compared with initiation of treatment. The increase in inflammatory mediators during

an exacerbation may result in an increase in bronchial wall thickness, luminal

exudates and expiratory flow limitation; all of which contribute in the clinical

spectrum of exacerbation. This inflanm1atory-clinical severity correlation is best

researched in COPD with no direct evidence available in bronchiectasis. 153•157

25

1.5.4 What precipitates an exacerbation in bronchiectasis?

Triggers of bronchiectasis exacerbations have not been studied. In other clu·onic

respiratory diseases162 (such as asthma,128•163 CF164

•165 and COPD166

'168

) respiratory

tract infections, especially with respiratory viruses, are common precipitants of

exacerbations. However, it is unknown what proportion of bronchiectasis

exacerbations are triggered by an infection and if so, the type of infection. It is also

unknown how often viral infections trigger an exacerbation. Other probable

precipitants of exacerbation include pollution (environmental or

occupational)140•153

•169 tobacco smoke, 170 biomass combustion, 171 poor nutrition and

overcrowding, though none of these have been directly implicated in bronchiectasis

exacerbation. Despite the importance of viral precipitants of exacerbation and huge

health care cost associated with it, there is no published prospective data. Knowing

the prevalence of viral triggers of exacerbation in bronchiectasis would not only be an

important epidemiological exercise as previously well documented in COPD; 166•168 it

could also potentially lead to understanding new patho-physiological mechanisms

relevant for bronchiectasis, as Johnston et a!. has shown for asthma. 163•172 This data

could also help in the judicious use of antibiotics and new anti-viral agents (such as

neuraminidase inhibitors and monoclonal antibodies), as they become increasingly

available. 173 Fmiher, virological data would also help in clarifying the role of vaccines

such as the influenza vaccine in bronchiectasis. 101

Despite the impmiance of infection, other factors may provoke exacerbation. In the

absence of data from children or adults with bronchiectasis, comparison with COPD

is made. In a study of 1016 patients with severe COPD, infection was the proven

cause in only 51% of exacerbations, with heart failure accounting for 26% and no

26

aetiology for the rest. 174 Epidemiological studies have identified more exacerbations

during periods of increased pollution. 175 Increases in black smoke particulate matter,

sulphur dioxide, ozone and nitrogen dioxide are associated with increases in

respiratory symptoms, admissions for exacerbation, and COPD associated

mmtality. 175 Pollutants have been shown to be pro-inflammatory in animal models. 176

Studies in bronchiectasis are required to better characterise the infective and non­

infective triggers of exacerbation.

1.5.5 How does acute pulmonary exacerbation affect the burden of

disease in bronchiectasis?

In addition to the paucity of quantitative studies addressing the burden of disease on

parents of children with bronchiectasis, there are no studies that have looked at acute

changes in these parameters with pulmonary exacerbations. Recurrent exacerbations

(in the preceding year) in adults have been reported to predict poor QOL in stable

bronchiectasis73 though similar paediatric data and data on acute effects of

exacerbation on burden of disease is unavailable. Further, in 15 adults with

bronchiectasis, Comtney et al. repmted a significant improvement in QOL scores

after treatment of pulmonary exacerbations. 139 Similar improvements have also been

repotted with treatment in adolescents with CF. 177 It is therefore intuitive but

conjectural, that QOL and burden of disease may acutely worsen during an

exacerbation. Worsening in clinical symptoms such as dyspnoea and sputum

production are associated with worsening QOL in adults with chronic respiratory

illnesses.45•178 Acute events such as pulmonary exacerbations that aggravate

symptoms are therefore likely to worsen the quality of life, though there is no direct

evidence, specially in paediatric cohorts. Another challenge in assessing the effect of

27

exacerbation on burden of disease is quantifying clinically significant change in the

QOL parameters. 179

1.6 Why is this thesis about bronchiectasis in

children?

Current literature has shown that bronchiectasis is increasingly being recognised as an

important cause of respiratory morbidity in children of developed and developing

countries. The above data summarises some of the current clinical gaps in paediatric

bronchiectasis and highlights some differences between children and adults with

bronchiectasis. This thesis addresses some of the major current gaps in the clinical

knowledge in bronchiectasis pmiicularly in relation to acute pulmonary exacerbations

as discussed in this review (section 1.1 -1.5) tlu·ough the following aims and

hypothesis.

1.6.1 Hypothesis and Aims

The overarching aim of the thesis is to address some of the major current gaps in the

clinical knowledge in paediatric bronchiectasis particularly pertaining to exacerbation.

The major hypothesis of this thesis is that children with bronchiectasis have different

characteristics to adults including pulmonary exacerbations that can be defined by

using a combination of clinical and investigational parameters.

28

Aims

The specific aims of the thesis are:

1. To determine the range of bronchial to accompanying arterial diameter ratio in

children undergoing MDCT chest for non-pulmonary conditions.

2. To examine the burden of disease and psychological influences (anxiety,

depression, stress) in parents of children with bronchiectasis and to assess the

magnitude of changes in these parameters with pulmonary exacerbations.

3. To study the determinants of changes in the lung function and growth

parameters in children with bronchiectasis over a tlu·ee and five year period.

4. To describe the microbiologic and cellular constituents of BAL fluid at the

time of diagnosing bronchiectasis and to evaluate the potential factors

determining the risk of infection by lower respiratory pathogens.

5. To ascertain the clinical and investigational features of pulmonary

exacerbations in bronchiectasis.

6. To formulate a robust, clinically relevant, repeatable and easy to use definition

of pulmonary exacerbation in children with bronchiectasis.

7. To identify and determine the point prevalence of respiratory viruses

(including newly-identified viruses) associated with pulmonary exacerbations

in children with bronchiectasis.

8. To perform systematic reviews using Cochrane methodology to evaluate the

efficacy of inhaled corticosteroids (ICS) in stable state bronchiectasis and in

reducing the severity and frequency of acute respiratory exacerbations and

long term pulmonary decline; and to assess the role of non steroid anti­

inflammatory drugs (NSAIDs) on symptom control and natural history of the

disease in children and adults with bronchiectasis.

29

1. 7 Thesis Design

Studies were performed to address the specific thesis aims and in so doing address

some of the gaps in knowledge previously outlined. In chapter 2, we have challenged

the radiological definition of bronchial dilatation that forms the key to diagnosing

bronchiectasis. This study is an essential step in understanding the differences in

radiological features of bronchiectasis in children from adults through redefining the

paediatric criteria for bronchiectasis.

Chapter 3 describes the burden of illness for parents of children with bronchiectasis is

described and the presence of symptoms of depression, anxiety and stress in the

parents is also evaluated. This is the first study to measure the parent perceived

quality of life in a paediatric cohort of bronchiectasis and report how pulmonary

exacerbations affect the burden of disease.

Chapter 4 evaluates the effect of disease on the growth and lung function parameters

of children with bronchiectasis and the factors that determine the change in these

parameters over the 3 to 5 year follow-up period. Since both anthropometric and lung

function parameters could be used as outcome variables of chronic disease in

paediatric cohorts, this study significantly adds to the knowledge on long term

morbidity of bronchiectasis in children, specially after treatment is instituted.

Chapter 5 describes the role of lower airway infection and inflammation in early

bronchiectasis by a retrospective analysis of BAL fluid in children with

bronchiectasis. It also studies the factors that may predict infection of the airway with

lower respiratory pathogens.

30

Chapter 6 forms the pilot study to determine the clinical features associated with a

pulmonary exacerbation in a retrospective cohott of children with bronchiectasis. The

data obtained from this study formed the basis of designing the prospective study to

define an exacerbation in bronchiectasis, described in chapter 7.

Chapter 7 evaluates the various clinical, investigational and statistical steps

undertaken to formulate a robust, clinically relevant, repeatable and easy to use

definition of pulmonary exacerbation in children with bronchiectasis.

As part of the same prospective cohort which was followed up for over two years, we

also looked at the respiratory viruses associated with a pulmonary exacerbation of

bronchiectasis, the details of which constitute chapter 8. This is the first study to

report role of viruses in triggering a pulmonary exacerbation in bronchiectasis.

One of the major clinical gaps on long term management of bronchiectasis and

associated pulmonary exacerbations is the lack of randomised controlled trials (RCT)

on role of preventer therapy. We therefore performed two Cochrane reviews of

currently available RCT's, the first addressing the role ICS in bronchiectasis and the

second measuring the effect of NSAID in bronchiectasis. Both these Cochrane

reviews constitute chapter 9.

The final chapter (chapter I 0) summarises and discusses the thesis findings, relates it

to other current work and discusses future research directions.

31

1.8 Summary of Chapter 1

Bronchiectasis is a well recognised, important and yet under-researched chronic

respiratory illness that results in physical and psychological morbidity in children. It

affects children in both affluent and developing countries. A review on the differences

between these settings have been sunnnarised in the paper180 that follows this chapter

as chapter lB.

This thesis addresses some of the maJor clinical gaps in our knowledge and

understanding of bronchiectasis in children. Addressing these gaps will potentially

lead to improving the clinical management of children with bronchiectasis.

Specifically, the studies in this thesis explore and highlight the differences between

children and adults with respect to radiologic evaluation, airway microbiology and

cellularity, lung function data over 5 years and exacerbation data.

32

Differences and similarities • 111 non-

cystic fibrosis bronchiectasis between

developing and affluent countries

33

Bronchoarterial ratio on High

Resolution CT scan of the chest in

children without pulmonary pathology­

Need to redefine bronchial dilatation

40

2.2 Summary of Chapter 2

In this chapter we have challenged the current radiological definition of bronchial

dilatation in children since adult criteria are still being extrapolated into paediatric

clinical practice. Since bronchial dilatation is the hallmark of bronchiectasis, our

study also reviewed the radiological definition of bronchiectasis in children.

We prospectively identified 41 children who were undergoing MDCT of the chest for

non-pulmonary conditions, most commonly as part of oncological work-up. We

calculated the mean BA ratio for each child and rep01ted our paediatric nonnative

data. We concluded that the BA ratio in children is significantly lower than 1 [Mean

(SD) 0.626 (0.068)], the cut-off usually taken to define bronchial dilatation in adults.

This ratio in children was also significantly lower than similar normative data

available from adults. We did not find any correlation with age in our coh01t. Our

study has highlighted the need to re-define the criteria for bronchial dilatation in

children.

50

3

The burden of disease in paediatric non­

cystic fibrosis bronchiectasis

51

3.4 Summary of Chapter 3

In this chapter we reported the burden of disease in a cohmt of 69 children with

bronchiectasis followed prospectively over 900 child-months. Burden was measured

by parent-proxy cough-specific QOL (PC-QOL) and Depression, Anxiety and Stress

scale (DASS) in stable and exacerbation states. We ascetiained that there was a

significant burden of disease, especially during exacerbation, on parents of children

with bronchiectasis. We reported that factors such as radiological extent, lung

fi.mction and underlying etiology did not affect the burden.

88

4

Longitudinal growth and lung function

in paediatric non-CF bronchiectasis -

what influences lung function stability?

89

4.3 Summary of Chapter 4

At the time of commencement of studies for this thesis, the longitudinal lung function data in

children with bronchiectasis were unavailable. It was also unclear if lung function parameters in

this group continue to decline as had been rep01ted in CF coh01ts. Moreover there was no

published data on effect of disease on anthropometric parameters. In this chapter we described

the lung function and antln·opometric parameters in 52 children with bronchiectasis over a 3 year

period and over 5 years in 25 children. We concluded that lung function and anthropometric

parameters are stable in this group over 3-5 years once appropriate treatment is initiated. We also

established that severe exacerbations are associated with accelerated lung function decline.

105

5

Lower airway microbiology and cellularity in

children with newly diagnosed non-CF

bronchiectasis

106

5.2 Summary of Chapter 5

It is well known that infection and inflammation form key elements in the pathogenesis and

progression of bronchiectasis though data is very limited in paediatric population. In this chapter

we described the lower airway microbiology and cellularity at diagnosis of bronchiectasis in a

retrospective review of BAL fluid in I 13 children. We found that 68% children had infection

with respiratory bacterial pathogens at diagnosis with Haemophilus irifluenzae being the most

common pathogen. Respiratory viruses were identified in 12% children. Pseudomonas

aeruginosa was rare while mycobacterial and fungal infection were absent. Children also had

marked airway neutrophilia, especially with higher bacterial loads.

115

6

Exacerbations • In non cystic fibrosis

bronchiectasis: Clinical features and

investigations

I I 6

6.2 Summary of Chapter 6

In this chapter we described the clinical features of 115 paediatric pnhnonologist

defined exacerbations in a retrospective cohort of 3 0 children with bronchiectasis. We

also studied the factors that predict failure of treatment with oral antibiotics. In the

absence of available data, this study was done as a "pilot" project to gather

information for designing our larger prospective cohort study on defining an

exacerbation in bronchiectasis (described in chapter 7). We reported that increase in

frequency of cough and a change in its character were the most common symptoms

associated with an exacerbation. Nearly a third of the exacerbations failed to resolve

with oral antibiotics and required hospital admission. Those on prophylactic

antibiotics were more likely to fail oral antibiotic therapy for acute exacerbation.

124

Defining Pulmonary Exacerbation in

Children with Non-Cystic Fibrosis

Bronchiectasis

125

7.3 Summary of Chapter 7

The lack of a validated definition of pulmonary exacerbation in paediatric

bronchiectasis is a limitation for clinical practice and research. This chapter described

the process of prospectively formulating a robust, clinically relevant, repeatable and

easy to use definition of pulmonary exacerbation in children with bronchiectasis. In

69 children with bronchiectasis who were followed for 6-30 months; changes in

clinical, systemic and lung function parameters from 81 exacerbations were

statistically evaluated using conditional logistic regression, receiver operating

characteristic (ROC), sensitivity, specificity and positive (PPV) and negative

predictive values (NPV) to formulate a definition of a pulmonary exacerbation.

The results presented in this chapter have described three options for definition of an

exacerbation useful for different clinical (primary vs. te1iiary care) and research

settings. These tlu·ee options were fanned by combination of major (wet cough and

cough severity), minor clinical (sputum colour, chest pain, dyspnoea, haemoptysis and

chest signs) and investigatory (serum C-reactive protein, amyloid-A and IL-6)

criterion. Our final combined model consisted of one major with one investigatory

criterion (PPV 91%, NPV 72%); two major criteria (PPV 79%, NPV 91%); or one

major and two minor criteria (PPV 79%, NPV 94%).

143

8

Role of Respiratory Viruses • Ill

Exacerbations of Non-Cystic Fibrosis

Bronchiectasis in Children

144

8.3 Summary of Chapter 8

In this chapter, we described prospectively the role of respiratory viruses (including

newly-identified viruses) in pulmonary exacerbations in 69 children with

bronchiectasis followed for 900 child-months. We rep01ted that respiratory viruses

were detected on nasopharyngeal aspirate during 48% of the exacerbations, with

human rhinovirus-A being the most common virus detected. We also reported that

virus-positive exacerbations were more likely to require hospitalisation and have

fever, hypoxia, chest signs and raised C-reactive protein when compared with vims­

negative exacerbations.

181

9

Role of preventer anti-inflammatory

therapy in bronchiectasis

182

9.3 Cochrane review update

An update of the Cochrane review contained within chapter 9.1 has been completed.

The review was updated with searches until October 2010. No new studies were

eligible for inclusion and there were no changes made to the authors' conclusions.

An update of the Cochrane review contained within chapter 9.2 has been completed.

The review was updated with searches until January 2010. No new studies were

eligible and there were no changes made to the authors' conclusions.

9.4 Summary of Chapter 9

At the time of c01runencement of studies for tltis thesis, many Cochrane reviews on

possible interventions were available. However the role of preventer therapy (ICS and

NSAID's) in bronchiectasis especially on exacerbation frequency was unclear. As the

major aim of our thesis was to fill clhtical knowledge gaps specially pertaining to

exacerbation, the available evidence from management perspective was evaluated and

systematically reviewed. As Cochrane methodology is cunently the most accepted

method of performing systematic reviews, this method was chosen to review the

evidence. In section 9.1, we evaluated the efficacy ofiCS in children and adults with

bronchiectasis during stable bronchiectasis; and for reducing the severity and

frequency of acute respiratory exacerbations and long term pulmonary decline. As

asthma-like symptoms are common in people with bronchiectasis, the routine use of

inhaled cmiicosteroids was considered as potentially beneficial in reducing

exacerbations, symptoms and pulmonary decline. The review found that there was

insufficient evidence for the routine use of ICS in people with bronchiectasis. While

res may be beneficial in a subgroup of people with bronchiectasis, its use had to be

234

balanced with adverse effects that include a potential increase in commensal bacterial

density in the sputum. This review was completely rewritten, reanalysed with new

conclusions added, from a previous review by Ram and colleagues181 that had

included only two trials on a total of 54 patients.

In section 9 .2, we assessed the role of NSA!Ds on symptom control and natural

history of the disease in children and adults with bronchiectasis. No randomised

controlled trials that assessed the use of oral NSAIDs in bronchiectasis were found.

Thus the routine use ofNSAIDs in bronchiectasis could not be recommended.

235

10

Conclusion

10.1 Discussion

Bronchiectasis is recognised as an important cause of chronic respiratory morbidity in

developing countries15"21 and in Indigenous people of affluent countries?3

•24 Over the

last decade, it is also increasingly diagnosed and recognised as an important cause of

respiratory illness in the non-Indigenous populations of affluent countries. 8•25

•26

•28 In

undmiaking the studies for this thesis, the major gaps in the knowledge about

bronchiectasis, especially pertaining to pulmonary exacerbations, were glaring.

Adult-based radiological criteria have been used to define and detect bronchiectasis in

children although they had never been critically evaluated. Bronchiectasis was

considered a disease of umelenting deterioration in lung function akin to CF lung

236

disease with role of early intervention unclear in overall outcome. There was no

standardised definition of exacerbation in children or adults leading to inconsistent

outcomes both clinically and in research. Futiher, there was no data available on the

clinical features, investigational outcomes, burden of disease and precipitants of an

exacerbation.

The work presented in this thesis has shown that, in the paediatric population, the

criteria to define bronchial dilatation and therefore bronchiectasis should not be the

same as used in adults. It has described the significant disease burden for parents of

children with bronchiectasis that is increased during a pulmonary exacerbation. It has

also highlighted that growth and lung function can be stabilised in this cohort once

appropriate therapy is instituted. Further, the formulation of a standardised,

statistically robust, clinically useful and easy to use definition of an acute pulmonary

exacerbation in paediatric bronchiectasis, is a significant advancement in paediatric

respiratory research knowledge. The studies within this thesis have further described

the infectious precipitants of exacerbations and its effect on lung functions and burden

of disease.

The key to improve outcomes in many clu·onic respiratory and non-respiratory

conditions is early diagnosis and management. This need for early diagnosis forms the

basis of the concept of disease screening, and the model of secondary and tet1iary

prevention. Early diagnosis has not only improved outcomes in many oncological and

neonatal metabolic diseases; it has also been reported to reduce pulmonary morbidity

in CF, 121 COPD122 and PCD. 123 Radiological features of bronchiectasis might improve

and even resolve once properly managed.9•182 Similarly, as discussed in chapter 4,

237

establislmtent of appropriate therapy has been shown to stabilise lung function in

children with bronchiectasis. For these reasons it is impmiant that the diagnosis of

bronchiectasis is made early and then managed appropriately to preserve the potential

of disease reversibility. It is in this context that chapter 2 of our thesis becomes

relevant. A children-specific radiological definition of bronchiectasis is impmiant in

detecting early bronchiectasis changes in children, where changes may be subtle and

often missed if adult-based criteria are used. Our new cut-off to define bronchial

dilatation, as discussed in chapter 2, helps in improving the sensitivity of HRCT for

detecting bronchiectasis, since children are likely to have less severe bronchiectasis

compared to adults. This will in turn help in early diagnosis and management,

especially in those with clinical features of clu·onic pulmonary suppuration.

The need for early detection becomes even more pet1inent in light of our findings that

even at the time of initial diagnosis; the majority of children with bronchiectasis had

infection with respiratory pathogens and significant airway neutrophilia, as discussed

in chapter 5. Early treatment of tltis infection and inflammation with appropriate

antibiotics and anti-inflanunatory agents may be a key to prevent disease progression

in this group. In this study we also demonstrated that Pseudomonas aeruginosa,

fungal agents and NTM are not impmiant pathogens in paediatric bronchiectasis, a

significant difference from adult bronchiectasis data. Whereas empirical antimicrobial

treatment in adults with bronchiectasis constitutes anti-Pseudomonal therapy, that the

suggestion of the use of empirical antibiotic therapy in paediatric bronchiectasis to

cover H injluenzae, S. pneumoniae and M catarrhalis is confirmed. 101

238

It is well accepted that quality of life assessment is an impot1ant component of any

medical review. 68 The family of the child may also face considerable burden due to

the chronic illness/0•75 causing stress, anxiety and depression. 76 Thus chapter 3

explored this important area and showed that there is a significant burden of illness,

especially during pulmonary exacerbation, on parents of children with bronchiectasis.

These findings suggest that management of bronchiectasis, especially during

pulmonary exacerbation, could be substantially improved. Appropriate counselling to

understand the burden of individual parents and alleviate it, where possible, would

significantly improve care for this patient group. General medical literature, available

both to paediatricians and general practioners, needs to explain the features of

pulmonary exacerbation, so that doctors are cognizant to the psychologically

vulnerable period in this group.

In keeping with our broad hypothesis of formulating a standardised definition of

pulmonary exacerbation in children with bronchiectasis using clinical and

investigational parameters, we have found that exacerbation could be defined by using

a combination of clinical features with additional systemic markers improving

predictive values. Our final combined model consisted of three options suitable for

different settings ranging from tettiary clinical, conununity and research based

settings. Presence of a "wet" cough and a significant frequency of cough (defined by

median cough score :=:: 2)183 were major criteria each having high sensitivity and

specificity in defining an exacerbation. We conclude that a child with bronchiectasis

with a frequent wet cough is likely to be in exacerbation. This is especially important

since many doctors (including general paediatricians) tend to ignore an ongoing wet

cough in children with bronchiectasis thus delaying antibiotic therapy in the absence

239

of fever or chest signs. This finding also indicates that even though bronchiectasis in

adults is considered to be a disease of chronic cough and purulent sputum production,

children with bronchiectasis may be minimally symptomatic or even asymptomatic

for prolonged periods once stabilised on appropriate ongoing management. What

constitutes appropriate management is still debatable, but many of these exacerbations

do require intravenous antibiotics when oral antibiotics fail, as discussed in chapter 6.

Systemic and aHway inflammation are important features of bronchiectasis in

adults184 and lead to considerable co-morbidity associated with the condition. In the

perfect model, airway inflammation by direct sampling should be measured with

every exacerbation. This is impractical (as young children often do not expectorate

sputum), costly and invasive in the paediatric population as bronchoscopy under

anaesthesia is usually required. Systemic sunogates of airway inflammation may act

as "biomarkers" of disease severity and might help in differentiating stable from

exacerbation state. This has been well researched in COPD134•144

"147 though data fi"om

bronchiectasis is limited. The limitation of such a surrogate is that inflammation and

infection in bronchiectasis is predominantly endobronchial, and the systemic "spill­

over" may only occur in severe lung disease or during an exacerbation. We report that

serum CRP, amyloid A and IL6 improve the ability to detect an exacerbation by

improving the specificity though none were in itself robust enough to predict an

exacerbation, since none had individual area under the curve (AUC) of ROC > 0.8,

considered as an acceptable standard. 185 So, we cmmot label any of these systemic

markers as "biomarkers" of exacerbation in bronchiectasis. Their role remains

important though in conjunction with the clinical features mentioned above,

especially in research and tetiiary clinical practice, where outcome arguably should be

240

more specific and their addition may improve the predictive value in defining an

exacerbation. This would possibly reduce over diagnosis (and thus over-treatment

including in-patient hospital stay), as well as facilitate standardised outcomes for

clinical studies and trials.

The role of exacerbation in the short tenn and long term morbidity in children with

bronchiectasis was also discussed in chapters 3, 4, 6 and 8. Chapter 4 described that

with each exacerbation requiring hospital admission, the FEV 1 fell by 1.6%, thereby

making exacerbation the only factor that was associated with lung function decline in

our group. These figures are comparable to CF studies that have also reported lung

function decline with exacerbations. 186 Also in Chapter 3 it is rep01ied that

pulmonary exacerbations are associated with significant worsening in burden of

disease on parents (parental depression, anxiety and stress scores) with in the cohort;

38-50% had scores reflecting abnormal depression, anxiety and stress during an

exacerbation. This further highlights the need for prevention, early detection and

aggressive management of pulmonary exacerbation, research on which to date has

been limited. The use of the derived definition of exacerbation in interventional trials

would improve consistency of outcomes and would make the studies more

comparable and results more applicable to a larger population.

Data from chronic respiratory conditions such as asthma, CF and COPD and clinical

experience in children with bronchiectasis have suggested that respiratory tract

infections, especially with respiratory viruses, are common precipitants of an

exacerbation. Yet at the time of thesis design, triggers (infectious or non-infectious) of

bronchiectasis exacerbation had not been studied. In our retrospective analysis of

241

exacerbations described in chapter 6, 21% of upper airway samples were positive for

respiratory viruses. From the described prospective cohmi followed over 900 child

months, it is concluded that nearly half of respiratory exacerbations were associated

with detection of respiratory viruses in the nasopharyngeal aspirates, with human

rhinovirus being the most common virus detected. Systemic features such as fever

and chest signs were uncommon in virus-negative exacerbations. These findings

suggest that withholding antibiotic therapy during exacerbation in the absence of

systemic features such as fever, a practice still followed by many general practioners

and paediatricians, is likely unjustified and deprives the child of benefit from

antibiotic therapy. Using antibiotics for all the exacerbations on the other hand, may

lead to overuse of antibiotics. The role of antibiotics in virus-positive exacerbation in

unknown, especially when concunent bacterial data were not obtained in the study.

There is limited data on the role of long term preventer therapy in reducing

exacerbation rate in bronchiectasis in children. Adult data suggests that long term

antibiotic therapy is usually beneficial in reducing the rate of exacerbation. 187 Murray

and colleagues in a recent RCT repotied significant reduction in rate of exacerbation

in 65 adults treated with nebnlised gentamycin over 12 months compared to

placebo.44 Similar benefit has also been reported with use of azithromycin. 137•188 The

evidence 011 role of ICS in prevention of exacerbation was reviewed using Cochrane

methodology in chapter 9. It was concluded that there was no difference in the

exacerbation frequency during short term (< 6 months) or long term use of ICS,

though there was only one study included in each of these groups. The role of oral

NSAID in exacerbation prevention was also presented and found no relevant trials

that had systematically addressed this issue.

242

10.2 Limitations of the thesis

The limitations of this thesis are stated within each chapter and primarily pertain to

the methodology, especially regarding the retrospective nature of some components of

the thesis. The data for the longitudinal lung function study (chapter 4), lower airway

microbiology study (chapter 5) and clinical features of exacerbation study (chapter 6)

were retrospectively collected. For formulating a definition of exacerbation (chapter

7) and studying its viral triggers and effect of exacerbation on burden of disease, we

chose the paediatric-pulmonologist defined exacerbations, where children required

additional treatment, as the gold standard. This is consistent with other studies

defining pulmonary exacerbations as 'use of rescue medications' ( cmticosteroids for

asthma127 and antibiotics for COPD.) 189 The paucity of data in this area precluded any

better reference standard. Nevertheless, in an ideal world, the definition should be

subjected to a RCT whereby use of the definition improves clinical outcomes.

Moreover, we have only partially validated the derived definitions. The validity of our

derivations of exacerbations is suppotted by objective data and high repeatability of

the factors (Kappa >0.75). Post treatment data further supports the validity and

robustness of our definition. However the use of these definitions should be ideally

futther validated by a different group in a different centre.

Some aspects of the thesis results may have been strengthened by increased patient

numbers. This is pmticularly evident in sub-group analysis of the exacerbation

definition in children with baseline wet cough (chapter 7) and 5 year follow up data in

the longitudinal lung fimction study (chapter 5). The findings in chapter 8 would have

been strengthened if viral data during stable clinical state or recovery phase were

available. Johnston et a!. detected a virus (by PCR) among 12% of children with

243

asthma during stable state. 163 In the absence of stable state data from our cohort,

causality of viral agents in inducing an exacerbation camwt be concluded. Also, we

did not have bacterial data to study if some or all of the effect could be explained by

bacterial co-infection.

Finally, the Cochrane review of role of NSAID in bronchiectasis did not have any

studies available. Further, in the Cocln·ane on res in bronchiectasis, no paediatric data

was available. The data on effect of res on exacerbation fi'equency was limited to

only one study each in shmt term and long term effects. Fmther, data extraction was

limited to only one to 4 studies for the outcomes examined. The small sample size

(max 101) for the meta-analysis was also a significant limitation. The maJor

contributor to the benefit ofiCS was from a non-placebo controlled study.

10.3 Conclusion

This thesis has proposed new criteria to define radiological bronchiectasis in children

that would assist earlier diagnosis of bronchiectasis. This is based on the lower BA

ratio in children, confirming that children differ from adults. The studies have fmther

suggested that once appropriate therapy is initiated, the lung function and growth in

children could be stabilised. The role of infection and inflammation early in disease

progression, as proposed by Cole it his vicious cycle hypothesis, 6 has been supported

by this thesis. In addition, the findings within the thesis have highlighted the major

differences in the microbiological flora between children and adults. It has also been

successful in formulating a clinically relevant and easy to use definition of

exacerbation in children with bronchiectasis. It has described that "wet" character of

cough and significant frequency of cough are the strongest predictors of exacerbation

in children with bronchiectasis, with systemic biomarkers such as SAA, IL6 and CRP

244

improving overall diagnosis. It has clearly highlighted the impotiance of

exacerbations not only in worsening lung functions and clinical state, but also in

increasing the burden of disease. Further, it has shown a clear association between

pulmonary exacerbation and respiratory viruses in bronchiectasis and in the process

described several newly-identified viruses such as Human parainfluenza-virus 4

(HPIV-4), Human coronaviruses (HCoV) and Human bocavirus (HBoV) not

previously reported in bronchiectasis. This thesis has also reviewed the available

literature and shown that additional evidence is needed to clarify the role of ICS and

NSAID's in bronchiectasis, especially in children.

10.4 Future pl'Ojects and Further Research Work

Fmiher work on bronchiectasis, particularly the identification, underlying

mechanisms and management of exacerbations in bronchiectasis is clearly needed.

Further studies could also be planned based on the new radiological definition of

bronchiectasis proposed in this thesis. Suggested work could include:

(I) Further validation of the various definitions of exacerbation

The definition of acute pulmonary exacerbation suggested in this thesis is only

partially validated. This definition needs to be prospectively validated in a new cohort

of children with bronchiectasis, preferably in a different centre. The definition also

needs to be validated in an older cohort of children with bronchiectasis where

symptom might be more severe and major criteria of "wet cough" may have to be

replaced with "increase in wet cough". Once the definition is validated, it can then be

used to answer the following questions:

a) What is the epidemiology and prevalence of exacerbation in bronchiectasis?

245

b) What is the duration of antibiotic therapy required for treatment of exacerbation?

c) What are the factors that define treatment response or failure?

d) What are the factors that precipitate an exacerbation in bronchiectasis?

e) What is the difference in time to next exacerbation between children treated with

oral vs. intravenous antibiotics?

f) What are the short term and long term effect of exacerbations on the radiological

and lung function parameters?

g) Could this definition (or a modification of it) be validated in CF cohorts?

(II) Role of respiratory viruses in precipitating exacerbation in bronchiectasis

Though our prospective study did explore the association of respiratory viruses with

exacerbations in bronchiectasis, the lack of viral data during stable clinical state was a

limitation. Time sequenced cohort studies during stable state, exacerbations and

recovery periods are needed to detetmine the role of viral infections and their

interaction with bacteria. This prospective study should also collect bacterial data to

explore the virus-bacterial interaction in precipitating an exacerbation in

bronchiectasis.

(III) Prospective follow-up lung fimction study in bronchiectasis

A well designed prospective follow-up study is required to define the long term effect

of modern treatment regimens on lung fimction in children with bronchiectasis. This

prospective study would also explore factors affecting the lung function over a

relatively long follow-up period. These factors could include frequency of

exacerbations, lower airway microbiology, use of prophylactic antibiotics etc.

246

QV) Novel and non-invasive biomarkers of exacerbation in bronchiectasis

In this thesis we have explored many novel systemic biomarkers to define an

exacerbation such as PCT, SAA, IL6 and fibrinogen, though none were in itself robust

enough to define an exacerbation. Moreover measuring serum bio-markers requires a

venipuncture, which may be considered a semi-invasive process, especially in

children. Non-invasive markers of disease severity and clinical state such as exhaled

matrix metalloproteinase (MMP)190•191 and nitric oxide192 should be explored in future

studies to define an exacerbation and grade its severity, specially in co!1iunction with

our definition of exacerbation.

(V) Defining child-specific QOL instrument in bronchiectasis

The burden of illness in childhood bronchiectasis was described within this thesis and

the effect of exacerbation uncovered. We used the parent-proxy cough-specific QOL

(PC-QOL) questionnaire to ascertain the burden of disease in our coh01i. Though

cough specific QOL questionnaire such as the Leicester Cough Questi01maire have

been validated in adults with bronchiectasis/4 no bronchiectasis specific QOL tool is

available in children. In adults, the StGeorge's Respiratory Questionnaire (SGRQ) is

often used73 but a similar child specific QOL tool for future paediatric research,

particularly interventional studies, would be of significant value.

(VI) RCT' s on role of inhaled hyperosmolar agents in prevention and management of

pulmonary exacerbations

Therapies shown to be effective in cystic fibrosis are often provided to patients with

bronchiectasis, without definitive evidence of benefit. Hypertonic saline inhalation is

known to accelerate tracheobronchial clearance in many conditions, probably by

247

inducing a liquid flux into the airway surface, which alters mucus rheology in a way

favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar

effect193 though role of these agents in prevention and acute management of

exacerbations in bronchiectasis have never been explored. This is impotiant

especially since these agents have minimal adverse effects, are easily available and

are relatively inexpensive.

10.5 Summary

In this final chapter the overall findings of the thesis are presented, conclusions drawn

and recommendations for future research outlined. Overall the work of this thesis has

shown that the radiological definition of bronchiectasis in children are not the same as

adults and a standardised definition of pulmonary exacerbation in children could be

formulated using a combination of clinical and systemic biomarkers. The thesis

results provide indisputable snpport to our hypothesis that paediatric bronchiectasis is

different to that described in adults, in tetms of clinical and investigational features.

The new definition of radiological bronchiectasis and pulmonary exacerbation

proposed in this thesis has brought attention to a condition which has long been

ignored, and would certainly standardise many future research studies and clinical

protocols. Continuing research aimed at utilizing the definition of exacerbation to

formulate "Best Management Practice Guidelines" for paediatric bronchiectasis is

essential in improving our understanding of this impotiant cause of chronic

respiratory morbidity.

248

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