Lower Respiratory Tract Infection in Adults

377 Pages·2017·3.8 MB·English

by  Collins, Andrea

Lower Respiratory Tract Infection in Adults -
Carriage as a Diagnostic, Home-based Care
and Vaccine Development

Thesis submitted in accordance with the
requirements of the University of Liverpool
for the degree of Doctor in Philosophy (PhD)

by
Dr Andrea M. Collins
MBChB, MRCP, Resp. SCE

November 2016

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Declaration .............................................................................................................................. viii
Acknowledgements ................................................................................................................... ix
Publications and Awards ........................................................................................................... xi
Publications arising from work within thesis ........................................................................ xi
Publications submitted or in preparation from work in thesis ............................................ xii
Publications arising during the course of the PhD ............................................................... xii
Awards .................................................................................................................................. xv
List of Figures .......................................................................................................................... xvi
List of Tables .......................................................................................................................... xvii
Glossary of Terms ..................................................................................................................xviii
Abstract ................................................................................................................................ xxviii
CHAPTER 1: Introduction ........................................................................................................... 1
1.1 Burden of Pneumonia and Lower Respiratory Tract Infection (LRTI) .............................. 1
1.2 Current Priorities in Pneumonia and LRTI ........................................................................ 3
1.2.1 Diagnostics for Pneumonia and LRTI ......................................................................... 4
1.2.1.1 Definitions - What are Pneumonia and LRTI? ..................................................... 4
1.2.1.1.1 Pneumonia ....................................................................................................... 4
1.2.1.1.2 LRTI ................................................................................................................... 6
1.2.1.2 Diagnostic Difficulties ......................................................................................... 7
1.2.1.3 Pneumococcal Pneumonia ................................................................................. 8
1.2.1.4 Microbiological Diagnosis of Pneumococcal Pneumonia ................................. 10
1.2.1.4.1 Overview ........................................................................................................ 10
1.2.1.4.2 Quantitative Polymerase Chain Reaction (qPCR) .......................................... 11
1.2.1.4 Pneumococcal Carriage .................................................................................... 14
1.2.1.4.1 Carriage in Health .......................................................................................... 14
1.2.1.4.2 Pneumococcal Carriage and Respiratory Infection ....................................... 17
1.2.1.4.3 Pneumococcal Carriage and Host Immunity ................................................. 18
1.2.2 Therapeutics ............................................................................................................ 19
1.2.2.1 Risk Stratification .............................................................................................. 19
1.2.2.2 Therapeutics ..................................................................................................... 24
1.2.2.2.1 Hospital at Home in General .......................................................................... 24
1.2.2.2.2 Hospital at Home for LRTI/ Pneumonia ......................................................... 26
1.2.3 Prevention ............................................................................................................... 30
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1.2.3.1 Current Pneumococcal Vaccines ...................................................................... 30
1.2.3.2 Polysaccharide Pneumococcal Vaccine ............................................................ 30
1.2.3.3 Pneumococcal Conjugate Vaccine .................................................................... 33
1.2.3.4 The CAPITA Study .............................................................................................. 39
1.2.3.5 Novel Pneumococcal Vaccines and Vaccine Testing Platforms ........................ 41
1.2.3.6 Experimental Human Pneumococcal Carriage/Colonisation (EHPC) Studies ... 45
1.2.3.6.1 The Usefulness of the EHPC Model in Novel Vaccine Testing ....................... 46
1.2.3.6.2 The Ethics of the EHPC Model ....................................................................... 46
1.3 Summary and Study Plans .............................................................................................. 47
CHAPTER 2: Methods ............................................................................................................... 50
2.1 Overview ........................................................................................................................ 50
2.2 Research Development and Innovation Department (RD&I) ........................................ 54
2.3 Ethics: Integrated Research Application System (IRAS) and Research and Ethics
Committee (REC) .................................................................................................................. 54
2.4 Medicines and Healthcare Products Regulatory Authority (MHRA) .............................. 60
2.4.1 Specific Issues Related to a CTIMP study ................................................................ 62
2.4.1.1 Women of Child-Bearing Potential (WOCBP) ................................................... 62
2.4.1.2 Over-volunteering ............................................................................................. 62
2.5 Other Approvals ............................................................................................................. 63
2.6 Sponsorship .................................................................................................................... 67
2.6.1 Overview .................................................................................................................. 67
2.6.2 Trial Steering Committees (TSCs) and Data Management (and Safety) Committees
(DM[S]Cs) .......................................................................................................................... 68
2.6.2.1 Adverse Events and Reporting .......................................................................... 74
2.6.3 Summary of Product Characteristics (SmPC) ............. Error! Bookmark not defined.
2.6.4 Annual Progress Reports (APR) .................................. Error! Bookmark not defined.
2.6.5 Data ............................................................................. Error! Bookmark not defined.
2.6.6 Safety Reporting ......................................................... Error! Bookmark not defined.
2.6.7 Study Closure .............................................................. Error! Bookmark not defined.
2.6.8 Roles and Responsibilities ....................................................................................... 77
2.7 Patient and Public Involvement (PPI) ............................................................................. 77
2.8 Recruitment and Advertising ......................................................................................... 78
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CHAPTER 3: Pneumococcal Carriage as a Diagnostic in Adults – Lower Respiratory Tract
Infection and Nasal Wash (LRTI NW) Study. ............................................................................ 80
3.1 INTRODUCTION .............................................................................................................. 80
3.2 METHODS ....................................................................................................................... 81
3.2.1 Screening and Recruitment ..................................................................................... 81
3.2.2 Sampling .................................................................................................................. 85
3.2.3 DNA Extraction and qPCR ........................................................................................ 85
3.2.4 Binax ........................................................................................................................ 85
3.2.5 Statistical Analysis Plan ............................................................................................ 86
3.3 RESULTS .......................................................................................................................... 86
3.3.1 Screening and Recruitment ..................................................................................... 86
3.3.2 Sampling: Rate of Colonisation................................................................................ 88
3.3.3 Sampling: Density of Colonisation by qPCR ............................................................. 91
3.3.4 Clinical Data ............................................................................................................. 91
3.4 DISCUSSION .................................................................................................................... 91
3.5 ACKNOWLEDGMENTS .................................................................................................... 96
CHAPTER 4: Audits to Assess the Causes of Increased Hospital Length of Stay and the
Feasibility of Early Supported Discharge in Adults with Pneumonia. ...................................... 99
4.1 INTRODUCTION .............................................................................................................. 99
4.2 METHODS AND RESULTS .............................................................................................. 101
1.2.1 Part 1 - Methods .................................................................................................... 101
1.2.2 Part 1 – Results ...................................................................................................... 101
1.2.3 Part 2 - Methods .................................................................................................... 103
1.2.4 Part 2 - Results ....................................................................................................... 111
4.3 DISCUSSION .................................................................................................................. 114
4.4 ACKNOWLEDGMENTS .................................................................................................. 117
CHAPTER 5: Home-based Care - HOME FIRST Feasibility Study for Early Supported Discharge
in Adults with Respiratory Infection. ..................................................................................... 118
5.1 INTRODUCTION ............................................................................................................ 118
5.2 METHODS ..................................................................................................................... 120
5.2.1 Overview ................................................................................................................ 120
5.2.2 Safety ..................................................................................................................... 122
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5.2.2.1 Patient Safety .................................................................................................. 122
5.2.2.2 Staff Safety ...................................................................................................... 123
5.2.3 Sites ........................................................................................................................ 123
5.2.4 Screening, Recruitment, Randomisation and Intervention ................................... 124
5.2.4.1 Screening ......................................................................................................... 124
5.2.4.2 Inclusion and Exclusion Criteria ...................................................................... 124
5.2.4.3 Repeat Reviews ............................................................................................... 131
5.2.4.4 Randomisation ................................................................................................ 131
5.2.4.5 Recruitment .................................................................................................... 131
5.2.4.6 Study Intervention – HOME FIRST .................................................................. 132
5.2.4.6.1 Initial and Subsequent Follow-up with HOMEFIRST .................................... 133
5.2.4.6.2 Discharge from HOME FIRST ........................................................................ 134
5.2.4.6.3 Readmission to Hospital from HOME FIRST ................................................ 134
5.2.4.7 Standard Hospital Care (SHC) Arm .................................................................. 135
5.2.4.8 Follow-up ........................................................................................................ 135
5.2.5 Outcome Measures ............................................................................................... 136
5.2.5.1 Primary ............................................................................................................ 136
5.2.5.2 Secondary........................................................................................................ 136
5.2.6 Sample Size and Statistical Methods ..................................................................... 137
5.3 RESULTS ........................................................................................................................ 137
5.4 DISCUSSION .................................................................................................................. 144
5.5 ACKNOWLEDGEMENTS ................................................................................................ 150
CHAPTER 6: Home-based Care - Home First Pilot: A Study of Early Supported Discharge in
Patients with Lower Respiratory Tract Infections. ................................................................ 151
6.1 INTRODUCTION ............................................................................................................ 151
6.2 METHODS ..................................................................................................................... 152
6.2.1 Overview ................................................................................................................ 152
6.2.2 Manual of Procedures (MOP) ................................................................................ 153
6.2.3 Ethical Principles .................................................................................................... 153
6.2.4 Safety and Adverse Event Reporting ..................................................................... 154
6.2.5 Organisation and Governance ............................................................................... 154
6.2.5.1 Timescale ........................................................................................................ 154
6.2.5.2 Population ....................................................................................................... 154
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6.2.5.3 Study Site ........................................................................................................ 154
6.2.5.4 Sponsor ........................................................................................................... 154
6.2.5.5 Funding ........................................................................................................... 155
6.2.5.6 REC .................................................................................................................. 155
6.2.6 Screening, Recruitment and Randomisation ......................................................... 155
6.2.6.1 Screening ......................................................................................................... 156
6.2.6.2 Inclusion and Exclusion Criteria ...................................................................... 157
6.2.6.3 Making Decisions with Physicians in Charge of Patients’ Care ....................... 159
6.2.6.4 Repeat Reviews and Consent/ Consultee Declaration ................................... 159
6.2.7 Study Intervention – HOME FIRST ......................................................................... 160
6.2.8 Aftercare by HOME FIRST ...................................................................................... 160
6.2.8.1 Initial and Subsequent Follow-up with HOMEFIRST ....................................... 160
6.2.8.2 Discharge from Hospital with HOME FIRST .................................................... 160
6.2.8.3 Readmission to Hospital from HOME FIRST ................................................... 161
6.2.8.4 Discharge from HOME FIRST ........................................................................... 163
6.2.9 Standard Hospital Care (SHC) Arm ........................................................................ 165
6.2.10 Follow-up ............................................................................................................. 165
6.2.11 Study Flowchart ................................................................................................... 165
6.2.12 Hospital Staff Engagement .................................................................................. 167
6.2.13 Sample Size, Statistical Methods, Outcome Measures and Randomisation ....... 167
6.2.14 General Research Staff Tasks and Responsibilities ............................................. 169
6.2.15 Quality Control and Safety Monitoring ............................................................... 170
6.2.15.1 Adverse Event Reporting, Patient and Staff Safety and Training ................. 170
6.2.15.2 Trial Monitoring ............................................................................................ 171
6.2.16 Database Completion .......................................................................................... 171
6.2.17 Communication ................................................................................................... 172
6.2.18 Amendments ....................................................................................................... 172
6.3 RESULTS ........................................................................................................................ 173
6.4 DISCUSSION .................................................................................................................. 185
6.5 ACKNOWLEDGEMENTS ................................................................................................ 190
CHAPTER 7: Vaccine Development - First Human Challenge Testing of a Pneumococcal Vaccine
- Double Blind Randomised Controlled Trial (PCV EHPC). ..................................................... 192
7.1 INTRODUCTION ............................................................................................................ 192
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7.2 METHODS ..................................................................................................................... 194
7.2.1 Ethical Principles .................................................................................................... 194
7.2.3 Trial Design and Participants ................................................................................. 195
7.2.4 Recruitment and Selection .................................................................................... 196
7.2.5 Exclusion Criteria and Details ................................................................................ 196
7.2.6 Randomisation, Blinding, Vaccination and Unblinding ......................................... 198
7.2.7 Nasopharyngeal Inoculation .................................................................................. 198
7.2.8 Nasal Washing and Detection of Pneumococcal Colonisation .............................. 199
7.2.9 Participant Monitoring and Safety ........................................................................ 200
7.2.10 Endpoints ............................................................................................................. 201
7.2.11 Statistical Methods, Analysis and Power Calculation .......................................... 202
7.2.12 Study Schedule .................................................................................................... 202
7.3 RESULTS ........................................................................................................................ 204
7.3.1 Screening and Recruitment ................................................................................... 204
7.3.2 Pneumococcal Colonisation Acquisition ............................................................... 206
7.3.3 Pneumococcal Colonisation Density and Intensity ............................................... 209
7.3.4 Natural Pneumococcal Colonisation ..................................................................... 213
7.3.5 Symptoms .............................................................................................................. 215
7.3.5.1 Post Vaccination.............................................................................................. 215
7.3.5.2 Post Inoculation .............................................................................................. 215
7.4 DISCUSSION .................................................................................................................. 216
7.5 ACKNOWLEDGEMENTS ................................................................................................ 218
CHAPTER 8: Discussion and Future Studies ........................................................................... 220
8.1 General Summary and Discussion of Findings ............................................................. 220
8.2 The Future .................................................................................................................... 222
Bibliography ........................................................................................................................... 227
Appendices ............................................................................................................................. 244
Appendix A ......................................................................................................................... 244
Appendix B ......................................................................................................................... 312
Appendix C ......................................................................................................................... 321
Appendix D ......................................................................................................................... 330
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Declaration

This thesis is the result of my own work and effort. In some instances, work was performed in
conjunction with colleagues.
The research in this thesis was carried out at the Liverpool School of Tropical Medicine (LSTM),
the Royal Liverpool and Broadgreen University Hospital (RLBUHT) and University Hospital
Aintree (UHA).
The material contained in this thesis has not been presented, nor is currently being presented,
either wholly or in part, for any other degree or qualification.

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Acknowledgements

I would like to thank:
• My little family - Tom, Rosie and Thomas for supporting me so much through this long
journey. I hope to have been a good role model and always there as a Mum to them both
- my most important job.
• My Mum and Dad for giving me the best that they could, always and without exception -
I now understand a parent’s love for their child much more and appreciate everything you
have done and do for me much more deeply.
• My Mum-in-law, Helen for all the love and time she gives to Rosie and Thomas when I’m
busy ‘Ph’D-ing’.
• Stephen - you have helped me and guided me through this process and supervised with
clarity, direction and care. You have taught me so much in terms of writing skills and what
a research career is about - I hope together we can all keep your Liverpool legacy going.
• Angie and Daniela - you are the best work colleagues I could ask for and I could never have
had all this thesis material to work with if it wasn’t for such great projects and such
efficient female minds.
• The members of our DMSCs: For the PCV EHPC study - Professor Robert Read, University
of Southampton (Chair), Professor David Lalloo and Dr Brian Faragher, Liverpool School of
Tropical Medicine (LSTM). For HOME FIRST pilot - Dr Rebecca Bancroft, Consultant
Geriatrician (RLBUHT), Arthur Kang’ombe, Statistician (LSTM), Dr John Blakey, CSL
Respiratory Medicine (UHA/LSTM) and Professor Sasha Shepperd, Professor of Health
Services Research (University of Oxford).
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• LSTM team - Toni Banyard, Elena Mitsi, Jenna Gritzfeld, Shaun Pennington, Ben Morton,
Dr Laura Macfarlane, Sarah Wilks and Dan Wooton. Jane Ardrey, Debbie Jenkins, Tracy
Seddon and Catherine Molloy for their administration support.
• Clinical Research Unit team – Dr Richard Fitzgerald, Dr Tav Ganguli, Lorraine Burgess, Becky
Lyons and all CRU staff.
• RLBUHT clinicians and research nurses, pharmacy, ward nurses and medical students –
namely Dr Hassan Burhan, Carole Hancock, Dr Justine Hadcroft, Dr Catherine Johnstone,
Dr Sherouk el-Batrawy, David Shaw, Leona Trainor, Fiona Claxton and Rebecca Huang.
• LSTM statistical support - Professors Duolao Wang and Brian Faragher.
• LSTM Well-Travelled Clinic staff and the tropical Clinical Trials Unit (tCTU).
• LSTM health economics support - Professor Louis Niessen and Jahangir Khan.
• Infectious Disease team.
• RLBUHT labs.
• The funders of this work - The Bill and Melinda Gates Foundation Grand Challenge
Exploration programme (OPP1035281), the National Institute of Health Research (NIHR)
and the Biomedical Research Centre (BRC) in Microbial Diseases and Liverpool Health
Partners.
• RD&I RLBUHT namely Heather Rogers and Debbie Atkinson.
• Liverpool Central, Liverpool East and Manchester RECs.
Specific individual contributions are detailed at the end of each chapter.
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