The role of influenza and acute respiratory infections as triggers for acute myocardial infarction

276 Pages·2013·3.6 MB·English

The role of influenza and acute respiratory
infections as triggers for acute myocardial
infarction

Charlotte Michelle Jane Warren-Gash

A thesis submitted in fulfilment of the requirements for the degree of
Doctor of Philosophy

UCL 2013

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Declaration
I, Charlotte Michelle Jane Warren-Gash confirm that the work presented in this
thesis is my own. Where information has been derived from other sources, I
confirm that this has been indicated in the thesis.

Candidate’s signature

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Abstract
Background: Influenza is an important global cause of morbidity and mortality.
Though some cardiac complications of influenza, such as myocarditis, are well-
recognised, its role as a trigger for acute cardiovascular events is less clear.
Improved understanding of this relationship will add to evidence to support
appropriate prevention and treatment strategies.
Methods: I investigated evidence that influenza and acute respiratory infections
could trigger acute myocardial infarction (AMI) through a systematic literature
review and meta-analysis (chapter 2) and original research studies (chapters 3-
7). These were an ecological weekly time series study using Poisson regression
models adjusted for temporal and environmental confounders in England &
Wales and Hong Kong (chapter 3); two self-controlled case series analyses using
the General Practice Research Database linked to influenza surveillance data
(chapter 4) and to cardiac disease registry and hospitalisation data (chapter 5); a
case control study in AMI patients and surgical controls during the 2009 influenza
pandemic in London (chapter 6); an exploratory mechanistic study (chapter 7).
Key findings:
 Acute respiratory infections, and seasonal influenza, triggered AMI
 A triggering effect may be greater for influenza than for other respiratory
infections (p=0.011)
 AMI risk was highest in the first three days after acute infection – adjusted
incidence ratio 4.19 (95% CI 3.18-5.53) – and persisted for around 28 days
 The proportion of AMI deaths due to seasonal influenza ranged from 3-5%,
rising to 13% in periods of highest influenza circulation
 The relative risk of AMI after acute respiratory infection was highest in
people aged ≥80 years
 Influenza vaccination protected against some adverse cardiac outcomes in
people with existing cardiovascular disease
Conclusions: Reducing the burden of influenza would benefit cardiovascular
health. Questions remain about key groups to target, as well as the optimal
type and delivery of interventions to reduce influenza-associated AMI risk.
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Acknowledgements
I am very grateful to Andrew Hayward at UCL and Liam Smeeth at LSHTM for
generously providing expert supervision, time and support throughout this
project. Many thanks also to Ben Cowling for helpful advice while supervising my
placement at the University of Hong Kong.

I would like to thank my collaborators – Richard Pebody from the Health
Protection Agency for providing influenza surveillance datasets, Krishnan
Bhaskaran and Sara Thomas from LSHTM for statistical and epidemiological
advice, Harry Hemingway and Adam Timmis from the MINAP Academic Group for
facilitating data access and guidance on study design, Heather Whitaker from the
Open University for assistance with self-controlled case series methods, Anna
Maria Geretti, George Hamilton and Roby Rakhit from the Royal Free Hospital for
practical advice and support with the case control study, Spiros Denaxas from
UCL for providing GPRD-MINAP linked data and Gabriel Leung from the
University of Hong Kong for agreeing to host my placement. Thank you to all the
nurses who helped with recruitment and the patients who agreed to participate
in the case control study.

Funding

Charlotte Warren-Gash was supported by a Clinical Research Training Fellowship
from the Medical Research Council.
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Publications arising from work in this thesis
1. Warren-Gash C, Smeeth L & Hayward AC. The role of influenza as a trigger for
acute myocardial infarction or cardiovascular death: a systematic review.
Lancet Infect Dis 2009; 9: 601-610 (based on work in chapter 2)

2. Warren-Gash C, Bhaskaran K, Hayward AC, Leung GM, Lo SV, Wong CM, Ellis J,
Pebody R, Smeeth L & Cowling BJ. Circulating influenza virus, climatic factors
and acute myocardial infarction: a time series study in England & Wales and
Hong Kong. J Infect Dis 2011; 203: 1710-1718 (based on work in chapter 3)

3. Warren-Gash C, Hayward AC, Hemingway H, Denaxas S, Thomas SL, Timmis
AD, Whitaker H & Smeeth L. Influenza infection and risk of acute myocardial
infarction in England & Wales: a CALIBER self-controlled case series study. J
Infect Dis 2012; 206: 1652-1659 (based on work in chapter 5)

4. Warren-Gash C. Research note: Diagnosing influenza for research.
Opticon1826 2012; 14: 37-39 (based on work in chapter 6)

5. Warren-Gash C, Geretti AM, Hamilton G, Rakhit R, Smeeth L & Hayward AC.
Influenza-like illness in acute myocardial infarction patients during the winter
wave of the influenza A H1N1 pandemic: a case control study. Submitted
(based on work in chapter 6)

6. Warren-Gash C, Smeeth L & Hayward AC. Influenza and myocardial infarction.
Expert Rev Cardiovasc Ther 2010; 8(2): 143-146 (based on work in chapters 2
and 8)

Major presentations based on work in this thesis
1. Warren-Gash et al. Circulating influenza virus, climatic factors and acute
myocardial infarction: an ecological study in Hong Kong and the UK. Poster
presentation at the Shape of Science symposium, Manchester, July 2010

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2. Warren-Gash et al. Circulating influenza virus, climatic factors and acute
myocardial infarction: an ecological study in Hong Kong and the UK. Poster
presentation at the Options for Control of Influenza Conference, Hong Kong,
Sept 2010

3. Warren-Gash et al. Seasonal influenza and acute myocardial infarction: a self-
controlled case series study using UK primary care data. Oral presentation at
the European Scientific Working Group on Influenza conference, Malta, Sept
2011 awarded Young Scientist Grant to attend conference

4. Warren-Gash et al. Influenza as a trigger for acute myocardial infarction: a
linked database study. Poster presentation at UCL Graduate School Research
Poster Competition, Feb 2012, awarded First Prize (out of 108 entries from
the Faculties of Medical Sciences & Population Health Sciences)

5. Warren-Gash et al. Influenza in patients with acute myocardial infarction: first
season of recruitment to a case control study. Poster presentation at the
Society for Social Medicine Annual Scientific Meeting, London, Sept 2012

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List of abbreviations
ACS – Acute coronary syndrome
AIC – Akaike information criterion
AMI – Acute myocardial infarction
ARI – Acute respiratory infection
CABG – Coronary artery bypass graft
CALIBER – CArdiovascular disease research using Linked Bespoke studies &
Electronic Records
CfI – Centre for Infections
CHD – Coronary heart disease
CI – Confidence interval
CRP – C-reactive protein
CVD – Cardiovascular disease
ECG – Electrocardiogram
ELISA – Enzyme-linked immunosorbent assay
GPRD – General Practice Research Database
HES – Hospital Episode Statistics
HI – Haemagglutinin inhibition
HPA – Health Protection Agency
HR – Hazard ratio
ICD – International Classification of Diseases
ILI – Influenza-like illness
IL-6 – Interleukin-6
IQR – Interquartile range
IR – Incidence ratio
MINAP – Myocardial Ischaemia National Audit Project
NICE – National Institute for Health and Clinical Excellence
NSTEMI – Non ST segment elevation myocardial infarction
OR – Odds ratio
PCI – Percutaneous coronary intervention
RCGP – Royal College of General Practitioners
RCT – Randomised controlled trial
RH – Relative humidity
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RR – Risk ratio or rate ratio (defined as needed)
RT-PCR – Reverse transcriptase polymerase chain reaction
SAA – Serum amyloid A
SIGN – Scottish Intercollegiate Guidelines Network
STEMI – ST segment elevation myocardial infarction
TNF-α – Tumour necrosis factor-α
URI – Upper respiratory infection
VWF – Von Willebrand factor
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Table of contents

Abstract ................................................................................................................................................. 3
Publications arising from work in this thesis ......................................................................... 5
List of abbreviations ......................................................................................................................... 7
Table of contents ................................................................................................................................ 9
List of tables .......................................................................................................................................14
List of figures .....................................................................................................................................17
1. Key features of influenza and acute myocardial infarction relevant to the
research aims ....................................................................................................................................19
1.1 Description of chapter contents .........................................................................................19
1.2 Infection as a trigger for acute myocardial infarction ...............................................19
1.3 Influenza epidemiology, clinical features, diagnosis & control ..............................20
1.4 Acute myocardial infarction epidemiology, risk factors, definition &
management ......................................................................................................................................25
1.5 Thesis rationale and aims .....................................................................................................32
2. Systematic literature review of the relationship between influenza and acute
myocardial infarction or death from cardiovascular disease.........................................34
2.1 Description of chapter contents .........................................................................................34
2.2 Study rationale ..........................................................................................................................34
2.3 Aims and objectives .................................................................................................................34
2.4 Methods ........................................................................................................................................35
2.4.1 Search strategy .............................................................................................................35
2.4.2 Inclusion and exclusion criteria ............................................................................35
2.4.3 Data extraction and synthesis ................................................................................36
2.5 Results ..........................................................................................................................................37
2.5.1 Search results ...............................................................................................................37
2.5.2 Overview of study designs .......................................................................................38
2.5.3 Ecological studies ........................................................................................................47
2.5.4 Individual observational studies – case only, case control and cohort ..48
2.5.5 Observational and intervention studies of influenza vaccine ....................54
2.6 Discussion ...................................................................................................................................60
2.7 Update: studies published since this review .................................................................65
3. Weekly time series study of influenza circulation and acute myocardial
infarction in England & Wales and Hong Kong ....................................................................70
3.1 Description of chapter contents .........................................................................................70
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3.2 Study rationale and introduction to data sources .......................................................70
3.2.1 Effects of weather conditions on AMI and influenza .....................................70
3.2.2 Clinical influenza surveillance................................................................................71
3.2.3 Laboratory influenza surveillance ........................................................................72
3.3 Aims and objectives .................................................................................................................73
3.4 Methods ........................................................................................................................................74
3.5 Results ..........................................................................................................................................78
3.5.1 Descriptions of AMI and influenza patterns .....................................................78
3.5.2 Modelling AMI seasonality and long-term trends ..........................................81
3.5.3 Associations between influenza and AMI ..........................................................83
3.5.4 Sensitivity analyses ....................................................................................................88
3.5.5 Association between influenza and hospitalisations for ‘counterfactual
conditions’, colon cancer and fractured neck of femur ...........................................90
3.5.6 Analysis stratified by age-group and gender ....................................................91
3.5.7 Predicted percentage of AMIs attributable to influenza ..............................93
3.6 Discussion ...................................................................................................................................94
4. Self-controlled case series analysis of acute respiratory infection and incident
myocardial infarction using the General Practice Research Database .......................99
4.1 Description of chapter contents .........................................................................................99
4.2 Study rationale and introduction to data sources and methods ............................99
4.2.1 General Practice Research Database ...................................................................99
4.2.2 Quality control in GPRD ......................................................................................... 100
4.2.3 Description of self-controlled case series ....................................................... 101
4.2.4 Application and advantages of self-controlled case series ...................... 101
4.2.5 Comparison of self-controlled case series, case control and cohort
methods .................................................................................................................................. 102
4.2.6 Assumptions affecting self-controlled case series ...................................... 103
4.3 Aims and objectives .............................................................................................................. 103
4.4 Methods ..................................................................................................................................... 104
4.5 Results ....................................................................................................................................... 113
4.5.1 Description of outcome .......................................................................................... 113
4.5.2 Description of exposure ......................................................................................... 114
4.5.3 Description of participants ................................................................................... 114
4.5.4 Effect of general acute respiratory infection on AMI ................................. 115
4.5.5 Comparison of effects of ARI episodes judged more and less likely to be
due to influenza on AMI .................................................................................................... 118
4.5.6 Sensitivity analysis excluding fatal events ..................................................... 120
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