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Abstract
Background We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals.
Methods and results One hundred and sixty-eight patients were evaluated 28–60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p<0.01) and had lower 10-year cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p<0.01) and Coronavirus Clinical Characterisation Consortium in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p<0.01). Healthcare worker status associated with less acute inflammation (peak C reactive protein 48 mg/L (IQR: 14–165) vs 112 mg/L (52–181)), milder illness reflected by WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2–6) vs 6 days (3–12)).
In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (OR: 2.99; 95% CI (1.01 to 8.89) by 28–60 days postdischarge).
After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were rehospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934).
Conclusion Healthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome.
Trial registration number NCT04403607.
- COVID-19
- Magnetic Resonance Imaging
- Myocarditis
- Risk Factors
Data availability statement
Data are available upon reasonable request. Data requests will be considered by the Steering Group, which includes representatives of the Sponsor, the University of Glasgow, senior investigators independent of the research team, and the chief investigator. The Steering Group will take account of the scientific rationale, ethics, logistics, and resource implications. Data access requests should be submitted by email to the Chief Investigator (Colin Berry, corresponding author). The source data include the deidentified numerical data used for the statistical analyses and deidentified imaging scans (MRI, CT) and ECGs. Data access will be provided through the secure analytical platform of the Robertson Centre for Biostatistics. This secure platform enables access to deidentified data for analytical purposes without the possibility of removing the data from the server. The Steering Group will consider requests for the transfer of deidentified data (including source imaging scans); if approved, a collaboration agreement would be expected. The Steering Group will consider any cost implications, and cost recovery would be expected on a not-for-profit basis.
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The protection of healthcare workers is essential to the provision of health services during an infectious disease pandemic.
Occupational exposure is a risk factor for infection from communicable disease including COVID-19.
Few prospective studies of the trajectory of COVID-19 disease in healthcare workers have been undertaken, and the burden of severe illness on workers with high level of exposure requires investigation.
WHAT THIS STUDY ADDS
We undertook a prospective study of 168 patients including 36 healthcare workers hospitalised due to COVID-19, performing cardiovascular and renal MRI at 28–60 days, with contemporary CT pulmonary and coronary angiography, and CT Thorax. We also obtained blood and urine biomarkers and participants completed patient-reported outcome measure questionnaires.
Despite better antecedent health than non-healthcare workers, adjudicated myocarditis was more likely in healthcare workers.
Post-COVID-19 syndrome was common but no greater than nonhealthcare workers.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
In this prospective cohort, occupational exposure to COVID-19 in healthcare workers associated with myocarditis and two in five healthcare workers required secondary care referrals for postCOVID-19 syndrome.
Infection control precautions and the provision of appropriate personal protective equipment to reduce exposure to COVID-19 are required in professions with greater exposure
Introduction
Symptoms of post-COVID-19 are common, leading to increased demands on healthcare services.1–8 Protecting healthcare workers from occupational health problems, notably nosocomial communicable disease such as COVID-19,9 is crucial. Healthcare workers are at an increased risk of infection due to frequent and prolonged exposure to COVID-19 from aerosols or contaminated secretions in clinical areas.10–13 Few prospective studies of COVID-19 disease in healthcare workers have been undertaken.
We hypothesised that healthcare workers might be at increased risk of severe infection and disease complications following hospitalisation with COVID-19 due to occupational exposure compared with non-healthcare workers. We investigated this hypothesis using multisystem imaging, biomarkers and their changes over the short and medium term. Patient-reported outcome measures recorded health status and physical and psychological function, and electronic health records were used to establish clinical outcomes and healthcare use.
Methods
Design
The Chief Scientist Office Cardiovascular and Pulmonary Imaging in SARS Coronavirus disease-19 (CISCO-19) study involved a prospective, observational, multicentre, longitudinal, secondary care cohort study design to assess the trajectory of multiorgan injury in survivors of COVID-19 during convalescence.14 15 Participants were assessed at enrolment (visit 1) and again, 28–60 days following discharge from hospital (visit 2). At each visit, clinical information, a 12-lead digital ECG, blood and urine biomarkers and patient-reported outcome measures were acquired. Cardiorenal MRI followed by contemporary chest CT, including pulmonary and coronary angiography, were acquired at the second visit. An analysis based on self-reported healthcare worker status was prespecified.
Participant identification
CISCO-19 was performed in three hospitals in the West of Scotland (population 2.2 million). Surviving patients receiving hospital care for COVID-19, with or without admission, were prospectively screened using an electronic healthcare information system (TrakCare, InterSystems, USA) and reports identifying PCR-positive hospital inpatients with COVID-19 (Roche Cobas 6800 or Seegene SARS-CoV-2 PCR).
Eligibility criteria
The inclusion criteria were: (1) age ≥18 years old; (2) history of an unscheduled attendance to hospital secondary to COVID-19 with positive COVID-19 PCR result; (3) ability to comply with study procedures and (4) ability to provide written informed consent. Imaging results were reported according to contemporary national guidelines by accredited radiologists.16
The exclusion criteria were: (1) contraindication to MRI or (2) lack of informed consent.
Screening
A screening log was prospectively completed and recorded reasons for being ineligible.
Diagnosis of myocardial injury
Myocardial injury was defined according to the Fourth Universal Definition of Myocardial Infarction. High sensitivity troponin I (Abbott Architect STAT TnI assay) was measured in hospitalised patients with sex-specific upper reference limit >99th percentile: men >34 ng/L, women >16 ng/L.
Multimodality imaging
CT
Comprehensive pulmonary assessment was performed by acquisition of an initial low radiation dose helical scan of the thorax. Cardiopulmonary transit times were assessed by a contrast bolus timing scan. Non-contrast followed by contrast-enhanced angiographic breath-hold ECG-gated volumes were acquired and timed for optimum pulmonary and systemic arterial (coronary) opacification. Non-contrast acquisitions were obtained in patients with severe renal dysfunction precluding contrast administration.
To assess for the presence and extent of flow-limiting coronary artery disease and coronary calcification, CT coronary angiography was performed incorporating fractional flow reserve CT assessment (FFRCT; HeartFlow, Redwood City, California). Obstructive coronary artery disease was defined by an FFRCT ≤0.80 in the presence of a corresponding coronary lesion, taking the lowest value in the vessel. Pulmonary vascular imaging was performed to assess for pulmonary arterial thrombus (embolism).17 Pulmonary features associated with COVID infection, for example, atelectasis, reticulation and/or architectural distortion, ground-glass opacity and pre-existing lung damage, for example, emphysema were delineated by CT. Incidental findings including cardiac and extracardiac were reported and managed according to local standards of care.
Cardiovascular MRI
Patients were invited to undergo protocol-directed MRI in the convalescent phase, 28–60 days after discharge. MRI was acquired using a research-dedicated 3.0 Tesla (3T) scanner (MAGNETOM Prisma, Siemens Healthineers, Erlangen, Germany) with two 18-channel surface coils placed anteriorly and a 32-channel spine coil placed posteriorly. The scan protocol included cine-imaging of cardiac anatomy and function and myocardial tissue characterisation using multiparametric techniques, namely, myocardial native longitudinal relaxation time (T1, milliseconds) before and following intravenous gadolinium contrast media (Magnevist, Bayer Healthcare), mapping transverse relaxation time (T2 in milliseconds), first pass contrast-enhanced perfusion and late gadolinium enhancement imaging.
The modified Lake Louise criteria were used to diagnose definite myocardial inflammation (abnormal T2 and T1 (native T1, late gadolinium enhancement or extracellular volume)) or probable myocardial inflammation (abnormal: T2 or T1).18 19 UK Biobank reference ranges were used to interpret cardiac structure and function,20 and scanner-specific contemporary local reference ranges defined thresholds for localised abnormalities in myocardial T1-relaxation and T2-relaxation times. Patients with severe renal dysfunction were not excluded and underwent MRI with or without contrast media according to the site radiology protocol.
Renal MRI
Multiparametric renal MRI included anatomical imaging and tissue characterisation by measurement of native T1 and T2 relaxation times (ms). Corticomedullary differentiation reflects variance in tissue contrast on T1-weighted imaging due to a shorter cortical T1 relaxation time relative to the medulla reflecting differences in water content between these tissues.21 22 Kidney disease may diminish corticomedullary differentiation, reported here as a ratio of T1 cortex divided by T1 medulla.21 22
Blinding
Patients completed health status questionnaires prior to imaging and their scan results. Core analyses were performed by researchers independent of patient characteristics, control status or other results. The cardiologists who formed the clinical adjudication panel were unaware of the patient-reported outcome measures. They were also unaware of the adjudications made by the other panel members.
Outcomes
Primary outcome
The predefined primary outcome was a diagnosis of adjudicated myocarditis (myocardial inflammation), a subgroup of acute myocardial injury. Adjudication was undertaken by a panel of cardiologists independent of the research team.
Myocarditis was clinically suspected in the presence of at least one clinical finding and at least one diagnostic test criterion, in the absence of (1) angiographically detectable, flow-limiting coronary artery disease (coronary stenosis ≥50%, FFRCT<0.80); (2) alternative extracardiac causes or known pre-existing cardiovascular disease which could explain the syndrome (eg, valve disease, congenital heart disease, hyperthyroidism, etc). The likelihood of myocarditis increases with each criterion met. In asymptomatic patients, two or more diagnostic criteria were required.
Adjudication of the primary outcome
We prespecified an adjudication procedure for the primary outcome to reduce ascertainment bias, involving a panel of cardiologists with specialty accreditation. The reviews were undertaken according to a prespecified charter.
Fourteen independent consultant cardiologists were provided with information on the European Society of Cardiology Working Group on Myocardial and Pericardial Disease position statement on myocarditis,18 a charter, and training cases, including a vignette with clinical presentation, severity of illness and objective findings from clinical and research procedures. Cases were pseudo-anonymised and assessed by at least five cardiologists in turn. The likelihood or not of myocarditis was scored using an ordinal Likert system (not present/unlikely/probable/very likely). A weighted summative score would inform the categorisation of the likelihood of myocarditis using clinical and diagnostic criteria in line with clinical guidelines. The median likelihood determined the final diagnosis for each case and control. Each rater reassessed 30 cases to assess intraobserve variability and test–retest reliability. Categorisations were also dichotomised into not present/unlikely versus probable/very likely myocarditis to produce a binary classification (no vs yes).
Health status and patient-reported outcome measures
Questionnaires were completed at enrolment (visit 1) and 28–60 days after discharge from the hospital. The generic (EuroQOL EQ-5D-5L questionnaire and the Brief Illness Perception Questionnaire assessed self-reported health status of the participants.23 24 An assessment for depression and anxiety was performed using the Patient Health Questionnaire-4.25 The Duke Activity Status Index predicted maximal oxygen utilisation (mL/kg/min) and functional capacity. A higher score reflected higher degrees of physical function.26 The International Physical Activity Questionnaire—Short Form (IPAQ-SF) measures physical activity, intensity and time spent sitting down. The score from IPAQ-SF reflected the total physical activity at each visit per participant in metabolic equivalent minutes per week.27
Longitudinal follow-up for clinical outcomes
Clinical research team members assessed electronic health records without participant contact in line with the protocol and a predefined charter for follow-up assessments of serious adverse events (SAEs), including death and rehospitalisation, andNational Health Service (NHS) resource utilisation, including procedures, outpatient clinic visits and medication prescriptions. Cardiovascular and respiratory SAE were independently reviewed and adjudicated by the clinical event committee. The events were entered into the database coordinated by the clinical trials unit.
Statistics
The statistical analyses, including a predefined analysis of healthcare worker status, were described in a statistical analysis plan. The statistical methods are described in the tables.
Sample size calculation
To detect an association between a history of pre-existing cardiovascular disease and incident myocardial inflammation (myocarditis) determined based on median likelihood from the clinical adjudication committee, we assumed the presence of prior cardiovascular disease in 25% of the study population and that the incidence of myocardial inflammation in those with and without prior cardiovascular disease would be 33% and 10%, respectively.28 Thirty-five patients with prior cardiovascular disease and 105 without would provide 80% power to detect this difference. It was envisaged that 10%–15% of the participants might have incomplete data, for example, artefact or claustrophobia, and, therefore, a target sample size of 160 would be recruited to complete the imaging visit.
Associations between healthcare worker status adjudicated the likelihood of myocarditis and mechanistic biomarkers, patient-reported outcome measures and the primary and secondary outcomes were assessed. Missing data are reported. CIs accompany significance tests with two-sided p values for estimated effect sizes and measures of association without adjustment for multiplicity. The p values for subgroup differences were calculated using the Fisher Exact test and the Kruskal-Wallis test for categorical and continuous data. A p value of less than 0.05 was considered statistically significant.
Trial management and timelines
The study was conducted in line with the current Guidelines for Good Clinical Practice in Clinical Trials and Strengthening the Reporting of Observational Studies in Epidemiology guidelines29 and coordinated by a Study Management Group. A Scientific Steering Group had oversight of the study. The CISCO-19 study was initially considered by the NHS Glasgow Patient and Public Involvement group during 2020. The study was also considered by lay members of the research ethics committee. Updates from the study have been contributed to the long COVID-19 Scotland group meetings, which have taken place approximately quarterly since 2020.
Sources of funding
This was an investigator-initiated clinical study funded by the Chief Scientist Office of the Scottish Government (COV/GLA/Portfolio project number 311300). The funder had no role in the design, conduct (non-voting TSC member), data analysis and interpretation, manuscript writing or dissemination of the results. CB, CD, NS, RT were supported by the British Heart Foundation (RE/18/6/34217).
The MRI study involved technologies provided by Siemens Healthcare and the National Institutes of Health. HeartFlow (HeartFlow, Redwood City, California) provided FFRCT. The study was cosponsored by NHS Greater Glasgow & Clyde Health Board and the University of Glasgow.
Results
One thousand six hundred and six patients who received hospital care for COVID-19 were screened between 22 May 2020 and 16 March 2021, and 267 patients provided written informed consent(figure 1).
Flow diagram of the clinical study. The procedures involved screening hospitalised patients with COVID-19, defined by a PCR-positive result for SARS-CoV-2 in a nasopharyngeal swab and obtaining written informed consent. A PCR-positive result defines the analysis population. Serial investigations were initiated in-hospital or early post-discharge (visit 1) and then repeated in association with multiorgan imaging at 28–60 days post-discharge (visit 2). Clinical follow-up continued for on average (SD) 450 (88) days (range 290, 627 days) post-discharge. *Claustrophobia prevented the completion of the full imaging protocol in 14 patients—however, 7 provided data for biomarkers, patient-reported outcome measures and limited imaging acquisitions before abandonment.
One hundred and sixty-eight patients, including 36 (21%) healthcare workers, were evaluated at 28–60 days after the last episode of hospital care, of whom 154 completed cardiovascular MRI with stress-perfusion, renal MRI and cross-sectional CT coronary and pulmonary angiography with high-resolution CT of the thorax. The remaining patients partially completed the imaging due to renal impairment precluding contrast and severe breathlessness, preventing adenosine stress-perfusion as protocolled or abandoned due to body habitus or claustrophobia. Blood biomarkers and questionnaires were obtained from these individuals, and, therefore, they were included as intention-to-treat. The average age was 54 years, 88% were white, 44% were women, 46% had a history of cardiovascular disease or treatment, 41% were in the lowest quintile of social deprivation and 21% were healthcare workers table 1.
Clinical characteristics of the study population by healthcare worker status.
Two (1.2%) patients had received a single dose of a SARS-CoV-2 vaccine prior to hospitalisation. Regarding COVID-19 therapy, 68% received oxygen, 54% received steroids, 26% received antiviral drug therapy, 20% received non-invasive respiratory support and 8% received invasive ventilation.
Healthcare workers
Compared with non-healthcare workers, healthcare workers were of comparable age (51.3 (8.7) years versus 55.0 (12.4) years; p=0.09) and were more often women (26 (72%) vs 48 (38%); p<0.01). They had a lower 10-year percentage cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p<0.01) and a lower ISARIC-4C in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p<0.01). Healthcare worker status was associated with less severe acute inflammation (peak C reactive protein (CRP) 48 mg/L (IQR: 14 to 165) vs 112 mg/L (52 to 181), illness severity reflected by the WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2 to 6) vs 6 days (3 to 12)).
Multisystem phenotyping and adjudicated myocarditis
Electrocardiology
Electrocardiographic features of myocarditis criteria defined by contemporary criteria did not differ by healthcare worker status (table 2).
Multisystem phenotyping by healthcare worker status: serial electrocardiography, biomarkers of inflammation, metabolism, renal function, haemostasis, and heart, lung, and kidney imaging at 28–60 days post-discharge
CT chest, coronary and pulmonary angiography
At 28–60 days following discharge from the hospital, healthcare worker status was associated with less abnormal lung volume (healthcare workers: 7.9% (14.1) visual estimate of total lung volume vs non-healthcare workers 16.0% (20.1)) compared with non-healthcare workers. Median CT fractional flow reserve was greater in healthcare workers, reflecting a lower burden of coronary artery disease (table 2).
Cardiovascular MRI
Compared with non-healthcare workers, healthcare workers had increased myocardial native T1 relaxation times and extracellular volume, consistent with myocardial inflammation (table 2). Myocardial mass was lower in healthcare workers reflecting the higher proportion of women in the healthcare worker group.
Renal MRI
There was no difference in renal inflammation between healthcare workers and non-healthcare workers.
Primary outcome
Healthcare worker status was associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis during adjusted multivariate logistic regression analysis (OR: 2.99; 95% CI (1.01 to 8.89)) (table 3).
Univariate and multivariable associates of adjudicated myocarditis (primary outcome), including demographic characteristics
The total variance across all adjudication ratings was 0.885 and between adjudicated ratings was 0.725 using an ordinal scale of values from 1 to 4 for the likelihood of myocarditis. The between-subject variation to the total variation ratio was 0.82. Adjudicating cardiologists each repeated 30 cases in a blinded fashion to assess intraobserver reliability. The average-weighted kappa statistic for classifying the likelihood of myocarditis into four levels was 0.69, and for the binary classification (probable/very likely vs not present/unlikely), it was 0.79.
Health status
Compared with non-healthcare workers, at enrolment and 28–60 days postdischarge, healthcare workers had a better health-related quality of life, lower illness perception, lower levels of anxiety and depression, higher levels of vigorous physical activity and similar predicted maximal oxygen utilisation (mL/kg/min) reflecting aerobic exercise capacity (table 4).
Patient-reported outcome measures of health status, illness perception, anxiety and depression and physical function by healthcare worker status
Serious adverse events
Follow-up was continued to 13 December 2021, for all participants. The mean (SD, range) duration of follow-up after hospital discharge was 450 (88) days (range 290–627 days).
Four patients died, including two deaths before and two after visit 2 at 28–60 days following hospital discharge after COVID-19 (table 5). No deaths occurred among healthcare workers. Twenty-two (17%) patients died or were rehospitalised, including one healthcare worker (p=0.038). One hundred and thirteen (67.9%) patients with post-COVID-19 had an episode of outpatient secondary care, including 27 (75%) healthcare workers and 86 (65%) non-healthcare workers. Referrals for symptoms consistent with NICE188 guideline criteria for long COVID-19 were very common in both groups but not significantly different by healthcare worker status (15 (42%) vs 50 (38%); p=0.934).
Clinical outcomes by healthcare worker status
Discussion
We investigated multisystem pathology, patient-reported health status, aerobic capacity and clinical outcomes for 14 months after hospitalisation for COVID-19. One in seven patients died or was readmitted to the hospital, and two-thirds had an episode of outpatient secondary care. Post-COVID-19 syndrome was prevalent, with 65 (39%) of all patients referred to secondary care with NICE188 guideline criteria for long COVID-19.
Almost one-quarter of the patients were healthcare workers and they were mostly women. Despite less severe acute illness and better antecedent health, compared with non-healthcare workers, healthcare workers had a threefold higher likelihood of adjudicated myocarditis, reflecting deep organ involvement of COVID-19. The aetiology of myocardial inflammation may be direct viral myocarditis or myocardial inflammation reflecting multisystem illness. Reverse causality may be relevant in that individuals with reasonably good background health have a greater reserve to withstand COVID-19 such that in those individuals who eventually become sufficiently unwell to require hospital care, the severity of COVID-19 is more pronounced. Healthcare workers have enhanced occupational exposure to SARS-CoV-2 in their workplace, as evidenced by the exposure of the clinicians in the research team, all of whom developed COVID-19 during the study, despite adhering to recommendations for personal protective equipment and social distancing measures. Several of the non-clinical research staff also developed COVID-19. There have been previous concerns regarding more significant viral load and increased exposure to aerosolised viral particles in healthcare workers.30 This may explain why healthcare workers had evidence of systemic involvement in deep organs, that is, myocarditis, despite seemingly lower levels of systemic inflammation reflected by CRP.
Despite better antecent health and less severe COVID-19 illness initially, post-COVID-19 syndrome was just as common in healthcare workers as non-healthcare workers. Referrals to secondary care for symptoms persisting beyond 84 days in keeping with long COVID-19 were made in two in five patients, and the proportions were similar between both groups. The overall burden of post-COVID-19 symptoms was high. The participants were enrolled before the roll-out of the COVID-19 vaccination programme in the United Kingdom, and all but two patients (1%) were unvaccinated. Occupational exposure and the risk of persistent symptoms have important implications for the safety and well-being of healthcare staff and health service workforce planning in the health service. Since vaccination prevents COVID-19 and reduces the likelihood of long COVID-19 symptoms,31 our results highlight the importance of healthcare workers being vaccinated against SARS-CoV-2.
A strength of this study is the blinded adjudication process which included a panel of at least five cardiologists to assess the likelihood of myocarditis in each case. A core laboratory approach blinded researchers to occupational status, demographics, disease severity and outcomes and preserved objectivity during the analysis of study imaging, electrocardiograms and blood or urine biomarkers. Statistical analysis was undertaken independently from the research team by two biostatisticians. There was no missing data for follow-up assessments, which were completed using electronic health records.
Limitations
To minimise COVID-19 transmission to our healthcare staff, imaging was scheduled from 28 days postdischarge. This approach aligns with the International Severe Acute Respiratory and Emerging Infection Coronavirus Clinical Characterisation Consortium study.32 Since acute imaging was not performed, some pathologies may have resolved by 28 days. Selection and ascertainment bias was minimised but not eliminated.
Conclusions
The illness trajectory of COVID-19 in healthcare workers involves a greater degree of myocardial involvement despite fewer cardiovascular risk factors and comorbidities. The burden of post-COVID-19 syndrome was high, affecting 42% of healthcare workers in this study, with implications for workforce planning. Preventive therapy for post-COVID-19 syndromes and longer term studies of prognosis are warranted.
Data availability statement
Data are available upon reasonable request. Data requests will be considered by the Steering Group, which includes representatives of the Sponsor, the University of Glasgow, senior investigators independent of the research team, and the chief investigator. The Steering Group will take account of the scientific rationale, ethics, logistics, and resource implications. Data access requests should be submitted by email to the Chief Investigator (Colin Berry, corresponding author). The source data include the deidentified numerical data used for the statistical analyses and deidentified imaging scans (MRI, CT) and ECGs. Data access will be provided through the secure analytical platform of the Robertson Centre for Biostatistics. This secure platform enables access to deidentified data for analytical purposes without the possibility of removing the data from the server. The Steering Group will consider requests for the transfer of deidentified data (including source imaging scans); if approved, a collaboration agreement would be expected. The Steering Group will consider any cost implications, and cost recovery would be expected on a not-for-profit basis.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by UK National Research Ethics Service (Reference 20/NS/0066). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We thank the staff and patients supporting this study and the Chief Scientist Office of the Scottish Government for financial support. We thank the CISCO-19 Study Management Group (Mrs Ammani Brown, Mrs Chloe Cowan, Dr Lindsay Gillespie, Ms Sharon Kean, Mr Jurgen Van-Melckebeke, Dr Kim Moran-Jones, Dr Debra Stuart, and Dr Maureen Travers) for their contributions towards the delivery of this study.
References
Footnotes
Twitter @_rsykes, @kenneth_mangion, @ColinBerryMD
Collaborators The CISCO-19 Investigators—Chief Investigator: Colin Berry BSc/MBChB/PhDGrant applicants. Kenneth Mangion MD/PhD, Catherine Bagot MBBS/MD, Colin Church MBChB/PhD, Christian Delles MD, Antonia Ho MBChB/PhD, David J. Lowe MBChB/MD, Alex McConnachie PhD, Giles Roditi MBChB, Rhian M. Touyz MD/PhD, Naveed Sattar MBChB/PhD, Ryan Wereski MBChB, Sylvia Wright MBChB, Colin Berry BSc/MBChB/PhD. Site investigators. Queen Elizabeth University Hospital—Kenneth Mangion MBChB/PhD, Pauline Hall Barrientos PhD, Kevin G. Blyth MBChB/PhD, Michael Briscoe MBChB, Colin Church MBChB/PhD, Christian Delles MBChB/PhD, Stephen Dobbin MBChB, Keith Gillis MBChB/PhD, Antonia Ho MBChB/PhD, Anna Kamdar BMedSci, David J. Lowe MBChB/MD, Kaitlin J. Mayne MBChB, Patrick B. Mark MBChB/PhD, Christopher McGinley MBChB, Connor McKee BMedSci/ MBChB, Andrew Morrow MBChB, Oliver Peck MBChB, Alastair J Rankin BSc/MBChB, Giles Roditi MBChB, Claire Rooney MBChB/PhD, Sarah A. Spiers PhD, David Stobo MBChB, Robert Sykes MBChB/BMedSci, Ryan Wereski MBChB, Sylvia Wright MBChB/PhD, Colin Berry BSc/MBChB/PhD.Royal Alexandra HospitalLynn Abel BN, Douglas Grieve MBChB/PhD.Glasgow Royal InfirmaryCatherine Bagot MBBS/MD, Hannah Bayes MBChB/PhD, Jaclyn Carberry MBChB/BMedSci, Daniel Doherty MBChB, Ian Fergus BSc, Vivienne B. Gibson PhD, Fraser Goldie MBChB, Laura Knox MBChB, Giles Roditi MBChB, Katherine Scott MBChB, David Stobo MBChB, Varun Sharma MBChB, Robert Sykes MBChB/BMedSci.Glasgow Clinical Research Facility and Study Management Group—Ammani Brown BN, Andrew Dougherty BN, Kirsty Fallon BN, Lesley Gilmour BN.Chloe Cowan BN, Lynsey Gillespie PhD, Sharon Kean, Jurgen Van-Melckebeke BSc, Kim Moran-Jones PhD, Debra Stuart PhD, Maureen Travers PhD.Glasgow Clinical Research Imaging Facility, Institute of Clinical Excellence, Queen Elizabeth University HospitalTracey Hopkins DCR/BSc(Hons)/PGd, Laura Dymock BSc(Hons), Evonne McLennan BSc(Hons)/PGc, Rosemary Woodward BSc/PGc, Fiona Savage BSc(Hons)/PGc, Nicola Tynan BSc(Hons)/PGc.Radiology, NHS Greater Glasgow and Clyde Health BoardSau Lee Chang MBChB, Mhairi Dupre MBChB, Lindsey Norton MBChB, Liam Peng MBChB, Giles Roditi MBChB, David Stobo MBChB. Laboratory Medicine and Biorepository, NHS Greater Glasgow and Clyde Health BoardClare Orange BSc, Rory Gunson PhD.Medical Physics, NHS Greater Glasgow and Clyde Sarah Allwood-Spiers PhD, George Bruce BSc, Rosario Gonzalez-Lopez PhD, Pauline Hall Barrientos PhD, Rebecca Stace BSc.University of GlasgowInstitute of Cardiovascular and Medical Sciences—Colin Berry MBChB/PhD, Elaine Butler BSc, Christian Delles MBChB/PhD, Jennifer S Lees MBChB/PhD, Kenneth Mangion MD/PhD, Patrick Mark MBChB/PhD, Andrew Morrow MBChB, Naveed Sattar MBChB/PhD, Robert Sykes MBChB/BMedSci, Rhian M. Touyz MD/PhD, Paul Welsh PhD. Institute of Infection, Immunity and Inflammation MRC Centre for Virology Research—Antonia Ho MBChB/PhD, Massimo Palmarini PhD.Institute of Health and Wellbeing Robertson Centre for Biostatistics—John G.F. Cleland MBChB/PhD, Sharon Kean, Bernard Kelly BSc, Alex McConnachie PhD, Alasdair McIntosh PhD, Dionne Russell BSc, Sarah Weeden PhD.Electrocardiology Core Laboratory—Peter W. Macfarlane DSc, Louise Inglis BSc(Hons), Jean Watt, Kathryn McLaren, Shahid Latif MAppSci (now deceased). Departments of Mathematics and Statistics—Nick Hill PhD, Dirk Husmeier PhD, Xiaoyu Luo PhD. National Institutes of Health—Peter Kellman PhD, Hui Xue PhD. Heartflow Amy Collinsworth MS, Sarah Mullen MBT, Campbell Rogers MD. Clinical Event Committee—Heerajnarain Bulluck MBChB/PhD, David Carrick MBChB/PhD, David Corcoran MBChB/PhD, Iain Findlay MBChB/MD, Ninian N. Lang, MBChB/PhD, Vera Lennie MBChB, Ross McGeoch MD, Sabrina Nordin MBChB/PhD, Alexander Payne MBChB, Nicola Ryan MBBCh, Gruschen Veldtman MBChB/PhD, Robin P. Weir MBChB/PhD, Stuart Watkins MBChB/MD. Coordinators—Andrew Morrow MBChB, Robert Sykes MBChB/BMedSci.Steering Committee College of Medical, Veterinary and Life Sciences, University of Glasgow—Neil Basu MD/PhD, Iain McInnes MBChB/PhD, Stefan Siebert MD/PhD.
Contributors CB designed the study and wrote the first draft of the manuscript with RS. AMcI and AMcC developed the statistical analysis plan and performed the statistical analyses. The co-authors reviewed the manuscript drafts. Each author has individually contributed to either the study’s delivery or helped devise the protocol. All authors have given final approval for the current version to be published. CB accepts full responsibility for the work and/or conduct of the study, had access to the data, and controlled the decision to publish.
Funding This was an investigator-initiated clinical study funded by the Chief Scientist Office of the Scottish Government (COV/GLA/Portfolio project number 311300).
Competing interests CB is employed by the University of Glasgow, which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Coroventis, GSK, HeartFlow, Menarini, Novartis, Siemens Healthcare, SomaLogic and Valo Health. These companies had no role in the design or conduct of the study or the data collection, interpretation, or reporting. HeartFlow derived FFRCT. None of the other authors has any relevant disclosures.
Provenance and peer review Not commissioned; internally peer reviewed.