Condition category
Infections and Infestations
Date applied
02/12/2019
Date assigned
06/12/2019
Last edited
24/08/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Some patients with Influenza (‘flu’) develop severe infection requiring admission to intensive care. Recent research suggests that patients with severe influenza may be susceptible to a second infection with a type of fungus called Aspergillus. Invasive aspergillosis (IA) carries high mortality but there are potentially life-saving treatments. Unfortunately, IA may currently be under-diagnosed in patients with influenza. This study will take place across seven hospitals trusts during the 2019/2020 and 2020/2021 influenza seasons. The main aim of the study is to assess what proportion of critically ill patients with severe influenza develop IA, and what factors increase the risk of this happening. The researchers will also look at whether those that do develop IA are more likely to have a prolonged ICU admission or die. This study could help to raise awareness of the potentially high incidence of IA in patients with severe influenza supporting the development of guidance ensuring that appropriate diagnostics are performed in these patients.
In 2020 a new coronavirus was identified as the cause of an outbreak of unexplained pneumonia in China. This coronavirus was later named ‘SARS-CoV-2’, and the disease it causes ‘COVID-19’. It is not yet known whether patients with severe COVID-19 infection are also at risk of IA. It may be that there is something special about the flu virus that predisposes people, or it could be that anyone with a severe respiratory viral infection is at risk. Comparing the rates of IA between patients with severe flu and COVID-19 infection could help answer this question.
Bronchoscopy is a procedure whereby a small camera is used to look inside the lungs. Fluid can then be squirted and re-collected to diagnose the cause of the infection (a bronchoalveolar lavage, BAL). Tests performed on BAL fluid can help diagnose IA but are not available at all hospitals. This study will store surplus BAL samples from patients, and later use them to evaluate a new test called the Aspergillus Lateral Flow Device. Surplus BAL, and blood samples from patients will also be stored and used at a later date to study why patients with influenza develop IA.

Who can participate?
Ventilated adults admitted to intensive care with severe influenza or COVID-19 ('coronavirus')

What does the study involve?
This is an observational study which means that the care and treatments patients receive will not be any different whether they decide to take part or not. A set of research blood tests will be taken once patients are enrolled into the study and once more 5-10 days later if the patient is still on ICU. If the clinical team feel a bronchoscopy is indicated as part of routine clinical care the study group will take a sample of surplus bronchoalveolar lavage fluid and/or store any leftover samples. A bronchoscopy will not be performed or delayed for the purpose of this study. After the flu season is over these stored blood and BAL samples will be tested using both galactomannan and the AspLFD to compare how well both tests perform in diagnosing invasive aspergillosis. Since this will occur after the flu season the results of this testing will not influence the treatment of those enrolled. In addition to the samples that will be taken and stored, the researchers will collect clinical information from the participants' medical notes until their discharge from hospital or 90 days, whichever is the latest.

What are the possible benefits and risks of participating?
As an observational study, the only way participants will be directly affected by this research study is the extra blood and BAL samples taken. It is therefore not expected that any patients will come to harm. Patients are also unlikely to directly benefit from taking part in this research either. It is important to realize that any extra testing performed on samples (such as with the AspLFD) will be done at a much later date in the Spring/Summer.

Where is the study run from?
St George's University Hospitals NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
July 2019 to August 2021

Who is funding the study?
Gilead Sciences (USA)

Who is the main contact?
1. Jonathan Youngs
jyoungs@sgul.ac.uk
2. Tihana Bicanic
tbicanic@sgul.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Jonathan Youngs

ORCID ID

http://orcid.org/0000-0001-8781-2615

Contact details

Institute of Infection and Immunity
Cranmer Terrance
Tooting
London
SW17 0RE
United Kingdom
+44 (0)2087255613
jyoungs@sgul.ac.uk

Type

Scientific

Additional contact

Dr Tihana Bicanic

ORCID ID

http://orcid.org/0000-0002-2676-838X

Contact details

Institute of Infection and Immunity
Cranmer Terrance
Tooting
London
SW17 0RE
United Kingdom
+44 (0)2087255828
tbicanic@sgul.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

CPMS 43440, IRAS 271269

Study information

Scientific title

Incidence and pathogenesis of invasive aspergillosis in intensive care patients with severe influenza or COVID-19 (AspiFlu)

Acronym

AspiFlu

Study hypothesis

The main objective of the study is to assess what proportion of critically ill patients with severe influenza develop invasive aspergillosis (IA), and what factors increase the risk of this happening. The study will also look at whether those that do develop IA are more likely to have a prolonged ICU admission or die.

Hypothesis: Evidence of invasive aspergillosis (IA) will be found in a significant proportion of ICU patients with severe influenza - comparable to the 20% found in recent retrospective studies.

Added 26/03/2020:
The incidence of IA will also be evaluated in a comparison group of critically ill patients with COVID-19. This may illuminate whether IA is an influenza-specific phenomenon, or should be considered in any critically unwell patient with viral pneumonia.

Hypothesis: The incidence of IA in ICU patients with COVID-19 will be lower.

Ethics approval

1. Approved 04/11/2019, Wales Research Ethics Committee 5 Bangor (Health and Care Research Wales, Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB, UK; Tel: +44 (0)7970 422139; Email: Wales.REC5@wales.nhs.uk), REC ref: 19/WA/0310
2. Amendment approved 18/03/2020 (details as above)

Study design

Observational; Design type: Cohort study

Primary study design

Observational

Secondary study design

Cohort study

Trial setting

Hospitals

Trial type

Other

Patient information sheet

See additional files

Condition

Aspergillosis

Intervention

Current intervention as of 24/08/2020:
After consent and enrolment patients will undergo a baseline set of blood tests including serum (5 ml) and Paxgene DNA (2.5 ml). At the London study sites, peripheral blood mononuclear cells (32 ml) will also be taken. A second serum sample (5 ml) will be taken 5-10 days later if the patient remains on ICU. BAL will only be performed at the discretion of the treating team as per standard clinical care. Surplus BAL samples from participants will be stored for analysis after the influenza season. Leftover serum will also be stored.

Data Collection
Clinical data will be collected from the electronic hospital records at baseline, during the patient’s ICU stay, and after ICU discharge - up to 90 days or hospital discharge (whichever is longer).

Data Analysis
The researchers will use the collected clinical and microbiological data and BAL/blood galactomannan results to determine the primary and secondary outcome measures, with input from the study statistician for the multivariable analyses.

Retrospective Diagnostic Evaluation
Once the prospective study is complete, stored BAL/blood samples will be tested retrospectively in parallel by two tests: galactomannan EIA (the current ‘gold standard’ biomarker test for IA) and by the AspLFD (the new test we wish to validate). This will be done after the influenza season so results will have no implications for participants. The BAL/blood AspLFD results will be compared against the IA status of the patient to evaluate test performance against the AspICU definition.

Planned Sub-studies
These will be subject to further funding and are laboratory studies to help us understand why certain patients with influenza might be at greater risk of developing IA. This will involve measuring levels of immune system cells and immune parameters known as cytokines to look at how influenza affects the immune. The researchers will also use stored DNA to look at specific immune genes that might play a role.

_____

Previous intervention:
After consent and enrolment patients in the influenza cohort will undergo a single-draw set of baseline blood tests. This will include peripheral blood mononuclear cells and Paxgene DNA. Approximately 30-40 ml of blood will be taken. BAL will only be performed at the discretion of the treating team as per standard clinical care. Surplus BAL samples from participants will be stored for analysis after the influenza season. Leftover serum will also be stored.

Data Collection
Clinical data will be collected from the electronic hospital records at baseline, during the patient’s ICU stay, and after ICU discharge - up to 90 days or hospital discharge (whichever is longer).

Data Analysis
The researchers will use the collected clinical and microbiological data and BAL/blood galactomannan results to determine the primary and secondary outcome measures, with input from the study statistician for the multivariable analyses.

Retrospective Diagnostic Evaluation
Once the prospective study is complete, stored BAL/blood samples will be tested retrospectively in parallel by two tests: galactomannan EIA (the current ‘gold standard’ biomarker test for IA) and by the AspLFD (the new test we wish to validate). This will be done after the influenza season so results will have no implications for participants. The BAL/blood AspLFD results will be compared against the IA status of the patient to evaluate test performance against the AspICU definition.

Planned Sub-studies
These will be subject to further funding and are laboratory studies to help us understand why certain patients with influenza might be at greater risk of developing IA. This will involve measuring levels of immune system cells and immune parameters known as cytokines to look at how influenza affects the immune. The researchers will also use stored DNA to look at specific immune genes that might play a role.

Intervention type

Other

Phase

Drug names

Primary outcome measure

1. Incidence and risk factors for invasive aspergillosis (IA) in the study cohort (as per modified AspICU criteria):
1.1. Diagnostic classification of Influenza-associated aspergillosis (IAA) during ICU admission as per modified AspICU criteria, determined at the end of ICU stay
1.2. Risk factors to be elicited from baseline clinical data points collected at enrolment (within three days of ICU admission) and ICU therapeutics/interventions collected at the end of ICU stay

Secondary outcome measures

Current secondary outcome measures as of 26/03/2020:
1. The incidence of IA in critically ill patients with influenza and a comparison group with COVID-19:
1.1. Diagnostic classification of COVID-19-associated aspergillosis during ICU admission using modified AspICU criteria as per patients with influenza
2. Morbidity and mortality associated with both influenza-associated IA and COVID-19-associated IA, measured by:
2.1. Duration (days) of mechanical ventilation at end of ICU stay
2.2. Duration (days) of ICU stay at end of ICU stay
2.3. Duration (days) of hospital stay at end of hospital stay
2.4. ICU all-cause mortality at end of ICU stay
2.5. Inpatient all-cause mortality at end of hospital stay
2.6. 90-day all-cause mortality at 90 days from study ICU admission
2.7. Survival analysis: time to death (all-cause mortality) for all patients at 90-days from study ICU admission
3. Utility of AspLFD device for diagnosis of IAA: sensitivity and specificity/negative and positive predictive values measured by diagnostic evaluation of results using stored samples against AspICU criteria. Performed retrospectively at a subsequent time after the influenza season

Previous secondary outcome measures:
1. Morbidity and mortality of IAA, measured by:
1.1. Duration (days) of mechanical ventilation at end of ICU stay
1.2. Duration (days) of ICU stay at end of ICU stay
1.3. Duration (days) of hospital stay at end of hospital stay
1.4. ICU all-cause mortality at end of ICU stay
1.5. Inpatient all-cause mortality at end of hospital stay
1.6. 90-day all-cause mortality at 90 days from study ICU admission
1.7. Survival analysis: time to death (all-cause mortality) for all patients at 90-days from study ICU admission
2. Utility of AspLFD device for diagnosis of IAA: sensitivity and specificity/negative and positive predictive values measured by diagnostic evaluation of results using stored samples against AspICU criteria. Performed retrospectively at a subsequent time after the influenza season

Overall trial start date

06/07/2019

Overall trial end date

05/08/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 26/03/2020:
1. Adults aged >18 years
2. Admitted to ICU for respiratory support requiring intubation and ventilation for >24 hours
AND EITHER:
3. Positive influenza or SARS-CoV-2 PCR from nasal, throat swab, BAL or other respiratory specimen taken either < 7 days pre, or < 3 days post, admission to ICU
OR
4. Influenza or SARS-CoV-2 suspected but PCR results awaited – under these circumstances the patient can be provisionally enrolled, but later excluded if no specimens taken within either < 7 days pre, or < 3 days post admission to ICU positive as above

Previous inclusion criteria:
1. Adults > 18 years
2. Admitted to intensive care for respiratory support requiring intubation and ventilation for > 24 hours
AND EITHER:
3. Positive influenza PCR from nasal, throat swab, BAL or other respiratory specimen taken within 48 hours (of admission to ICU – pre or post
OR
4. Influenza suspected but influenza PCR results awaited – under these circumstances the patient can be provisionally enrolled, but later excluded if no specimens taken within 48 hours pre/post admission to ICU is positive as above

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 90 of both influenza and COVID-19; UK Sample Size: 90 of both influenza and COVID-19

Participant exclusion criteria

1. Respiratory failure not the primary reason for ICU admission
2. History of proven/ probable invasive pulmonary aspergillosis

Recruitment start date

13/12/2019

Recruitment end date

31/03/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Guy's and St Thomas' NHS Foundation Trust
Trust Offices Guy's Hospital Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

King's College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

St George's University Hospitals NHS Foundation Trust
St George's Hospital Blackshaw Road Tooting
London
SW17 0QT
United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Wythenshawe Hospital and Manchester Royal Infirmary Cobbett House Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

University Hospital of Wales
Cardiff and Vale University Health Board
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

Glenfield Hospital
University Hospitals of Leicester NHS Trust
Leicester
LE3 9QP
United Kingdom

Trial participating centre

Royal Papworth Hospital NHS Foundation Trust
Papworth Road Cambridge Biomedical Campus
Cambridge
CB2 0AY
United Kingdom

Sponsor information

Organisation

St George’s University Hospitals NHS Foundation Trust

Sponsor details

Joint Research and Enterprise Services (JRES)
Subhir Bedi
St Georges University of London
Corridor 10
Ground Floor Jenner Wing
London
SW17 0RE
United Kingdom
+44 (0)2087254986
researchgovernance@sgul.ac.uk

Sponsor type

Hospital/treatment centre

Website

https://www.nhs.uk/Services/hospitals/Overview/DefaultView.aspx?id=29686

Funders

Funder type

Industry

Funder name

Gilead Sciences

Alternative name(s)

Gilead, Gilead Sciences, Inc., Gilead Sciences Inc

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)

Location

United States of America

Results and Publications

Publication and dissemination plan

1. Peer-reviewed scientific journals
2. Conference presentation
3. Presented at a stakeholder forum for ICU clinicians across the three sites
4. Main findings may also be presented at patient and public engagement events

IPD sharing statement
The datasets generated during and/or analysed during the current study will be stored in a publically available repository:
St George’s University of London (SGUL) research data repository (http://sgul.figshare.com). The anonymised Redcap database will be deposited. This contains no patient-identifiable information. Data will be available after an embargo period of 1 year to allow publication of the initial AspiFlu findings. Relevant summary data will be shared as part of the publication process.
The data will be shared at the discretion of the Chief Investigator with bona fide researchers wishing to use the data for purposes that lie within the scope consented to in the AspiFlu study. Applications for data held on the SGUL research data repository are administered and processed by the SGUL Research Data Management Service following an independent and transparent process. Consent forms include the use of anonymised data and/or results being used for future research
comments on data anonymisation. The database does not contain any patient-identifiable information. External users of the data will be bound by a data-sharing agreement which will set out the user(s)’ main responsibilities when re-using the data.

Intention to publish date

05/08/2022

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Editorial Notes

24/08/2020: The following changes have been made: 1. The intervention has been changed. 2. The target number of participants has been changed from "Planned Sample Size: 70; UK Sample Size: 70" to "Planned Sample Size: 90 of both influenza and COVID-19; UK Sample Size: 90 of both influenza and COVID-19". 3. University Hospital of Wales, Glenfield Hospital and Royal Papworth Hospital were added to the trial participating centres. 4. The plain Emnglish summary has been updated to reflect these changes. 09/04/2020: The ethics approval amendment date was added. 26/03/2020: The following changes were made to the trial record: 1. The study hypothesis, secondary outcome measures, inclusion criteria, and plain English summary were updated. 2. The recruitment end date was changed from 31/03/2020 to 31/03/2021. 3. The overall trial end date was changed from 05/08/2020 to 05/08/2021. 4. The intention to publish date was changed from 05/08/2021 to 05/08/2022. 5. The updated participant information sheet has been uploaded. 6. The public title was changed from 'Aspergillosis in patients with severe influenza' to 'Aspergillosis in patients with severe influenza or coronavirus'. 7. The scientific title was changed from 'Incidence and pathogenesis of invasive aspergillosis in intensive care patients with severe influenza (AspiFlu)' to 'Incidence and pathogenesis of invasive aspergillosis in intensive care patients with severe influenza or COVID-19 (AspiFlu)'. 13/12/2019: Manchester University NHS Foundation Trust was added as a trial participating centre. 06/12/2019: Uploaded protocol Version 2.0, 26 November 2019 (not peer reviewed). 02/12/2019: Trial's existence confirmed by the NIHR.