Condition category
Infections and Infestations
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status

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 three London teaching hospitals during the 2019/2020 influenza season. 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. 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

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 single set of research blood tests will be taken once patients are enrolled into the study. 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?
1. Guy's and St Thomas' NHS Foundation Trust (UK)
2. King's College Hospital NHS Foundation Trust (UK)
3. St George's University Hospitals NHS Foundation Trust (UK)
4. Manchester University NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
July 2019 to August 2020

Who is funding the study?
Gilead Sciences (USA)

Who is the main contact?
1. Jonathan Youngs
2. Tihana Bicanic

Trial website

Contact information



Primary contact

Dr Jonathan Youngs


Contact details

Institute of Infection and Immunity
Cranmer Terrance
SW17 0RE
United Kingdom
+44 (0)2087255613



Additional contact

Dr Tihana Bicanic


Contact details

Institute of Infection and Immunity
Cranmer Terrance
SW17 0RE
United Kingdom
+44 (0)2087255828

Additional identifiers

EudraCT number

Nil known 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 (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.

Ethics approval

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:, REC ref: 19/WA/0310

Study design

Observational; Design type: Cohort study

Primary study design


Secondary study design

Cohort study

Trial setting


Trial type


Patient information sheet

See additional files




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



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

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


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

1. Adults > 18 years
2. Admitted to intensive care for respiratory support requiring intubation and ventilation for > 24h
3. Positive influenza PCR from nasal, throat swab, BAL or other respiratory specimen taken within 48 hours (of admission to ICU – pre or post
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


Age group




Target number of participants

Planned Sample Size: 70; UK Sample Size: 70

Participant exclusion criteria

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

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

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

Trial participating centre

King's College Hospital NHS Foundation Trust
Denmark Hill
United Kingdom

Trial participating centre

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

Trial participating centre

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

Sponsor information


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
SW17 0RE
United Kingdom
+44 (0)2087254986

Sponsor type

Hospital/treatment centre



Funder type


Funder name

Gilead Sciences

Alternative name(s)

Gilead, Gilead Sciences, Inc.

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)


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 ( 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


Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

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.