Point-of-care testing for respiratory pathogens in critical care

ISRCTN	ISRCTN65693049
DOI	https://doi.org/10.1186/ISRCTN65693049
Integrated Research Application System (IRAS)	216585
Protocol serial number	34003, IRAS 216585
Sponsor	Southampton General Hospital
Funder	Biofire Diagnostics

Submission date: 19/06/2017
Registration date: 21/06/2017
Last edited: 28/02/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Current plain English summary as of 12/02/2020:
Background and study aims
Pneumonia (chest infection) is a serious illness which is usually caused by bacteria. When identified, it warrants swift treatment with antibiotics and sometimes requires high-dependency or intensive care unit admission.

The choice of which of the many antibiotics to use in patients with pneumonia is ‘best-guess’: it is guided by what bacteria are likely be present. As a result we use antibiotics which kill many different bacteria. We know that use of these antibiotics promotes antibiotic resistance. The World Health Organisation have identified antibiotic resistance as one of the biggest threats to global health today.

Current tests looking for bacteria in sputum take several days to generate results so do not allow doctors to be more targeted with their antibiotic use. Rapid ‘point-of-care’ tests for pneumonia have been developed which can provide accurate results in about 1 hour rather than several days. We wish to explore if using a rapid test improves the use of antibiotics and improves patient care.

Who can participate?
Adults aged 18 and older who are admitted to critical care and are on antibiotics for pneumonia.

What does the study involve?
After the patient is enrolled in the trial 3 samples are obtained: a sputum sample, a urine sample and a blood sample. They are allocated to either get the current standard clinical care or a new molecular test that looks for bacteria and viruses in the sputum. Those who get the new test also get a blood test which measures a marker of infection (called procalcitonin) and a urine test which looks for part of a bacteria which commonly causes chest infections.

Patients who get the new test have all tests done immediately by the research team which typically takes around 2 hours. The research team (who are infection speciality registrars or consultants) also interpret the results and feed them back to the responsible clinical team along with any antibiotic advice if the results facilitate a change in therapy.

What are the possible benefits and risks of participating?
Participants may benefit from identifying an organism which has caused their disease considerably quicker and this may better direct the antibiotic therapy they receive.

There are no notable risks with participating.

Where is the study run from?
Southampton General Hospital (UK)

When is the study starting and how long is it expected to run for?
August 2016 to July 2025

Who is funding the study?
The study is funded by Southampton Biomedical Research Centre (UK) and the National Institute for Health Research (UK)

Biofire Diagnostics are supplying the consumables free of charge but had no input into the design or running of the study.

Who is the main contact?
1. Dr Tristan Clark
t.w.clark@soton.ac.uk
2. Dr Stephen Poole
Stephen.Poole@uhs.nhs.uk

Previous plain English summary:
Background and study aims
Acute respiratory tract infections are responsible for over four million deaths each year and are the third most common cause of death worldwide. Respiratory viruses are the most common detectable pathogen (virus) in adults with acute respiratory infection. Influenza and other respiratory virus infections often remain undiagnosed in patients admitted to critical care due to lack of systematic testing. Even when testing occurs, treatment is often delayed because of slow turnaround times of laboratory methods. Treatment for influenza in hospitalised adults requires medications called neuraminidase (e.g. Tamiflu / oseltamivir). Prompt treatment with neuraminidase inhibitors reduces the risk of death and therefore the sooner patients receive them, the better their outcomes will be. Point-of-care tests (POCT) for respiratory viruses have been limited in clinical practice by unacceptably low sensitivities and by an inadequate range of detectable viruses. Newer molecular systems, such as the FilmArray Respiratory Panel, have comparable sensitivity to laboratory tests and are able to detect a wide range of viruses generating a result in about an hour. The aim of the study is to evaluate the impact of point-of-care testing for respiratory viruses in adults with severe acute respiratory illness in critical care units.

Who can participate?
Adults aged 18 and older who are admitted to the hospital with a respiratory issue

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive nose and throat swab taken (which is like a ‘cotton bud’) by research staff. This swab is taken immediately to and analysed for many different viruses that can cause respiratory on the POCT. The results are available in about one hour and participants are informed of the results, as will the doctors and nurses looking after them. Those in the second group receive the standard care. Participants have their hospital case notes and clinical data reviewed to see if a rapid testing can diagnose respiratory viruses sooner and improves health outcomes.

What are the possible benefits and risks of participating?
Participants may benefit from having diagnosed with a respiratory virus sooner than otherwise, leading to a more rapid use of antivirals and appropriate isolation facility use. There are no notable risks with participating.

Where is the study run from?
Southampton General Hospital (UK)

When is the study starting and how long is it expected to run for?
August 2016 to July 2025

Who is funding the study?
Biofire Diagnostics (UK)

Who is the main contact?
1. Dr Tristan Clark
t.w.clark@soton.ac.uk

Contact information

Dr Tristan Clark
Public

University of Southampton Faculty of Medicine
12 University Road
Southampton
SO17 1BJ
United Kingdom

ORCID ID	0000-0001-6026-5295
Phone	+44 2381 204989
Email	t.w.clark@soton.ac.uk

Dr Stephen Poole
Public

Clinical Research Fellow in Infectious Diseases
University Hospital Southampton NHS Foundation Trust
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Phone	+44 2381 204989
Email	stephen.poole@uhs.nhs.uk

Study information

Primary study design	Interventional
Study design	Randomised; Interventional; Design type: Diagnosis, Management of Care
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Pragmatic randomized controlled trial of molecular point-of-care testing for respiratory pathogens versus routine clinical care in critically ill adults with Pneumonia: SARIPOC
Study acronym	SARIPOC
Study objectives	Current study hypothesis as of 13/02/2020: The aim of the study is to evaluate the clinical impact of molecular point-of-care testing for respiratory pathogens in adults with severe acute respiratory illness in critical care units. Previous study hypothesis: The aim of the study is to evaluate the clinical impact of molecular point-of-care testing for respiratory viruses in adults with severe acute respiratory illness in critical care units.
Ethics approval(s)	Regional Ethics Committee (REC) Southcentral – Berkshire, 25/05/2017, 17/SC/0110
Health condition(s) or problem(s) studied	Infectious diseases
Intervention	Current interventions as of 12/02/2020: Participants are randomly allocated to either the intervention or the control group using a 1:1 software randomization service. Intervention group: Participants in this group receive testing for respiratory pathogens at the point-of-care using the FilmArray Pneumonia Panel with results communicated to the clinical team. Additionally, a procalcitonin blood test and pneumococcal urinary antigen testing are performed. The results are available in about two hours and patients will be informed of the results, as will the doctors and nurses looking after them. This is done in addition to standard care. Control group: Participants in this group receive the standard clinical care alone. This may include sending a sputum sample to the laboratory for testing (the results for this usually take 1 to 2 days). Retrospective hospital case notes and clinical data are evaluated. Previous interventions: Participants are randomly allocated to either the intervention or the control group using a 1:1 internet-based randomisation service. Intervention group: Participants in this group receive nose and throat swabs, and have a lower respiratory sample taken if available, which is then tested for respiratory virus at the point-of-care using the FilmArray Respiratory Panel with results communicated to the clinical team. The results are available in about one hour and patients areinformed of the results, as will the doctors and nurses looking after them This is done in addition to the standard care. Control group: Participants in this group receive the standard clinical care alone. This may include sending a nose and throat swab to the laboratory for testing (the results for this usually take 1 to 2 days). Retrospective hospital case notes and clinical data are evaluated.
Intervention type	Other
Primary outcome measure(s)	Current primary outcome measure as of 19/03/2021: The proportion of patients treated with results directed antimicrobials within 48 hours of a lower respiratory tract test result (this is defined as the use of antimicrobial agents that are started or continued on the basis of appropriateness (or the optimal choice) for a detected pathogen(s), where a putative pathogen(s) considered by the investigators to be plausibly causative, is identified; or the appropriate de-escalation or cessation of antimicrobials occurs where no pathogen is identified). Previous primary outcome measure from 12/02/2020 to 19/03/2021: All primary and secondary outcome measures are measured retrospectively using electronic hospital case notes at the end of hospital stay or 30 days, and 60 days. The proportion of patients treated with results directed antimicrobials. This is defined as the use of antimicrobial agents that are started or continued on the basis of appropriateness (or the optimal choice) for a detected pathogen(s), where a putative pathogen(s) considered by the investigators to be plausibly causative, is identified; or the appropriate de-escalation or cessation of antimicrobials occurs where no pathogen is identified. Original primary outcome measure: Proportion of influenza-positive patients treated with neuraminidase inhibitors (NAI) within 7 days of admission to hospital, measured retrospectively on discharge or at 30 days, using electronic hospital prescribing systems
Key secondary outcome measure(s)	Current secondary outcome measures as of 19/03/2021: 1. Median time to results directed antimicrobial therapy within 48 hours of a lower respiratory tract test result, days 2. Proportion with results-directed escalation or de-escalation in antimicrobial therapy within 48 hours of a lower respiratory tract test result. Escalation/de-escalation defined as addition/ cessation of a second agent or increase/decrease in antibiotic stewardship ‘ranking’ 3. Median time to results directed escalation/ de-escalation within 48 hours of lower respiratory tract result, hours 4. Proportion treated with ineffective empirical antimicrobial therapy (defined by the absence of an antimicrobial agent active against the specific class of microorganisms responsible for the infection or the administration of an antimicrobial agent to which the microorganism responsible for infection is resistant) at recruitment 5. Median duration of ineffective antimicrobial therapy (hours), up to 14 days 6. Median duration of all antimicrobial therapy for this episode of pneumonia (hours), up to 14 days 7. Median number of different antimicrobial agents used for this episode of pneumonia (hours) up to 14 days 8. Number of antibiotic-free hours in the 14 days following recruitment 9. Median number of hours piperacillin/tazobactam in the 14 days following recruitment 10. Median number of hours of meropenem in the 14 days following recruitment 11. Median turn-around time for results, hours and days 12. Proportion of patients with a credible pathogen identified for this episode of pneumonia. Credible pathogen as determined by two independent infection specialists, with a third adjudicating in event of disagreement. 13. Concordance between pathogen identification between molecular methods (FilmArray) and culture 14. Concordance between genotypic and phenotypic isolate sensitivities 15. Proportionate in-hospital, 30- and 60-day mortality 16. Median duration of hospitalisation (days), measured for the duration of hospitalisation or up to 30 days (whichever is shortest) 17. Median time on non-invasive ventilation (days), measured for the duration of hospitalisation or up to 30 days (whichever is shortest) 18. Median time on invasive ventilation (days), measured for the duration of hospitalisation or up to 30 days (whichever is shortest) 19. Median time on ionotropic support (days), measured for the duration of hospitalisation or up to 30 days (whichever is shortest) 20. Median time in critical care (days), measured for the duration of hospitalisation or up to 30 days (whichever is shortest) 21. Proportion with antimicrobial associated adverse events, measured for the duration of hospitalisation or up to 30 days (whichever is shortest) 22. Relationship between sputum pathogen quantification within 48 hours of recruitment (colony-forming units/CFUs and/or genome copies/ml) and clinical outcome measures (30-day mortality, length of stay and time on organ support) 23. Utility of serum biomarkers (Procalcitonin) at recruitment in differentiating between bacterial and viral infection (as detected by microbiological sampling) and predict outcome (clinical outcome measures as described above) 24. Proportion and nature of pathogen detection in pneumonia occurring following macro-aspiration 25. Proportion and nature of pathogen detection in patients with SARS-CoV-2 infection 26. Proportion and nature of pathogen detection in relation to the preceding duration of antibiotic therapy (hours) Previous secondary outcome measures from 12/02/2020 to 19/03/2021: 1. Median number of days to treatment with results directed antimicrobials 2. Proportion of participants with an escalation in antimicrobial therapy following test results (defined as addition of second agent or increase in antibiotic stewardship ‘ranking’) 3. Proportion of participants with a de-escalation (defined as either removal of a second agent or de-escalation according to ranking above) in antibiotics following results 4. Median number of days to escalation or de-escalation in antimicrobial therapy 5. Proportion of participants treated with inappropriate empirical antimicrobial therapy (defined by the absence of an antimicrobial agent active against the specific class of microorganisms responsible for the infection or the administration of an antimicrobial agent to which the microorganism responsible for infection is resistant). 6. Median number of days of inappropriate antimicrobial therapy 7. Median number of days of all antimicrobial therapy 8. Median number of days of intravenous antimicrobial therapy 9. Median number of different antimicrobial agents used 10. Proportion of participants correctly treated with influenza antivirals 11. Median number of days to treatment with appropriate influenza antivirals 12. Median number of days of treatment with inappropriate influenza antivirals 13. Proportion of participants correctly isolated in single room accommodation 14. Median number of days to appropriate isolation facility use 15. Median number of days of inappropriate isolation facility use 16. Median turn-around time for results (h) 17. Proportion of participants with a pathogen identified 18. Concordance between pathogen identification between molecular methods (FilmArray) and culture 19. Concordance between genotypic and phenotypic isolate sensitivities 20. Proportionate in-hospital mortality at 30 and 60 days 21. Median number of days of hospitalisation 22. Median number of days on organ support 23. Median number of days in critical care 24. Proportion of participants re-presenting to hospital within 30 days post discharge 25. Proportion of participants readmitted to hospital within 30 days post discharge 26. Proportion of participants with Clostridium difficile infection 27. Proportion of participants with antimicrobial associated adverse events 28. Proportion of participants with detection of multi-resistant pathogens whilst in hospital 29. Proportion of participants with recurrent infection Previous secondary outcome measures: 1. Proportion of cases of influenza identified are measured using electronic hospital case notes at end of hospital stay or 30 days 2. Proportion of cases of non-influenza respiratory viruses detected are measured using electronic hospital prescribing systems at end of hospital stay or 30 days 3. Proportion of all NAI use occurring in influenza positive patients are measured using electronic hospital prescribing systems at end of hospital stay or 30 days 4. Time from admission to NAI commencement in hours are measured using electronic hospital prescribing systems 5. Duration of NAI use in influenza positive and negative patients in days are measured using electronic hospital prescribing systems 6. Proportion of patients treated with antibiotics are measured using electronic hospital prescribing systems at end of hospital stay or 30 days 7. Duration of antibiotic use (in days) are measured using electronic hospital prescribing systems 8. Number of antibiotic agents received and spectrum are measured using electronic hospital prescribing systems at end of hospital stay or 30 days 9. Proportion of patients isolated are measured using hospital case notes at end of hospital stay or 30 days 10. Duration of isolation facility use are measured using hospital case notes at end of hospital stay or 30 days 11. Proportion of influenza cases correctly isolated are measured using hospital case notes at end of hospital stay or 30 days 12. Time from admission to isolation of influenza cases are measured using hospital case notes at end of hospital stay or 30 days 13. Time from admission to de-isolation of influenza negative cases are measured using hospital case notes at end of hospital stay or 30 days 14. Time on organ support (in days) is measured using hospital case notes 15. Time on supplementary oxygen (in days) is measured using hospital case notes 16. Time in critical care unit (level 2 /3 duration) (in days) is measured using hospital case notes 17. Duration of hospitalisation (in days) is measured using hospital case notes 18. Proportion of patients with complications and serious adverse events are measured using hospital case notes at end of hospital stay or 30 days 19. In hospital, 30 and 60 day mortality is measured
Completion date	01/07/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	200
Total final enrolment	200
Key inclusion criteria	Current participant inclusion criteria as of 12/02/2020: 1. Admitted to the Respiratory High Dependency Unit (RHDU), or an Intensive Care Unit (ICU), or about to be transferred to RHDU, GICU, NICU or under the care of the RHDU or ICU team in another hospital area, within University Hospital Southampton NHS Foundation Trust (UHS) 2. Aged ≥18 years 3. Has a working diagnosis of CAP, HAP or VAP* and physician decides to start new antibiotic treatment or modify existing antibiotic treatment. CAP defined by the BTS as: ‘symptoms and signs of acute lower respiratory tract infection associated with new radiographic shadowing for which there is no other explanation’. CAP patients who are intubated and ventilated remain classified as CAP. HAP defined as by the IDSA as: ‘new lung infiltrate, plus clinical evidence that the infiltrate is of an infectious origin, which includes the new onset of fever, purulent sputum, leucocytosis, and decline in oxygenation... arising >48 h after hospital admission’. HAP patients who are intubated and ventilated remain classified as HAP. VAP defined as by the IDSA as: ‘new lung infiltrate plus clinical evidence that the infiltrate is of an infectious origin, which include the new onset of fever, purulent sputum, leucocytosis, and decline in oxygenation... occurring >48 h after endotracheal intubation’ Previous participant inclusion criteria: 1. Admitted to the Respiratory High Dependency Unit (RHDU), or an Intensive Care Unit (ICU), or about to be transferred to either RHDU or ICU, or under the care of the RHDU or ICU team in another hospital area, within University Hospital Southampton NHS Foundation Trust (UHS) 2. Aged ≥18 years old 3. Duration of respiratory illness less than 10 days prior to hospitalisation 4. Presented to hospital less than 72 hours prior to enrolment 5. Has a severe acute respiratory illness *An episode of severe acute respiratory illness is defined as an acute pulmonary illness (including pneumonia, bronchitis and influenza-like illness) or an acute exacerbation of a chronic respiratory illness (including exacerbation of COPD, asthma or bronchiectasis), requiring high dependency or intensive care. For the study, a severe acute respiratory illness as a provisional, working, differential or confirmed diagnosis must be made by a treating clinician.
Key exclusion criteria	Current participant exclusion criteria as of 12/02/2020: 1. A purely palliative approach being taken by the treating clinicians 2. Previously included in this study 3. Consent declined or consultee consent declined 4. Underlying Cystic Fibrosis or other condition characterized by persistent colonization with resistant organisms 5. Not expected to survive the next 24 h in the opinion of the responsible clinical team Involvement in observational trials may not exclude a participant from this trial, and this is at the CI’s discretion. Previous participant exclusion criteria: 1. Not fulfilling all the inclusion criteria 2. A purely palliative approach being taken by the treating clinicians 3. Previously included in this study 4. Declines nasal / pharyngeal swabbing 5. Consent declined or consultee consent declined 6. Severe acute respiratory illness is related to solely to critical illness and/or is not the principal illness leading to ICU/HDU admission
Date of first enrolment	01/07/2017
Date of final enrolment	01/07/2021

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

Southampton General Hospital

University Hospital Southampton NHS Foundation Trust
Tremona Road
Southampton
SO16 6YD
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Tristan Clark (t.w.clark@soton.ac.uk). Data will be made available in 3 months following publication for a period of 5 years. All of the individual participant data collected during the trial, after de-identification will be made available. It will be available to researchers who provide methodologically sounds proposal to achieve the aims in the approved proposal including individual participant meta-analysis. Proposals should be directed to the above PI. All data will be de-identified. Informed consent will be obtained from all patients. There are no known ethical or legal restrictions currently.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		09/09/2022	30/09/2022	Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version v4.1	08/02/2021	13/07/2021	No	No

Additional files

ISRCTN65693049_Protocol_v4.1_8Feb2021.docx: uploaded 13/07/2021

Editorial Notes

28/02/2025: Contact details updated.
30/09/2022: Publication reference added.
13/07/2021: The following changes were made to the trial record:
1. The total final enrolment was added.
2. Uploaded protocol (not peer-reviewed) as an additional file. Version 4.1, 08 February 2021.
19/03/2021: The following changes were made to the trial record:
1. The primary and secondary outcome measures and contact details were updated.
2. The target number of participants was changed from 300 to 200.
3. IPD sharing statement added.
13/02/2020: Internal review.
12/02/2020: The following changes have been made:
1. The recruitment end date has been changed from 01/07/2020 to 01/07/2021.
2. The intention to publish date has been changed from 30/09/2021 to 30/09/2022.
3. The public title has been changed from "Point-of-care testing for respiratory viruses in critical care" to "Point-of-care testing for respiratory pathogens in critical care".
4. The scientific title has been changed from "Pragmatic randomised controlled trial of routine molecular Point-of-Care testing for respiratory viruses versus routine clinical care in adults with Severe Acute Respiratory Illness: a pilot Study (SARIPOC)" to "Pragmatic randomized controlled trial of molecular point-of-care testing for respiratory pathogens versus routine clinical care in critically ill adults with Pneumonia: SARIPOC".
5. The IRAS number has been added.
6. The study hypothesis has been updated.
7. The trial setting has been changed from "Not specified" to "Hospitals".
8. The trial type has been changed from "Treatment" to "Diagnostic".
9. The interventions have been updated.
10. The primary outcome measure has been updated.
11. The secondary outcome measures have been updated.
12. The participant inclusion criteria have been updated.
13. The participant exclusion criteria have been updated.
14. The publication and dissemination plan has been updated.
15. The plain English summary has been updated to reflect the changes above.
03/04/2019: The condition has been changed from "Specialty: Infectious diseases and microbiology, Primary sub-specialty: Other; UKCRC code/ Disease: Infection/ Other infectious diseases" to "Infectious diseases" following a request from the NIHR.