Randomized Controlled Trial

. 2025 Feb;51(2):272-286.

doi: 10.1007/s00134-024-07772-2. Epub 2025 Feb 17.

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Virve I Enne¹, Susan Stirling², Julie A Barber³, Juliet High², Charlotte Russell², David Brealey^{4

5}, Zaneeta Dhesi^{6

7}, Antony Colles², Suveer Singh^{8

9}, Robert Parker¹⁰, Mark Peters¹¹, Benny P Cherian¹², Peter Riley¹³, Matthew Dryden^{14

15}, Ruan Simpson¹⁶, Nehal Patel¹⁷, Jane Cassidy¹⁸, Daniel Martin^{19

20}, Ingeborg D Welters^{21

22}, Valerie Page²³, Hala Kandil²⁴, Eleanor Tudtud²⁵, David Turner²⁶, Robert Horne²⁷, Justin O'Grady²⁶, Ann Marie Swart², David M Livermore²⁶, Vanya Gant²⁸; INHALE WP3 Study Group and Committees

Collaborators, Affiliations

Collaborators

INHALE WP3 Study Group and Committees:
Ian Turner-Bone, Laura Wilding, Helen Winmill, Carly Tooke, Philip Milner, Jeronimo Cuesta, Zoran Aman, Rhian Bull, Jaime Carungcong, Patricia Correia da Costa, Luke Moore, Nabeela Mughal, Julian Sonksen, Karen Reid, Olugbenga Akinugbe, Lauran O'Neill, Michael Karlikowski, Julie North, Angela Aramburo, Justin Wang, Kamal Liyanage, Laura Tous, Jenny Tan, Pooja Patel, Mark de Neef, Helder Filipe, Sara Garcia Mingo, Damian Mack, David Shaw, Karen Williams, Victoria Waugh, Naseem Ahmed, Nigel Klein, Federico Ricciardi, Alyssa Pandolfo, Sarah-Jane Stewart, Laura Shallcross, Georgia Bercades, Ingrid Hass, Deborah Smyth, Minnie Gellamucho, Kerry Dresser, Adam P Wagner, Xiaobei Zhao, Giovanni Pipi, Paul Dark, Andre Charlett, Susan Bennett, Paul Aveyard, Robert Masterton, Martin Llewelyn, Katie Saunders, John Simpson, Rosy Reynolds, Giovanni Satta, Benny Cherian, Matthew Dryden, Peter Riley, David Livermore, Elizabeth Cooper, Jennie Griffiths, Margaret McWilliams, Patrick Thompson, Penny Vicary, Amander Wellings, Rebecca Harmston

Affiliations

¹ Centre for Clinical Microbiology, Royal Free Hospital, University College London, London, UK. v.enne@ucl.ac.uk.
² Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK.
³ Department of Statistical Science, University College London, London, UK.
⁴ Critical Care Unit, University College London Hospitals, London, UK.
⁵ NIHR University College London Hospitals Biomedical Research Centre, University College London Hospitals, London, UK.
⁶ Centre for Clinical Microbiology, Royal Free Hospital, University College London, London, UK.
⁷ Department of Microbiology, University College London Hospitals, London, UK.
⁸ Respiratory and Intensive Care Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
⁹ Department of Critical Care, Royal Brompton and Harefield Foundation Trust, London, UK.
¹⁰ Department of Critical Care Medicine, Aintree University Hospital, Liverpool, UK.
¹¹ Paediatric Intensive Unit, UCL Great Ormond St Institute of Child Health NIHR Biomedical Research Centre, London, UK.
¹² Microbiology and Infectious Diseases, Barts Health NHS Trust, London, UK.
¹³ Department of Infection, St George's University Hospitals NHS Foundation Trust, London, UK.
¹⁴ Department of Microbiology, Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK.
¹⁵ Global Operations, UK Health Security Agency, Porton Down, UK.
¹⁶ Department of Microbiology, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
¹⁷ Department of Anaesthesia and Critical Care, University Hospitals of North Midlands NHS Trust, Stoke, UK.
¹⁸ Paediatric Intensive Care Unit, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
¹⁹ Intensive Care Unit, Royal Free London NHS Foundation Trust, London, UK.
²⁰ Medical School, University of Plymouth, John Bull Building, Plymouth, UK.
²¹ Royal Liverpool Intensive Care Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
²² Institute of Life Course and Clinical Sciences, University of Liverpool, Liverpool, UK.
²³ Intensive Care Unit, West Hertfordshire Teaching Hospitals NHS Trust, Watford, UK.
²⁴ Department of Microbiology, West Hertfordshire Teaching Hospitals NHS Trust, Watford, UK.
²⁵ Critical Care Unit, Cromwell Hospital, London, UK.
²⁶ Norwich Medical School, University of East Anglia, Norwich, UK.
²⁷ School of Pharmacy, University College London, London, UK.
²⁸ Department of Microbiology, University College London Hospitals, London, UK. vanyagant@nhs.net.

PMID: 39961847
PMCID: PMC11903508
DOI: 10.1007/s00134-024-07772-2

Randomized Controlled Trial

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Virve I Enne et al. Intensive Care Med. 2025 Feb.

. 2025 Feb;51(2):272-286.

doi: 10.1007/s00134-024-07772-2. Epub 2025 Feb 17.

Authors

Collaborators

INHALE WP3 Study Group and Committees:
Ian Turner-Bone, Laura Wilding, Helen Winmill, Carly Tooke, Philip Milner, Jeronimo Cuesta, Zoran Aman, Rhian Bull, Jaime Carungcong, Patricia Correia da Costa, Luke Moore, Nabeela Mughal, Julian Sonksen, Karen Reid, Olugbenga Akinugbe, Lauran O'Neill, Michael Karlikowski, Julie North, Angela Aramburo, Justin Wang, Kamal Liyanage, Laura Tous, Jenny Tan, Pooja Patel, Mark de Neef, Helder Filipe, Sara Garcia Mingo, Damian Mack, David Shaw, Karen Williams, Victoria Waugh, Naseem Ahmed, Nigel Klein, Federico Ricciardi, Alyssa Pandolfo, Sarah-Jane Stewart, Laura Shallcross, Georgia Bercades, Ingrid Hass, Deborah Smyth, Minnie Gellamucho, Kerry Dresser, Adam P Wagner, Xiaobei Zhao, Giovanni Pipi, Paul Dark, Andre Charlett, Susan Bennett, Paul Aveyard, Robert Masterton, Martin Llewelyn, Katie Saunders, John Simpson, Rosy Reynolds, Giovanni Satta, Benny Cherian, Matthew Dryden, Peter Riley, David Livermore, Elizabeth Cooper, Jennie Griffiths, Margaret McWilliams, Patrick Thompson, Penny Vicary, Amander Wellings, Rebecca Harmston

Affiliations

¹ Centre for Clinical Microbiology, Royal Free Hospital, University College London, London, UK. v.enne@ucl.ac.uk.
² Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK.
³ Department of Statistical Science, University College London, London, UK.
⁴ Critical Care Unit, University College London Hospitals, London, UK.
⁵ NIHR University College London Hospitals Biomedical Research Centre, University College London Hospitals, London, UK.
⁶ Centre for Clinical Microbiology, Royal Free Hospital, University College London, London, UK.
⁷ Department of Microbiology, University College London Hospitals, London, UK.
⁸ Respiratory and Intensive Care Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
⁹ Department of Critical Care, Royal Brompton and Harefield Foundation Trust, London, UK.
¹⁰ Department of Critical Care Medicine, Aintree University Hospital, Liverpool, UK.
¹¹ Paediatric Intensive Unit, UCL Great Ormond St Institute of Child Health NIHR Biomedical Research Centre, London, UK.
¹² Microbiology and Infectious Diseases, Barts Health NHS Trust, London, UK.
¹³ Department of Infection, St George's University Hospitals NHS Foundation Trust, London, UK.
¹⁴ Department of Microbiology, Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK.
¹⁵ Global Operations, UK Health Security Agency, Porton Down, UK.
¹⁶ Department of Microbiology, Portsmouth Hospitals NHS Trust, Portsmouth, UK.
¹⁷ Department of Anaesthesia and Critical Care, University Hospitals of North Midlands NHS Trust, Stoke, UK.
¹⁸ Paediatric Intensive Care Unit, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
¹⁹ Intensive Care Unit, Royal Free London NHS Foundation Trust, London, UK.
²⁰ Medical School, University of Plymouth, John Bull Building, Plymouth, UK.
²¹ Royal Liverpool Intensive Care Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
²² Institute of Life Course and Clinical Sciences, University of Liverpool, Liverpool, UK.
²³ Intensive Care Unit, West Hertfordshire Teaching Hospitals NHS Trust, Watford, UK.
²⁴ Department of Microbiology, West Hertfordshire Teaching Hospitals NHS Trust, Watford, UK.
²⁵ Critical Care Unit, Cromwell Hospital, London, UK.
²⁶ Norwich Medical School, University of East Anglia, Norwich, UK.
²⁷ School of Pharmacy, University College London, London, UK.
²⁸ Department of Microbiology, University College London Hospitals, London, UK. vanyagant@nhs.net.

PMID: 39961847
PMCID: PMC11903508
DOI: 10.1007/s00134-024-07772-2

Abstract

Purpose: INHALE investigated the impact of seeking pathogens by PCR on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia (HAP and VAP).

Methods: This pragmatic multicentre, open-label RCT enrolled adults and children with suspected HAP and VAP at 14 ICUs. Patients were randomly allocated to standard of care, or rapid in-ICU syndromic PCR coupled with optional prescribing guidance. Co-primary outcomes were superiority in antibiotic stewardship at 24 h and non-inferiority in clinical cure of pneumonia 14 days post-randomisation. Secondary outcomes included mortality, ICU length of stay and evolution of clinical scores.

Results: 554 eligible patients were recruited from 5th July 2019 to 18th August 2021, with a COVID-enforced pause from 16th March 2020 and 9th July 2020. Data were analysed for 453 adults and 92 children (68.4% male; 31.6% female). ITT analysis showed 205/268 (76.5%) reviewable intervention patients receiving antibacterially appropriate and proportionate antibiotics at 24 h, versus 147/263 (55.9%) standard-of-care patients (estimated difference 21%; 95% CI 13-28%). However, only 152/268 (56.7%) intervention patients were deemed cured of pneumonia at 14 days, versus 171/265 (64.5%) standard-of-care patients (estimated difference - 6%, 95% CI - 15 to 2%; predefined non-inferiority margin -13%). Secondary mortality and ΔSOFA outcomes narrowly favoured the control arm, without clear statistical significance.

Conclusions: In-ICU PCR for pathogens resulted in improved antibiotic stewardship. However, non-inferiority was not demonstrated for cure of pneumonia at 14 days. Further research should focus on clinical effectiveness studies to elucidate whether antibiotic stewardship gains achieved by rapid PCR can be safely and advantageously implemented.

Keywords: Antibiotic stewardship; Hospital-acquired pneumonia (HAP); Molecular diagnostics; Point-of-care; Rapid PCR; Syndromic PCR; Ventilator-associated pneumonia (VAP).

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of interest: DB reports payments for educational sessions from bioMérieux and Gilead and consultancy fees from Paion. VE reports consultancy and speaker fees from bioMérieux, personal fees from Alchemab Therapeutics, and in-kind contributions from Inflammatix Inc. JOG has reports personal fees and/or in-kind contributions and/or research funding from Oxford Nanopore Technologies (ONT), Simcere, Becton–Dickinson and Heraeus Medical. He is now an employee of ONT and holds shares in the company. VG reports speaker fees from bioMérieux and consultancy fees from Gilead, MSD, Pfizer and Shionogi. JH reports consultancy fees from bioMérieux. HK reports speaker fees from bioMérieux. DML reports personal fees from Adjutec, AstraZeneca, bioMérieux, Centauri, GenPax, GSK, Hikma, Merck/MSD, Nordic, Paion, Pfizer, Shionogi, Sumitovant, Summit, Thermofisher, Wockhardt and Zambon, He also reports shareholdings from GenPax, GSK, Merck, Oxford Nanopore and PerkinElmer/Revvity, comprising less than 10% of portfolio value. He also has nominated holdings in Arecor, Celadon Pharmaceuticals, Destiny Pharma, Eluceda Ltd., Genedrive, Poolbeg, Optibiotix, Probiotix Health, SkinBiotherapeutics, Trellus and Verici Dx (all of which have research/products pertinent to medical and diagnostic innovation) through Enterprise Investment Schemes but has no authority to trade these shares directly. All are outside the submitted work. All other authors declare no competing interests.

Figures

**Fig. 2**
Kaplan–Meier plot for mortality

See this image and copyright information in PMC

References

1. Magill SS, Edwards JR, Bamberg W et al (2014) Multistate point-prevalence survey of health care-associated infections. N Engl J Med 370(13):1198–1208 - PMC - PubMed
1. Papazian L, Klompas M, Luyt C-E (2020) Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med 46(5):888–906 - PMC - PubMed
1. Limper AH (2012) 97—overview of pneumonia. In: Goldman L, Schafer AI (eds) Goldman’s Cecil medicine, 24th edn. W.B. Saunders, Philadelphia, pp 587–596
1. Luckraz H, Manga N, Senanayake EL et al (2018) Cost of treating ventilator-associated pneumonia post cardiac surgery in the National Health Service: results from a propensity-matched cohort study. J Intensive Care Soc 19(2):94–100 - PMC - PubMed
1. Martin-Loeches I, Torres A, Povoa P et al (2019) The association of cardiovascular failure with treatment for ventilator-associated lower respiratory tract infection. Intensive Care Med 45(12):1753–1762 - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

RP-PG-0514-20018/Programme Grants for Applied Research

LinkOut - more resources

Full Text Sources
- PubMed Central
- Springer
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Collaborators

Affiliations

INHALE WP3, a multicentre, open-label, pragmatic randomised controlled trial assessing the impact of rapid, ICU-based, syndromic PCR, versus standard-of-care on antibiotic stewardship and clinical outcomes in hospital-acquired and ventilator-associated pneumonia

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical