Additional information

CRediT contribution statement

Virve I Enne (https://orcid.org/0000-0002-0250-6377): Conceptualisation, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualisation, Writing – original draft, Writing – reviewing and editing.

Sarah-Jane F Stewart (https://orcid.org/0000-0003-2396-9028): Data curation, Formal analysis, Methodology, Visualisation, Writing – original draft, Writing – review and editing.

Adam P Wagner (https://orcid.org/0000-0002-9101-3477): Data curation, Formal analysis, Investigation, Methodology, Validation, Visualisation, Writing – original draft, Writing – reviewing and editing.

David Turner (https://orcid.org/0000-0002-1689-4147): Conceptualisation, Funding acquisition, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing – original draft, Writing – reviewing and editing.

Charlotte Russell (https://orcid.org/0000-0002-9335-5681): Data curation, Investigation, Project Administration, Writing – original draft.

Juliet High (https://orcid.org/0000-0003-2555-2349): Data curation, Methodology, Project administration, Supervision, Visualisation, Writing – original draft, Writing- reviewing and editing.

Susan Stirling (https://orcid.org/0000-0001-6663-7846): Data curation, Formal analysis, Methodology, Visualisation, Writing – reviewing and editing.

Julie A Barber (https://orcid.org/0000-0001-5762-762X): Formal analysis, Funding acquisition, Methodology, Supervision, Validation, Writing – reviewing and editing.

Robert Horne (https://orcid.org/0000-0002-3068-8438): Conceptualisation, Funding acquisition, Methodology, Supervision, Visualisation, Writing – reviewing and editing.

David M Livermore (https://orcid.org/0000-0002-9856-3703): Conceptualisation, Funding acquisition, Methodology, Supervision, Validation, Visualisation, Writing – original draft, Writing – reviewing and editing.

Vanya A Gant (https://orcid.org/0000-0001-6985-4969): Conceptualisation, Funding acquisition, Methodology, Validation, Visualisation, Writing – original draft, Writing – reviewing and editing.

Acknowledgements

The INHALE investigators and authors of this report would like to thank the following individuals for their contributions to the research.

INHALE study staff and team members

Hollian Richardson, Brenda Nominakur and Dewi Owen for their contributions to WP1.

Alp Aydin, Federico Ricciardi and Rossella Baldan for their contributions to WP1 and WP2.

Antony Colles for data management throughout the programme.

Kerry Dresser, Zaneeta Dhesi, Kerry Roulston and Naseem Ahmed for their contributions to WP3.

Alyssa Pandolfo, Natalie Bidad, Zoe Moon, Yogini Jani, Thomas Reader and Stephen Brett for their contributions to WP4.

Ann Marie Swart, David Brealey and Justin O’Grady for general contributions to all work packages.

INHALE clinical site PIs and staff

INHALE Programme Steering Committee

Prof. Paul Dark, Dr Andre Charlett, Ms Susan Bennett, Prof. Paul Aveyard, Prof. Robert Masterton.

INHALE patient and public involvement panel

Elizabeth Cooper, Jennie Griffiths, Margaret McWilliams, Patrick Thompson, Penny Vicary, Amander Wellings, Rebecca Harmston.

INHALE Data Monitoring Committee

Prof. Martin Llewelyn, Dr Katie Saunders, Prof. John Simpson, Dr Rosy Reynolds, Dr Giovanni Satta.

INHALE Antibiotic Stewardship Outcome Adjudication Committee

Dr Benny Cherian, Dr Matthew Dryden, Dr Peter Riley, Dr Ruan Simpson.

We would additionally like to thank bioMérieux and ONT for providing instruments and consumables; bioMérieux also provided logistics support. We would also like to thank the NIHR Clinical Research Network for support, The UCL Joint Research office for sponsorship and NCTU for support.

Patient data statement

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it is important that there are safeguards to make sure that they are stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation

Data-sharing statement

The data dictionary and deidentified patient data analysed and presented in this study are available from NCTU following publication, on reasonable request and subject to appropriate data sharing agreements. The statistical analysis plan for WP3 is publicly available at https://norwichctu.uea.ac.uk/inhale/.

Ethics statement

For WP1, inclusion of the study within the UCL DNA Infection Bank ethical framework (REC 17/LO/1530) was sought, allowing collection of anonymised surplus clinical specimens and associated data. Approval was given on 18 July 2016.

For WP2, ethical permission was sought and received from Camden and Kings Cross research ethics committee, reference REC 16/LO/1618 on 28 September 2016. This included WP5 data collection and was later amended and approved on 8 February 2018 to include WP4 work.

For WP3, the trial was approved by the London-Brighton and Sussex Research Ethics Committee (19/LO/0400) and HRA approval was obtained on 9 April 2019. This application included WP4 and WP5 work and was later amended and approved on 6 April 2020 to include the COVID-19 observational substudy.

Information governance statement

University College London (UCL) is committed to handling all personal information in line with the UK Data Protection Act (2018) and the General Data Protection Regulation (EU GDPR) 2016/679.

Under the Data Protection legislation University of East Anglia (UEA) and UCL are the Data Processors; UCL is the Data Controller and we process personal data in accordance with their instructions. You can find out more about how we handle personal data, including how to exercise your individual rights and the contact details for UCL’s Data Protection Officer here www.ucl.ac.uk/legal-services/privacy/participants-health-and-care-research-privacy-notice

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the NIHR Journals Library report publication page at https://doi.org/10.3310/GJVG0801.

Primary conflicts of interest: Infrastructure support for this was provided by the NIHR University College London and Imperial College London Biomedical Research Centres. biomérieux provided FilmArray Torch instruments, Pneumonia Panel tests and QC materials free of charge. ONT provided reagents free of charge. The manufacturers had no input into the conception, design, data analysis or interpretation of the study and no input into writing of the manuscript.

Virve I Enne reports consultancy and speaker fees from bioMérieux, personal fees from Alchemab Therapeutics, and in-kind contributions from Inflammatix Inc. Adam Wagner reports multiple grant funding from the NIHR (NIHR133013; NIHR133455; NIHR131889; NIHR131573; NIHR128550; NIHR200171; NIHR200020). Vanya A Gant reports speaker fees from bioMérieux and consultancy fees from Gilead, MSD, Pfizer and Shionogi. Juliet High reports consultancy fees from bioMérieux. David Livermore 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 Dechra, GenPax, GSK, Merck, Oxford Nanopore and PerkinElmer/Revvity, comprising < 10% of portfolio value. He also has nominated holdings in Arecor, Celadon Pharmaceuticals, Destiny Pharma, Eluceda Ltd, Genedrive, Poolbeg, 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. David M Livermore served as an assessor on the HTA Healthcare Associate infection Board (2008–9).

All other authors declare no competing interests.

Copyright and credit statement

Every effort has been made to obtain the necessary permissions for reproduction, to credit original sources appropriately and to respect copyright requirements. However, despite our diligence, we acknowledge the possibility of unintentional omissions or errors and we welcome notifications of any concerns regarding copyright or permissions.

Publications

Journal articles

Charalampous T, Kay GL, Richardson H, Aydin A, Baldan R, Jeanes C, et al. Nanopore metagenomics enables rapid clinical diagnosis of bacterial lower respiratory infection. Nat Biotechnol 2019;37:783–92. URL: https://ueaeprints.uea.ac.uk/id/eprint/71681

Dhesi Z, Enne VI, O’Grady J, Gant V, Livermore DM. Rapid and point-of-care testing in respiratory tract infections: an antibiotic guardian? ACS Pharmacol Transl Sci 2020;3:401–17. https://doi.org/10.1021/acsptsci.0c00027

Wagner AP, Enne VI, Livermore DM, Craig JV, Turner DA; INHALE Study Group. A review of health economic models and ventilator associated pneumonia (VAP). J Hosp Infect 2020;106:745–56. https://doi.org/10.1016/j.jhin.2020.09.012

High J, Enne VI, Barber JA, Brealey D, Turner DA, Horne R, et al. INHALE: the impact of using FilmArray Pneumonia Panel molecular diagnostics for hospital-acquired and ventilator-associated pneumonia on antimicrobial stewardship and patient outcomes in UK Critical Care-study protocol for a multicentre randomised controlled trial. Trials 2021;22:680. https://doi.org/10.1186/s13063-021-05618-6

Pandolfo A, Horne R, Jani Y, Reader TW, Bidad N, Brealey D, et al. Intensivists’ beliefs about rapid multiplex molecular diagnostic testing and its potential role in improving prescribing decisions and antimicrobial stewardship: a qualitative study. Antimicrob Resist Infect Control 2021;10:95. https://doi.org/10.1186/s13756-021-00961-4

Enne VI, Aydin A, Baldan R, Owen DR, Richardson H, Ricciardi F, et al. Multicentre evaluation of two multiplex PCR platforms for the rapid microbiological investigation of nosocomial pneumonia in UK ICUs: the INHALE WP1 study. Thorax 2022;77:1220–8. https://doi.org/10.1136/thoraxjnl-2021-216990

Pandolfo A, Horne R, Jani Y, Reader TW, Bidad N, Brealey D, et al. Understanding decisions about antibiotic prescribing in ICU: an application of the Necessity Concerns Framework. BMJ Qual Saf 2022;31:199–210. https://doi.org/10.1136/bmjqs-2020-012479

Stewart SJF, Pandolfo A, Moon Z, Jani Y, Brett SJ, Brealey D, et al. UK clinicians’ attitudes towards the application of molecular diagnostics to guide antibiotic use in ICU patients with pneumonias: a quantitative study. J Antimicrob Chemother 2024;79:123–7. https://doi.org/10.1093/jac/dkad355

Enne VI, Stirling S, Barber JA, High J, Russell C, Brealey D, et al. 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. Intensive Care Med 2025;51:272–86. https://doi.org/10.1007/s00134-024-07772-2

Stewart SJF, Pandolfo AM, Jani Y, Moon Z, Brealey D, Enne VI, et al. Guidelines vs mindlines: a qualitative investigation of how clinicians’ beliefs influence the application of rapid molecular diagnostics in intensive care. Antimicrob Agents Chemother 2025;69:e0115624. https://doi.org/10.1128/aac.01156-24

Wagner AP, Enne VI, Gant V, Stirling S, Barber Ja, Livermore DM et al. Cost-effectiveness of rapid, ICU-based, syndromic PCR in hospital-acquired pneumonia: analysis of the INHALE WP3 multi-centre RCT. Critical Care 2025;29(1):352. https://doi.org/10.1186/s13054-025-05428-1

Stewart SJF, Enne VI, Pandolfo AM, Jani YH, Brealey D, Brett SJ, et al. Machine says yes, doctor says no: an ecological momentary assessment analysis examining clinicians' perceptions of, and their antibiotic prescribing behaviour when using rapid molecular diagnostic tests in intensive care. Antimicrob Resist Infect Control 2026;15:42. https://doi.org/10.1186/s13756-025-01690-8

Conference presentations

Jeanes C, Richardson H, Ozongwu C, Personne Y, Enne VI, O'Grady J. Presented as oral presentation at 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Vienna, April 2017.

Aydin S, Owen DR, Richardson H, Baldan R, Charalampous T, Gant V, et al. Rapid Metagenomic Sequencing to Predict the Antimicrobial Resistance of Bacteria Directly from Endotracheal Aspirates in VAP Patients. Presented as late-breaker poster presentation at 28th ECCMID, Madrid, April 2018.

Owen DR, Richardson H, Aydin S, Baldan R, Nomamiukor B, Gant V, et al. A Comparison of Routine Microbiology Culture, Comprehensive Culture and 16S Metagenomic Sequencing in Identifying Bacterial Pathogens in Hospital-Acquired Pneumonia. Presented as poster presentation at 28th ECCMID, Madrid, April 2018.

Richardson H, Charalampous T, Baldan R, Aydin S, Owen D, Kay G, et al. Rapid Metagenomic Sequencing-Based Investigation of Hospital-Acquired and Ventilator-Associated Pneumonia. Presented as oral presentation at 28th ECCMID, Madrid, April 2018.

Enne VI, Aydin A, Richardson H, Owen D, Baldan R, Russell C, et al. INHALE WP1: An Observational Study Comparing the Performance of Two Multiplex PCR Platforms against Routine Microbiology for the Detection of Potential Pathogens in Patients with Suspected Hospital-Acquired/Ventilator-Associated Pneumonia (HAP/VAP) across 15 UK Intensive Care Units (ICUs). Presented as poster presentation at 29th ECCMID, Amsterdam, April 2019.

Enne VI, Baldan R, Russell C, Aydin A, Richardson H, Owen D, et al. INHALE WP2: Appropriateness of Antimicrobial Prescribing for Hospital-Acquired and Ventilator-Associated Pneumonia (HAP/VAP) in UK ICUs Assessed against PCR-Based Molecular Diagnostic Tests. Presented as a poster presentation at 29th ECCMID, Amsterdam, April 2019.

Owen DR, Alfassam H, Arumainayagam C, Aydin A, Richardson H, Baldan R, et al. Prediction of the Antimicrobial Resistance Profiles of E. coli and K. pneumoniae Directly from Respiratory Samples Using Oxford Nanopore Technologies (ONT) MinION Nanopore Metagenomic Sequencing. Presented as a mini-oral presentation at 29th ECCMID, Amsterdam, April 2019.

Wagner AP, Turner D, Enne VI, Baldan R, Russell C, Livermore DM.  Health Economics of Nosocomial Pneumonia in UK Intensive Care Units (ICU): An Exploratory Study. Presented as ePoster at 40th International symposium of Intensive Care and Emergency Medicine (ISICEM), held online in September 2020.

Enne VI, Aydin A, Baldan R, Owen D, Richardson H, Ricciardi F, et al. Rapid Identification of Antibiotic Resistance in Respiratory Samples Using the Automated Biofire FilmArray and Curetis Unyvero Rapid PCR-Based Pneumonia Panels. Presented as ePoster presentation at 31st ECCMID conference, which took place online in July 2021.

Pandolfo AM, Jani Y, Brett SJ, Brealey D, Singh S, Enne VI, et al. Understanding ICU Clinicians’ Beliefs about Broad-spectrum Antibiotic Usage and Molecular Diagnostic Utility During the COVID-19 Pandemic. Presented as oral presentation at 31st ECCMID conference, which took place online in July 2021.

Pandolfo AM, Horne R, Jani Y, Reader TW, Bidad N, Brealey D, et al. Understanding Prescribers’ Beliefs about Molecular Diagnostic Tests as Barriers and Facilitators to Test Uptake in ICUs: A Qualitative Study. Presented as oral presentation at 31st ECCMID conference, which took place online in July 2021.

Dhesi Z, Brealey D, High J, Gant V, De Neef M, Page V, et al. Utility of a 29-mRNA Host-Response Assay, together with PCR-Based Rapid Pathogen Diagnostics to Identify Pneumonias in Intensive Care Unit (ICU) Patients. Presented as poster presentation at 32nd ECCMID Congress, Lisbon, April 2022.

Enne VI, Stirling S, Barber JA, High J, Russell C, Dresser K, et al. INHALE WP3: Clinical Outcomes and Antimicrobial Stewardship Analyses from of a Multi-Centre RCT (INHALE) Testing the Utility of Rapid Multiplex PCR for Hospital-Acquired and Ventilator-Associated Pneumonia in Critical Care. Presented as oral presentation at IDWeek 2022, Washington, DC. Open Forum Infectious Diseases, Vol 9, Suppl_2, 2022.

Pandolfo AM, Horne R, Jani Y, Moon Z, Brealey D, Enne VI, et al. Understanding Intensive Care Clinicians’ Beliefs of Rapid Multiplex Molecular Diagnostic Tests in Clinical Practice: A Qualitative Application of the Necessity Concerns Framework. Presented as oral presentation at 32nd ECCMID Congress, Lisbon, April 2022.

Roulston K, Dhesi Z, Livermore DM, Gant V, Enne VI. Impact of Filmarray (bioMerieux) for the Diagnosis of Bacterial Pneumonia in COVID-19 Patients on Antibiotic Prescribing Decisions at Five UK ICUs. Presented as oral presentation at 32nd ECCMID Congress, Lisbon, April 2022.

Stewart SJF, Moon Z, Pandolfo AM, Jani Y, Brett S, Brealey D, et al. ICU Clinicians’ Beliefs about Prescribing Broad Spectrum Antibiotics and Attitudes towards Rapid Molecular Diagnostics within the Context of COVID-19. Presented as poster presentation at 32nd ECCMID Congress, Lisbon, April 2022.

Dhesi Z, Enne VI, Barber J, Russell C, High J, Gant V, et al. Microbiology of Hospital-Acquired and Ventilator Associated Pneumonia as Detected by Multiplex PCR in Intensive Care Unit Patients from the UK: An INHALE Sub-study. Presented as flash talk presentation at 33rd ECCMID Congress, Copenhagen, April 2023.

Enne VI, Stirling S, Barber JA, High J, Russell C, Dresser K, et al. INHALE WP3: Clinical Outcomes and Antimicrobial Stewardship Analyses from of a Multi-Centre RCT (INHALE) Testing the Utility of Rapid Multiplex PCR for Hospital-Acquired and Ventilator-Associated Pneumonia in Critical Care. Presented as oral presentation at 33rd ECCMID Congress, Copenhagen, April 2023.

Stewart SJF, Pandolfo A, Enne VI, Russell C, Moon Z, Jani Y, et al. ICU Clinicians’ Perceptions of Rapid Multiplex PCR for Diagnosis of Pneumonia and Barriers to Application in Practice: An INHALE Trial Sub-Study. Presented as poster presentation at 33rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Copenhagen, April 2023.

Wagner AP, Turner D, Stirling S,Barber J, Enne VI, Gant V, et al. Economic Evaluation of the INHALE Trial: Are Rapid Molecular Diagnostics Cost-Effective for the Management of Nosocomial Pneumonia in UK Intensive Care Units (ICU)? Presented as poster presentation at 33rd ECCMID Congress, Copenhagen, April 2023.

Enne VI, Aydin A, Richardson H, Owen D, Baldan R, Russelll C, et al. INHALE WP1: Variability of Routine Microbiology for the Investigation of Hospital-Acquired and Ventilator-Associated Pneumonia (HAP/VAP) across 11 Laboratories Serving 15 UK ICUs. Presented as an e-poster oral presentation at 29th ECCMID, Amsterdam, April 2021.

Other

Pre-print

Dhesi Z, Enne VI, Brealey D, Livermore DM, High J, Russell C, et al. 2020. Organisms causing secondary pneumonias in COVID-19 patients at 5 UK ICUs as detected with the FilmArray test. MedRvix. https://doi.org/10.1101/2020.06.22.20131573

Work package 3 statistical analysis plan

https://norwichcrtu.uea.ac.uk/ctudocs_public/inhale/Analysis%20plan%20v1.0%20-%20INHALE%2022-02-2022.pdf

Health-economic analysis plan

https://norwichcrtu.uea.ac.uk/ctudocs_public/inhale/heap_1_4.pdf

Thesis

Dhesi Z. Rapid Diagnosis and Treatment of Hospital-Acquired and Ventilator-Associated Pneumonia in Intensive Care Unit Patients. Doctoral thesis [MD (Res)], UCL (University College London). 2021.

Lay dissemination

The INHALE WP3 results have been depicted in an infographic for more accessible dissemination – see Appendix 11. The team also sent a study update and a thank you letter to participants of WP3, an initiative suggested by the PPI panel. The infographic will be sent out once the corresponding paper is published.

The PPI panel also produced a poem about the research – a video recording of it can be viewed here: www.youtube.com/watch?v=7_2bqWlJzFE

One of the PPI panel members also wrote a blog about participation in research for those with problems accessing the internet, see: https://arc-eoe.nihr.ac.uk/news-blogs/blogs/blog-why-people-should-be-involved-who-do-not-have-internet

In addition to production of the above outputs, the team have also participated in various public engagement events for dissemination of the research to lay audiences. These were the Royal Free Trust open day, UCLH open day, the Rise of Resistance Festival, the HRA Make it Public conference, the Science Museum Build a Body event and the Norwich Science Festival.

For the latter two events, the INHALE team developed an educational game to teach visiting children about antimicrobial resistance and the role of diagnostics.