Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND

Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia.

METHODS

In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing.

RESULTS

Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%).

CONCLUSIONS

Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing.

CLINICAL TRIALS REGISTRATION

NCT04047719.

Informations de copyright

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Déclaration de conflit d'intérêts

Potential conflicts of interest. S. P. B. reports being a consultant to C3J Therapeutics. R. F. C. reports being a scientific advisor or consultant for ADMA Biologics, Pulmotec, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinoigi, Genentech, Astellas, Adagio Therapeutics, Oxford Immunotec, Qiagen, Karius, and Ansun Pharmaceuticals and received research grants paid to his institution from National Institutes of Health (NIH)/National Cancer Institute (NCI), Merck/Merck, Sharp & Dohme (MSD), Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, Freestyle, and Eurofins-Viracor, and reports payment or honoraria as a speaker for Qiagen and Viracor-Eurofins. S. D. reports research grants paid to his institution from Karius, Merck, Gilead, Ansun Biopharma, Allovir, Geovax. He has served on advisory boards of Merck, Takeda, Allovir, and Aseptiscope, Inc. He is on speaker's bureau of Merck, Astellas and Takeda, and reports payment or honoraria from Viracor for educational event at ID week 2022 and from MJH for cytomegalovirus (CMV) symposium at American Society of Hematology (ASH) 2022. He has stock options in Aseptiscope, Inc, Matinas Biopharma, and Cidara Therapeutics. He reports consulting fees from Merck and Allovir; support for attending meetings and/or travel from American Society of Transplantation and Cellular Therapy—Tandem 2022 and 2023 (registration credit), ID week 2022—Infectious Diseases Society of America (IDSA) (partial support—airfare), and Immunocompromised Host Society (ICHS) 2022 (air fare and hotel expenses); Patent # 9416395, Assigned to City of Hope. Inventors—Markus Kalkum, Karine Bagramyan, Diana Diaz-Arevalo, James I. Ito, Sanjeet S. Dadwal (assigned to City of Hope) and US Provisional Patent Application no. 63/067,855: Inventors—Markus Kalkum, Daniel Roeth, Sanjeet S. Dadwal (assigned to City of Hope); a role as Chair of Transplant Infectious Disease Special Interest Group of American Society of Transplant and Cellular Therapy (ASTCT). J. A. H. reports research grants paid to his institution from Karius and consulting for Karius and support for travel to advisory board meeting from Karius. Y. J. L. has served as an investigator for Astellas, Karius, AiCuris, and Scynexis and has received research grant support from Merck & Co Inc. G. H. is a recipient of research grants from Allovir, Karius, and AstraZeneca and also serves on the scientific advisory boards of and receives consulting fees from Karius and AstraZeneca, and reports grants or contracts from NIH; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MDOutlook, PeerView Medical Education, International AIDS Society. A. L. reports consulting fees from Karius. F. K. reports honorarium from Medscape and research support from Eurofins-Viracor. G. A. P. reports research support from MSD and Takeda/Shire and consulting and other fees from AlloVir, Amplyx, SLC Behring, Cidara, MSD, Takeda and Octapharma. C. B. S. reports research grant support from NIH, GlaxoSmithKline, ViiV, Abbott, Merck, Gilead, Chimerix, Shire/Takeda, Schering-Plough, Ablynx, Janssen, Ansun Biopharma, and Karyopharm Therapeutics; participation on Janssen Respiratory Viruses Advisory Board and Merck Scientific Input Engagement (SIE) Panel for Molnupirivir. M. F. reports research grant support from NIH, and research funding (UCSF PI Fung) from Scynexis and Vatic, Ltd. M. T. M. reports being a consultant for UpToDate and Karius and a co-inventor of patents on Methods to Detect and Treat Acute Respiratory Infections. E. K. M. reports consulting fees from Karius Inc as a Clinical Events Committee member/reviewer—received payments as clinical adjudicator for another Karius project. D. B. M. reports consulting fees from Karius Inc.. A. D. B . reports payment or honoraria from Novartis for lecture on Sepsis Watch, AI program developed at Duke. J. L. T. reports advisory board participation for Sanofi, Natera, Theravance and Altavant Sciences (now Enzyvant Therapeutics) in addition to grants to the institution from Boehringer-Ingelheim, AstraZeneca, Sanofi, NIH, Cystic Fibrosis Foundation and CareDx; and consulting fees from Sanofi. C. E. B. reports grants or contracts from American Lung Association and NIH (National Heart, Lung, and Blood Institute [NHLBI] and National Institute of Allergy and Infectious Diseases [NIAID] funded projects—not related to this project); participation as member of a Data and Safety Monitoring Board (DSMB) for VASSPR—an ICU-based trial with no relationship to this project. R. B. reports stock holdings in Merck, Johnson & Johnson, COVIDien, Pfizer, Sanofi, McKesson, and Viatris and consulting fees from Elixir. E. L. T. reports personal fees from Biomeme and Predigen, stock options in Danaher, and being an employee of Danaher Corp. O, W. reports support for attending meetings and/or travel from Karius (as Clinical Events Classification [CEC] Project Leader initiated and attended meetings with Karius for the PICKUP study); a role as CEC Project Leader coordinated CEC committee meetings within Duke Clinical Research Institute (DCRI) for the PICKUP trial. M. M. reports being an employee of Karius Inc, Redwood City, California, and may own stock options. D. H. reports being a former employee of Karius Inc, Redwood City, California, and a patent issued for related work while at Karius as employee (WO-2020106987-A1—Detection and Prediction of Infectious Disease). R. D. reports being a former employee of Karius Inc, Redwood City, California, and is owner of Karius stock options. D. S. L. reports being an employee of Karius Inc, Redwood City, California, and may own stock options. S. B. reports being an employee of Karius Inc, Redwood City, California, and may own stock options, and reports support for attending meetings and/or travel and patents planned, issued, or pending with Karius Inc. B, A. P. reports being an employee of Karius Inc, Redwood City, California, patents planned, issued or pending with Karius Inc, and may own stock options. T. A. B. reports being an employee of and having a leadership or fiduciary role with Karius Inc, Redwood City, California, and may own stock options. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; royalties from UpToDate, stock options from Valanbio and ArcBio, honoraria from IDSA for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. T. L. H. reports being an advisor and consultant to Aridis, Basilea Pharmaceutica, Karius, and Lysovant; royalties from UpToDate; reports grants or contracts with Karius (adjudication committee) and with NIH; reports consulting fees from Pfizer and Affinivax; participation on DSMB for platform trial for SNAP Trial; and on advisory board for Basilea. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.