Dataset Information

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

ABSTRACT:

Background

Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit.

Methods

We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events.

Results

Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%).

Conclusions

Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.

SUBMITTER: Madut DB

PROVIDER: S-EPMC11292041 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Madut Deng B DB Chemaly Roy F RF Dadwal Sanjeet S SS Hill Joshua A JA Hill Joshua A JA Hill Joshua A JA Lee Yeon Joo YJ Haidar Ghady G Luk Alfred A Drelick Alexander A Chin-Hong Peter V PV Benamu Esther E Khawaja Fareed F Nanayakkara Deepa D Papanicolaou Genovefa A GA Small Catherine Butkus CB Fung Monica M Barron Michelle M Davis Thomas T McClain Micah T MT Maziarz Eileen K EK Bedoya Armando D AD Gilstrap Daniel L DL Todd Jamie L JL Barkauskas Christina E CE Heldman Madeleine R MR Bigelow Robert R Leimberger Jeffrey D JD Tsalik Ephraim L EL Wolf Olivia O Mughar Mona M Lau Constance C Noll Nicholas N Hollemon Desiree D Duttagupta Radha R Lupu Daniel S DS Bercovici Sivan S Perkins Bradley A BA Blauwkamp Timothy A TA Fowler Vance G VG Holland Thomas L TL Bergin Stephen P SP

Open forum infectious diseases 20240722 8

<h4>Background</h4>Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit.<h4>Methods</h4>We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a seco ...[more]

PMID: 39091643

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Project description:IntroductionImmunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value.AimThe objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients.MethodsA semi-Markov model was utilized from the US third-party payer's perspective such that only direct costs were included, using a lifetime time horizon with discount rates of 3% for costs and benefits. Three comparators were considered: (1) All UC, which included non-invasive (NI) and invasive testing and early bronchoscopy; (2) All UC & mcfDNA; and (3) NI UC & mcfDNA & conditional UC Bronch (later bronchoscopy if the initial tests are negative). The model considered whether a probable causative infectious etiology was identified and if the patient received appropriate antimicrobial treatment through expert adjudication, and if the patient died in-hospital. The primary endpoints were total costs, life-years (LYs), equal value life-years (evLYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio per QALY. Extensive scenario and probabilistic sensitivity analyses (PSA) were conducted.ResultsAt a price of $2000 (2023 USD) for the plasma mcfDNA, All UC & mcfDNA was more costly ($165,247 vs $153,642) but more effective (13.39 vs 12.47 LYs gained; 10.20 vs 9.42 evLYs gained; 10.11 vs 9.42 QALYs gained) compared to All UC alone, giving a cost/QALY of $16,761. NI UC & mcfDNA & conditional UC Bronch was also more costly ($162,655 vs $153,642) and more effective (13.19 vs 12.47 LYs gained; 9.96 vs 9.42 evLYs gained; 9.96 vs 9.42 QALYs gained) compared to All UC alone, with a cost/QALY of $16,729. The PSA showed that above a willingness-to-pay threshold of $50,000/QALY, All UC & mcfDNA was the preferred scenario on cost-effectiveness grounds (as it provides the most QALYs gained). Further scenario analyses found that All UC & mcfDNA always improved patient outcomes but was not cost saving, even when the price of mcfDNA was set to $0.ConclusionsBased on the evidence available at the time of this analysis, this CEA suggests that mcfDNA may be cost-effective when added to All UC, as well as in a scenario using conditional bronchoscopy when NI testing fails to identify a probable infectious etiology for ICHP. Adding mcfDNA testing to UC diagnostic testing should allow more patients to receive appropriate therapy earlier and improve patient outcomes.

Project description:BackgroundMetagenomic next-generation sequencing (mNGS) is increasingly being used for microbial detection in various infectious syndromes. However, data regarding the use of mNGS in solid organ transplant recipients (SOTR) are lacking.ObjectivesTo describe and analyze real-world clinical impact of mNGS using plasma microbial cell-free DNA (mcfDNA) in SOTR.Design: Retrospectively reviewed all adult SOTR who underwent mNGS testing using plasma mcfDNA at Baylor St Luke's Medical Center from March 2017 to February 2023.MethodsClinical impact (positive, neutral, and negative) was assessed using standardized objective criteria. Three Infectious Diseases physicians independently performed clinical adjudication to determine the correlation of mcfDNA results with clinical diagnosis. A descriptive analysis of the patient and clinical characteristics was performed.ResultsA total of 113 mcfDNA tests in liver (42%), kidney (35%), lung (20%) and heart (13%) transplant recipients were performed in the study period. The most common clinical syndromes were pneumonia (36%), fever of unknown origin (16%), and intra-abdominal infections (15%). Most (80, 71%) of the mcfDNA test results were positive for microorganisms. Twenty-seven (24%) cases were classified as positive clinical impact, 82 (73%) were neutral and 4 (3%) were negative, respectively.ConclusionIn SOTR, mcfDNA sequencing can add a positive clinical impact in a quarter of the cases and identify microorganisms beyond conventional microbiological testing across clinical syndromes. The negative clinical impact was rare. However, larger prospective studies are needed to define the optimal timing and utilization of mcfDNA in the sequence of diagnostic evaluation for syndrome-specific workup in SOTR.SummaryMetagenomic next-generation sequencing (mNGS) is a novel diagnostic tool that can identify difficult-to-detect microorganisms in SOTR. Our study demonstrates that the mNGS test resulted in a positive clinical impact in 1 out of 4 patients.

Project description:Sequencing of plasma microbial cell-free DNA (mcfDNA) has gained increased acceptance as a valuable adjunct to standard-of-care testing for diagnosis of infections throughout the body. Here, we report the analytical and clinical validation of a novel application of mcfDNA sequencing, the non-invasive detection of seven common antimicrobial resistance (AMR) genetic markers in 18 important pathogens. The AMR markers include SCCmec, mecA, mecC, vanA, vanB, blaCTX-M, and blaKPC. The AMR markers were computationally linked to the pathogens detected. Analytical validation showed high reproducibility (100%), inclusivity (54 to 100%), and exclusivity (100%). Clinical accuracy was assessed with 114 unique plasma samples from patients at seven study sites with concordant culture results for target bacteria from a variety of specimen types and correlated with available phenotypic antimicrobial susceptibility test results and genotypic results. The positive percent agreement (PPA), negative percent agreement (NPA), and diagnostic yield (DY) were estimated for each AMR marker. DY was defined as the percentage of tests that yielded an actionable result of either detected or not detected. The results for the combination of SCCmec and mecA for staphylococci were PPA 19/20 (95.0%), NPA 21/22 (95.4%), DY 42/60 (70.0%); vanA for enterococci were PPA 3/3 (100%), NPA 2/2 (100%), DY 5/6 (83.3%); blaCTX-M for gram-negative bacilli were PPA 5/6 (83.3%), NPA 29/29 (100%), DY 35/49 (71.4%); and blaKPC for gram-negative bacilli were PPA 0/2 (0%), NPA: 23/23 (100%), DY 25/44 (56.8%). The addition of AMR capability to plasma mcfDNA sequencing should provide clinicians with an effective new culture-independent tool for optimization of therapy.ImportanceThis manuscript is ideally suited for the Innovative Diagnostic Methods sections as it reports the analytical and clinical validation of a novel application of plasma microbial cell-free DNA sequencing for direct detection of seven selected antimicrobial resistance markers in 18 target pathogens. Clearly, it has potential clinical utility in optimizing therapy and was incorporated into the Karius test workflow in September 2023. In addition, the workflow could readily be adapted to expand the number of target bacteria and antimicrobial resistance markers as needed.

Project description:Sepsis is a common life-threatening disease in the intensive care unit (ICU) that is usually treated empirically without pathogen identification. As a non-invasive and high-throughput technology, plasma microbial cell-free DNA (mcfDNA) sequencing can detect unknown pathogens independent of previous clinical or laboratory information. In this study, a total of 199 cases suspected of bloodstream infection (BSI) from January 2020 to June 2020 were collected, and potential pathogens were detected by simultaneous blood culture and plasma mcfDNA sequencing. Other clinical microbiological assays were performed within 7 days of plasma mcfDNA sequencing, including smear, culture of samples taken from relevant infected sites, and β-D-glucan/galactomannan (BDG/GM) tests, among others. The diagnoses were classified as sepsis [94 (47.2%)], non-sepsis [87 (43.7%)], and non-infectious disease [18 (9.0%)]. The sensitivity and specificity of plasma mcfDNA sequencing for diagnosing sepsis were 68.1 and 63.2%, respectively, which were significantly better than those of blood culture, especially for the common bacteria that cause hospital-acquired infection, namely, Acinetobacter baumannii (p < 0.01) and Klebsiella pneumoniae (p < 0.01), and DNA viruses (plasma mcfDNA sequencing only, p < 0.01). However, there was no significant difference in the rate of positivity between plasma mcfDNA sequencing and blood culture for antibiotic-non-exposed cases (43.6 vs. 30.9%, p = 0.17). In the non-sepsis group, 44.8% of cases (13/29) detected only by plasma mcfDNA sequencing showed infections in other parts of the body, such as lower respiratory infection (LRI), intra-abdominal infection (IAI) and central nervous system infection (CNSI). For some common pathogens (not including anaerobes), turnaround time (TAT) 3 (TAT from the initiation of blood sample processing by nucleic acid extraction to the completion of sequencing analysis) was longer than TAT1 (TAT from blood culture bottles in Virtuo to off Virtuo). With disease progression, significant dynamic changes in microbial species were clearly detected by plasma mcfDNA sequencing.

Dataset Information

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Background

Methods

Results

Conclusions

Publications

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Similar Datasets

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