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PubMed2026

Integrating metagenomic next-generation sequencing into a multimodal diagnostic framework for spinal infection: enhancing etiological identification and clinical prediction.

BACKGROUND: Spinal infection (SI) remains diagnostically challenging because of heterogeneous etiologies, nonspecific clinical manifestations, and the limited sensitivity of conventional microbiological approaches, particularly following empirical antimicrobial exposure. Although metagenomic next-generation sequencing (mNGS) enables unbiased pathogen detection, its incremental clinical value beyond pathogen identification and its role within integrated diagnostic strategies remain incompletely established. METHODS: We retrospectively analyzed 208 consecutive patients with suspected SI between August 2022 and August 2025. Final diagnoses were established using a multidisciplinary-adjudicated composite reference standard incorporating clinical, radiological, microbiological, and histopathological evidence. The diagnostic performance of mNGS was compared with conventional culture and histopathology. Furthermore, multimodal predictive models integrating clinical variables and microbiological information were developed using L1-regularized logistic regression. RESULTS: In the comparative cohort, mNGS achieved a significantly higher diagnostic yield than culture (66.5% vs. 27.41%, P < 0.001). Among confirmed SI cases, mNGS demonstrated higher sensitivity than conventional culture (91.67% vs. 40.15%, P < 0.001). mNGS identified a substantially broader pathogen spectrum, ranging from fastidious organisms such as Mycobacterium tuberculosis and Brucella to rare pathogens including Talaromyces marneffei and Coxiella burnetii, and maintained robust sensitivity (98.2%) despite prior antibiotic exposure. While an integrated clinical model achieved an AUC of 0.916, mNGS as a standalone modality provided superior discriminative power (AUC = 0.889) compared to histopathology (AUC = 0.836), the Conventional Biomarker Model (AUC = 0.742), and culture (AUC = 0.693). CONCLUSIONS: mNGS is a high-yield diagnostic tool for spinal infection, particularly in culture-negative and antibiotic-pretreated scenarios. Integrating mNGS into a multimodal clinical framework facilitates etiological clarity and precision antimicrobial therapy.

Humans↗

PubMed2004

Development of rationally designed nucleic acid signatures for microbial pathogens.

The detection and identification of microbial pathogens are critical challenges in clinical medicine and public health surveillance. Advances in genome analysis technology are providing an unprecedented amount of information about bacterial and viral organisms, and hold great potential for pathogen detection and identification. In this paper, a rational approach to the development and application of nucleic acid signatures is described based on phylogenetically informative sequence features, especially single nucleotide polymorphisms. The computational tools that are available to enable the development of the next generation of microbial molecular signatures for clinical diagnostics and infectious disease surveillance are reviewed and the impact on public health and national security will be discussed.

Bacteria↗

PubMed2003

Low occurrence of pathogenic Yersinia enterocolitica in clinical, food, and environmental samples: a methodological problem.

While Yersinia enterocolitica is an important pathogen, which can cause yersiniosis in humans and animals, its epidemiology remains obscure. The pig is the major reservoir of pathogenic Y. enterocolitica of bioserotype 4/O:3, the most common type found in humans. Y. enterocolitica is thought to be a significant food-borne pathogen, although pathogenic isolates have seldom been recovered from foods. The low isolation rate of this pathogenic bacterium in natural samples, including clinical, food, and environmental samples, may be due to the limited sensitivity of culture methods. During the last decade, numerous DNA-based methods, such as PCR and colony hybridization assays, have been designed to detect pathogenic Y. enterocolitica in natural samples more rapidly and with better sensitivity than can be achieved by culture methods. In addition, the occurrence of pathogenic Y. enterocolitica in natural samples is clearly higher with PCR than with culture methods. The methods available for detection of pathogenic Y. enterocolitica in natural samples are reviewed in this article.

Bacteriological Techniques↗

PubMed2007

System for simultaneous detection of 16 pathogens related to urethritis to diagnose mixed infection.

OBJECTIVE: Urethritis is not always caused by a single pathogen, and isolation of more than two pathogens from one patient is not uncommon. We developed a method to simultaneously detect 16 pathogens related to urethritis. METHODS: We designed specific primers used for amplification of urethritis pathogens in our 16-well microplate assay. Sixteen microliters of each reaction mixture containing template DNA was added to each well to amplify 16 pathogens simultaneously. RESULTS: After we evaluated the specificity and sensitivity of this microplate polymerase chain reaction method, we used it to detect pathogens in clinical samples. Of 163 clinical samples, 49.7% (81/163) were positive for specific pathogens, and 6.7% (11/163) showed mixed infection. A specific pathogen was not identified in 43.6% (71/163) of cases. CONCLUSIONS: We developed a 16-well microplate assay with 16 specific primers to identify pathogens associated with urethritis.

Humans↗

PubMed2025

Performance evaluation of a commercial multiplex pathogen panel for detection of bacteria in sputum specimens from non-ICU patients with suspected lower respiratory tract infection.

Rapid diagnostic testing can improve pathogen detection and lead to targeted antibiotics. The BioFire FilmArray Pneumonia Panel (BFPP) is a multiplex PCR that has displayed strong concordance with traditional microbiologic techniques. However, most existing literature focuses on deep respiratory specimens, and there is sparse literature on performance in sputum specimens. This retrospective, single-center study included adult patients between 1 September 2022 and 31 August 2024 who had collection of a BFPP with standard of care (SOC) culture from a sputum specimen on a non-intensive care unit (ICU) floor or in the emergency department if admitted to a non-ICU floor. Out of 189 BFPPs performed on 189 sputum specimens, a total of 141 bacterial targets were detected. Between the BFPP and SOC culture, the overall positive percent agreement and negative percent agreement (NPA) were 96.3% and 54.9%, respectively. The positive predictive value (PPV) was 26.3% while the negative predictive value was 98.9%. Patients with greater than 24 h of antibiotic exposure prior to BFPP collection had a lower PPV compared to patients with less than 24 h or no exposure (13.6% vs 29.6% vs 30.4%). The lowest concordance was observed for Haemophilus influenzae (15.4%), Moraxella catarrhalis (18.2%), Streptococcus pneumoniae (19%), and Staphylococcus aureus (22.7%), several of which are fastidious in culture. BFPP showed a high NPA, with all bacterial targets having an NPA greater than 90%, except H. influenzae (82%). Based on these data, a negative BFPP in sputum specimens could help to rule out a bacterial pneumonia, but the benefit of a positive test remains unclear.IMPORTANCEThis study evaluates the BioFire FilmArray Pneumonia Panel (BFPP) by comparing its performance to standard of care cultures exclusively in sputum specimens from non-intensive care unit patients with suspected lower respiratory tract infection. Findings show an overall high positive percent agreement and negative predictive value but a low negative percent agreement and positive predictive value, suggesting that a negative test in sputum specimens could be beneficial when attempting to rule out a bacterial infection, but the benefit of a positive test remains unclear, particularly if common airway colonizing bacteria are detected and at low semi-quantitative thresholds. Clinical symptoms should guide test interpretation in patients with positive BFPP results but negative culture growth.

Humans↗

PubMed2004

Integrated portable genetic analysis microsystem for pathogen/infectious disease detection.

An integrated portable genetic analysis microsystem including PCR amplification and capillary electrophoretic (CE) analysis coupled with a compact instrument for electrical control and laser-excited fluorescence detection has been developed. The microdevice contains microfabricated heaters, temperature sensors, and membrane valves to provide controlled sample positioning and immobilization in 200-nL PCR chambers. The instrument incorporates a solid-state laser and confocal fluorescence detection optics, electronics for sensing and powering the PCR reactor, and high-voltage power supplies for conducting CE separations. The fluorescein-labeled PCR products are amplified and electrophoretically analyzed in a gel-filled microchannel in <10 min. We demonstrate the utility of this instrument by performing pathogen detection and genotyping directly from whole Escherichia coli and Staphylococcus aureus cells. The E. coli detection assay consists of a triplex PCR amplification targeting genes that encode 16S ribosomal RNA, the fliC flagellar antigen, and the sltI shigatoxin. Serial dilution demonstrates a limit of detection of 2-3 bacterial cells. The S. aureus assay uses a femA marker to identify cells as S. aureus and a mecA marker to probe for methicillin resistance. This integrated portable genomic analysis microsystem demonstrates the feasibility of performing rapid high-quality detection of pathogens and their antimicrobial drug resistance.

Animals↗

PubMed2002

Clinical, genetic and microbiological findings in a Brazilian family with aggressive periodontitis.

BACKGROUND/AIM: Aggressive periodontitis comprises a group of rapidly progressive forms of periodontitis. Besides bacteria, a high level of subject susceptibility must be involved in the expression of disease. In the present study, we report the clinical, microbiological and genetic profile of a 14-individual family with aggressive periodontitis. METHOD: PCR was utilized to detect pathogenic bacteria of affected sites. DNA was obtained from epithelial cells through a mouthwash with 3% glucose and scrapping of the oral mucosa. RFLP-PCR was used to analyze cytokine genetic polymorphisms. RESULTS: Localized aggressive periodontitis was diagnosed for an 18-year-old systemically healthy non-smoking proband, with siblings displaying aggressive periodontitis. Bacteroides forsythus and Treponema denticola were the most frequent pathogens. The proband presented Actinobacillus actinomycetemcomitans and detectable levels of Porphyromonas gingivalis, Bacteroides forsythus and Treponema denticola. Allele 2 of IL-1alpha (-889) polymorphism was found in all individuals as well as allele 1 of the IL-1beta (+3953) gene. Alleles 1 and 2 (50 % each) of IL-1beta (-511), allele 1 of TNF-alpha (-308) and allele 2 (in homo or heterozygosity) of IL-RN (intron 2) gene were present. CONCLUSION: The results show that the present microbiological and genetic parameters were not relevant for the prediction of periodontitis susceptibility in this family.

Adolescent↗

PubMed2005

Pathogens causing community gastroenteritis in Australia.

BACKGROUND AND AIM: Many individuals with gastrointestinal symptoms do not seek medical attention and so there is little known about the pathogens involved in most cases of community gastroenteritis. We aimed to identify the pathogens responsible for community gastroenteritis and to examine the associated symptoms. METHODS: In a prospective study of 2811 subjects over 15 months, fecal pathogens were examined following highly credible gastroenteritis (HCG) events. The population consisted of family units of at least two children (< or =15 years-old) and two adults each. Fecal samples were tested for a range of bacterial, viral and protozoal pathogens. Gastroenteric episode duration and symptoms such as vomiting, nausea and diarrhea were measured. RESULTS: One or more pathogens were identified in 198 of a total 791 specimens collected. Pathogens detected most often were Norovirus virus (10.7%), pathogenic E. coli (6.7%), Campylobacter spp. (3.0%) and Giardia sp. (2.5%). Children were more prone than adults to all the pathogens tested, except E. coli. Children infected with Campylobacter were 8.3 times more likely (95% CI: 2.7-25.4) to have a longer duration of diarrhea than children with Norovirus (P < 0.001). Similarly, children infected with E. coli had increased persistence of diarrhea compared to Norovirus (OR = 3.5; 95% CI: 1.3-9.5; P = 0.02). Infection with Norovirus in children meant greater persistence of vomiting symptoms than infection with Campylobacter (P = 0.005), E. coli (P = 0.03), or if no pathogen was identified (P = 0.004). Adults usually vomited for fewer days than children while duration of diarrhea was similar to children. CONCLUSIONS: Many of the pathogens responsible for cases of gastroenteritis in the Australian community are likely to go undetected by current surveillance systems and routine clinical practice.

Adolescent↗

PubMed1997

[An epidemiological investigation for gram-positive coccus, especially PRSP, in Kinki area].

An epidemiological investigation for penicillin-resistant Streptococcus pneumonia (PRSP) was performed at 18 medical institutes in Kinki area by the questionnaire from Kinki Infection Working Group 1995. This investigation was the first report that was performed for a long term (one year) and a large area. The most frequent specimen was sputum from out-patients (50.3%) and inpatients (48.8%), and especially from spinal fluid of 3 cases were detected. Polymicrobial infection with more than 3 pathogens was 15.7%, and it was more frequent than MRSA previously investigated. Simultaneous pathogens detected with PRSP were Candida species, Haemophilus influenzae and Staphylococcus aureus. In terms of chemosusceptibility, VCM (100%), FMOX (97.9%), IPM/CS (85.9%), CEZ (93.4%) and CDTR-PI were determined to be high by sensitive. However, the sensitivity of CCL, which was one of the most common antibiotics, was only 37.7%.

Drug Resistance, Microbial↗

PubMed1988

Clostridium difficile and acute enterocolitis.

Clostridium difficile belonging to groups not normally detected in infancy was the only potential pathogen detected in the stools of two infants with severe enterocolitis. Further information regarding the virulence of this organism was obtained by use of a recently introduced typing scheme.

Clostridium↗

PubMed1999

The welfare problems associated with using transgenic mice to bioassay for bovine spongiform encephalopathy.

Prion diseases are fatal neurodegenerative disorders, epitomized by the the recent bovine spongiform encephalopathy (BSE) epidemic in cattle and the emergence of a novel variant of Creutzfeldt-Jacob disease (vCJD) in humans. In prion disease, the agent of infection is believed to be composed of proteinaceous particles, termed prions, which are converted from a normal isoform into a pathogenic isoform during pathogenesis. A bioassay to detect pathogenic prions of BSE in bovine products consumed by humans was unattainable until the development of transgenic mice, due to the significantly lower susceptibility of wild-type mice to BSE. Transgenic mice have now been generated which express the bovine prion protein and are susceptible to BSE. Following an intracerebral injection with brain homogenate of BSE-infected cattle, transgenic mice develop numerous clinical signs of prion disease, including truncal ataxia (inability to coordinate the torso's muscular activity), increased tone of the tail, generalized tremor, and lack of a forelimb extensor response. In this study, the ethical score system devised by Porter (1992) was applied to the BSE bioassay as a tool for identifying welfare issues affecting animals used in the bioassay. We acknowledge that there are limitations to the use of the information arising from the application of the Porter scoring scheme for assessing the justification to proceed with any animal experiment; notwithstanding these problems, however, our application of the Porter model to the BSE bioassay enabled us to identify potential targets for refinement: pain involved, duration of distress and the duration of the experiment. This was despite lenient scoring for the duration of distress and pain experienced by the mice, and optimal scoring for the quality of animal care. The targets identified for refinement are discussed in relation to the method of inoculation, the duration of the bioassay, and the duration of the clinical phase, with the objective of exploring ways of reducing the severity of the bioassay.

Animal Experimentation↗

PubMed2001

Real time biodetection of individual pathogenic microorganisms in food and water.

The primary objective of this research is to examine the feasibility of using an innovative technique based on laser-induced fluorescence coupled with flow cytometry to detect pathogenic microorganisms in food or water in real time. Our initial application is the rapid detection of E. coli O157:H7 in ground beef. The research performed demonstrated conclusively that this approach is feasible, and that the technique has key advantages over current alternatives including: it is (1) able to totally examine a large volume of food or water in real time, (2) capable of detecting single microorganisms (alternative techniques require in excess of 10(4) microorganisms), (3) intrinsically automatic, and (4) sensitive only to the selected bacteria. We have demonstrated the feasibility of detecting individual E. coli bacteria with a breadboard system. The performance of this system allows for rapid detection of individual specific pathogenic microorganisms. Two of the most significant commercial applications of this technique are the detection of infectious microorganisms in contaminated food and water. Food-borne microbial pathogens account for approximately 7 million illnesses and 9,000 deaths in the U.S. annually, with an estimated economic loss of at least $6 billion [1]. In addition, this method has the potential for a broad range of other commercial applications, including the detection of small numbers of molecules, such as the ultrasensitive detection of explosives and groundwater contaminants.

Animals↗

PubMed2004

[Bacterial meningitis: determination of pathogens and therapeutic management].

Recent aspects of pathogen determination and therapeutic management are reviewed based on a clinical analysis of 50 of our adult patients with bacterial meningitis (BM). The sensitivity for detecting pathogens using gram-stained smears and cultures of CSF was high in untreated patients, but low in patients previously treated with antibiotics. Latex agglutination for antibodies of pathogens is rapid and has a potential for determining pathogens in partially treated meningitis. The PCR also has a potential for determining pathogens in pre-treated, culture-negative cases and for detecting whether the bacterial pathogen is resistant or sensitive to antibiotics. The initial empiric regimen of antibiotics has been modified with elevation in the detection rate of drug-resistant bacilli. The proportion of patients undergoing treatment with VCM and/or Carbapenems has recently increased at our department. A combination of dexamethasone under administration of antibiotics has also been established as effective in adult BM. On admission, some patients are difficult to diagnose as BM rather than herpes simplex encephalitis (HSVE). A serum CRP value of >2.0 mg/dl proved useful for such different diagnosis in our patients. The predictors of a poor outcome based on multivariate logistic analysis in our BM patients were level of unconsciousness and sepsis.

Adult↗

PubMed2004

Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is the most common subepidermal immunobullous disease, characterized by circulating IgG autoantibodies targeting BP180 and BP230 hemidesmosomal proteins. Several immunological studies have demonstrated that the membrane proximal noncollagenous domain NC16a of BP180 is the immunodominant region targeted by BP autoantibodies. Recently, a commercial BP180 NC16a-specific enzyme-linked immunosorbent assay (ELISA) has become available for detecting pathogenic anti-BP180 autoantibodies in BP sera. However, it remains unclear whether the diagnostic potential of the ELISA is equivalent to that of the 'gold-standard' diagnostic technique of immunofluorescence (IF). OBJECTIVES: To examine the usefulness of a commercially available BP180-NC16a ELISA in the initial serodiagnosis of BP. METHODS: Sera from a large cohort of patients with BP (n = 102) and control subjects (age- and sex-matched normal volunteers, n = 60; pemphigus foliaceus, n = 18; pemphigus vulgaris, n = 16) were assayed by BP180-NC16a ELISA. All BP sera were obtained at presentation before initiation of systemic immunosuppressive therapy. The values of IgG antibody levels measured by ELISA were compared with those measured by indirect IF on salt-split skin. Results Receiver operating characteristic analysis was used to calculate the cut-off value for the ELISA in the diagnosis of BP which maximizes both sensitivity and specificity, and to estimate the diagnostic accuracy of the ELISA as represented by the area under the curve (AUC = 0.965). A cut-off value of 9 was associated with a sensitivity of 89% (91 of 102 BP sera showed a positive result) and a specificity of 98%. Fifty-eight of 60 normal controls and all the pemphigus sera showed a negative result. There was a correlation between the mean ELISA values and indirect IF titres (Spearman rank correlation 0.286; P = 0.004). CONCLUSIONS: Our results suggest that the BP180-NC16a ELISA is a useful tool for the detection of pathogenic anti-BP180 IgG autoantibodies at the initial disease stage of BP. Because it is not only highly sensitive and specific, but is also easy to perform, is objective, and semiquantitative, the ELISA may provide valuable information for the accurate and reliable serodiagnosis of BP.

Aged↗

PubMed1992

Solid-phase polymerase chain reaction: applications for direct detection of enteric pathogens in waters.

The techniques in current use for detection of pathogens in environmental samples are restricted to those organisms whose replication in either culture media or cell culture is feasible. These methods lack the selectivity and sensitivity necessary for their unequivocal detection and identification. We have developed an assay for the detection of bacterial cells in large volumes of water. Low concentrations of cells containing target sequences were concentrated on membrane filters and were subjected to amplification directly using a stepwise polymerase chain reaction. This procedure, together with nucleic acid probes, has enhanced the limit of detection to the level of a single bacterial cell. This technique could be used for the detection of any bacteria or virus in water or air.

Base Sequence↗

PubMed2004

DNA sequence detection using selective fluorescence quenching of tagged oligonucleotide probes by gold nanoparticles.

Simple, fast, economical, and sensitive detection of specific DNA sequences is crucial to pathogen detection and biomedical research. We have designed a novel fluorescent assay for DNA hybridization based on the electrostatic properties of DNA. We exploit the ability to create conditions where single-stranded DNA adsorbs on negatively charged gold nanoparticles while double-stranded DNA does not. Dye-tagged probe sequences have their fluorescence efficiently quenched when they are mixed with gold nanoparticles unless they hybridize with components of the analyte. Subfemtomole amounts of untagged target are detected in minutes using commercially available materials. Target sequences in complex mixtures of DNA and single-base mismatches in DNA sequences are easily detected.

Base Pair Mismatch↗

PubMed1997

[Usefulness of etiologic studies in children hospitalized for pneumonia].

OBJECTIVE: The aims of this study were: 1) To assess the effectiveness of viral culture and serology. 2) To check if there are clinical differences between patients with viral or bacterial infections. 3) Assessment of treatment, previous to and during the hospital stay. PATIENTS AND METHODS: A prospective study was carried out between January 1994 and June 1995 on 56 inpatients diagnosed of pneumonia. The mean age was 3 years (range: 2 months- 14 years). Viral cultures on cell monolayers was carried out in 46 patients. Serology was carried out in 33 patients older than six months of age. Blood cultures were obtained in 27 patients and a tuberculine reaction was studied in 15 patients. On the basis of microbiological results, three groups were formed (viral, bacterial and unknown) and clinical symptoms, thorax X-rays, and laboratory data were compared. RESULTS: The etiologic agent was detected in 36 patients (64%). The most frequent pathogens detected were adenovirus and respiratory syncytial virus with 11 patients (19%) each, followed by Mycoplasma pneumoniae with 9 patients (16%): Viral cultures were positive in 16 patients (35%) and serology in 22 patients (66%). Viral infection was detected in 20 patients (36%) and bacterial infection in 16 (28%). Mixed infection (bacterial/viral) was found in 5 patients (9%). The patients with viral infections showed significant differences (p < 0.01) for age (younger) and tachypnea compared with those with bacterial infections. Sixty-six percent of the patients had received antibiotic treatment previous to hospital admission and 87% during their hospitalization. CONCLUSIONS: Although the etiologic studies were positive in 64% of the patients, the delay in obtaining the results make them scarcely useful in determining whether to initiate or not antibiotic therapy (87% of inpatients). Clinical data, radiology results and leukocyte counts do not show any difference between viral and bacterial infections.

Adolescent↗

PubMed2026

Predicting bloodstream infection by plasma cell-free metagenomic sequencing: a prospective cohort study.

BACKGROUND: Patients receiving myelosuppressive chemotherapy or haematopoietic cell transplantation are at high risk for life-threatening bloodstream infections. A novel pre-emptive treatment paradigm guided by pathogen detection before symptoms appear might reduce this risk, but no validated screening test is available. This study evaluated the sensitivity and specificity of plasma microbial cell-free DNA metagenomic sequencing (mcfDNA-Seq) for predicting bloodstream infections in children and adolescents receiving therapy for high-risk leukaemia. METHODS: In this prospective cohort study, between Aug 9, 2017, and Feb 28, 2022, leftover clinical plasma samples were prospectively collected up to once per day from patients who were younger than 25 years, receiving care for leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA), and at high risk for life-threatening bloodstream infections. mcfDNA-Seq was used to identify pathogen DNA in blood samples obtained during the 7 days before to 1 day after bloodstream infection onset, and in control samples from the same population in the absence of fever or infection. The testing laboratory was masked to sample status. Primary outcomes were predictive sensitivity of mcfDNA-Seq for detecting the expected bloodstream infection pathogen during the 3 days preceding the day of bloodstream infection onset, with a prespecified favourable sensitivity of 50%, and predictive specificity of mcfDNA-Seq in control samples. Exploratory analyses comprised assessing sensitivity and specificity restricted to bacteria or common bloodstream infection pathogens, and after applying a data-derived DNA fragment concentration cutoff; estimating the predictive sensitivity on each of the 7 days before bloodstream infection onset; identifying clinical characteristics that affected predictive sensitivity or specificity; and examining the clinical relevance of additional organisms identified by mcfDNA-Seq during bloodstream infection episodes. Diagnostic sensitivity was also assessed on samples collected on the day of, or day after, diagnosis of bloodstream infection. This study is registered with ClinicalTrials.gov, NCT03226158. FINDINGS: 94 evaluable bloodstream infections occurred in 60 (38%) of 158 enrolled participants; 19 episodes were previously described in the pilot phase of this study. The predictive sensitivity of mcfDNA-Seq was 51·9% (95% CI 40·5-63·1) for all bloodstream infection episodes, 53·8% (42·2-65·2) for bacterial infection only, and 51·9% (40·5-63·1) when applying a DNA fragment concentration cutoff of 140 molecules per μL. Sensitivity was lowest at day -7 and increased daily until the day of diagnosis. Diagnostic sensitivity was 81·3% (95% CI 71·0-89·1) for all bloodstream infection episodes and 83·1% (72·9-90·7) for bacterial infections only. Predictive specificity was 82·7% (95% CI 76·0-88·2), but improved to 88·9% (83·0-93·3) for common bloodstream infection pathogens, and to 93·8% (88·9-97·0) when also applying the DNA fragment concentration cutoff. Predictive sensitivity was higher in participants with acute lymphoblastic leukaemia (adjusted odds ratio [aOR] 11·1 [1·7-74·2] vs those with acute myeloid leukaemia), and it was lower in polymicrobial infections (aOR 0·0 [0·0-0·2] vs monomicrobial Gram-positive infections). Clinical false-positive results were positively associated with gastrointestinal disturbance alone (p=0·037) or combined with recent administration of high-dose cytarabine (p=0·012). Additional organisms identified by mcfDNA-Seq that were not identified by blood culture were less likely than expected organisms to have an increasing DNA concentration during the days preceding bloodstream infection diagnosis. INTERPRETATION: mcfDNA-Seq can detect causative pathogens before the onset of some bloodstream infection episodes in profoundly immunocompromised patients. Predictive specificity might be improved by restricting results to a subgroup of relevant organisms, excluding patients with high risk of false-positive results, or applying a higher concentration cutoff. Clinical trials are needed to evaluate mcfDNA-Seq-guided pre-emptive therapy for preventing life-threatening bloodstream infections in patients with high risk. FUNDING: The National Cancer Institute, American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, and Karius.

Adolescent↗