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Meta-Analysis
. 2025 Mar 19;3(3):CD011926.
doi: 10.1002/14651858.CD011926.pub3.

Molecular assays for the diagnosis of sepsis in neonates: a diagnostic test accuracy review

Thomas H Dierikx  1   2 , Douwe H Visser  3 , Tim de Meij  2 , James Versalovic  4 , Mariska Mg Leeflang  5 , Chris Cooper  6   7 , Mohan Pammi  8
Affiliations
Meta-Analysis

Molecular assays for the diagnosis of sepsis in neonates: a diagnostic test accuracy review

Thomas H Dierikx et al. Cochrane Database Syst Rev. .

Abstract

Background: Microbial cultures for diagnosis of neonatal sepsis have low sensitivity and reporting delay. Advances in molecular microbiology have fostered new molecular assays that are rapid and may improve neonatal outcomes.

Objectives: To assess the diagnostic accuracy of various molecular methods for the diagnosis of culture-positive bacterial and fungal sepsis in neonates and to explore heterogeneity among studies by analyzing subgroups classified by gestational age and type of sepsis onset and compare molecular tests with one another.

Search methods: We searched CENTRAL, MEDLINE, Embase and trial registries in August 2023. We checked reference lists of included studies and systematic reviews where subject matter related to the intervention or population examined in this review.

Selection criteria: We included studies that were prospective or retrospective, cohort or cross-sectional design, which evaluated molecular assays (index test) in neonates with suspected sepsis in comparison with microbial cultures (reference standard).

Data collection and analysis: Two review authors independently screened studies, extracted data and assessed the methodological quality of the studies. We performed meta-analyses using the bivariate model and entered data into Review Manager.

Main results: Seventy-four studies were eligible for inclusion, of which 68 studies provided data for meta-analysis. The total number of participants was 14,309 (1328 infants who were culture-positive and 12,981 infants who were culture-negative) from 68 studies that were included in the meta-analysis. The summary estimate of sensitivity was 0.91 (95% confidence interval (CI) 0.85 to 0.95) and of specificity was 0.88 (95% CI 0.83 to 0.92) (low-certainty evidence). We explored heterogeneity by subgroup analyses of type of test, gestational age, type of sepsis onset and prevalence of sepsis. We found insufficient explanations for the heterogeneity (low- to very low-certainty evidence). Sensitivity analyses including studies that analyzed blood samples, using good methodology and those that did not use multiple samples from the same participant revealed similar results (low-certainty evidence).

Authors' conclusions: Molecular assays have the advantage of producing rapid results and have moderate diagnostic accuracy. Molecular assays may prevent overuse of antibiotics in neonates with suspected sepsis. The efficacy and cost-effectiveness of these molecular assays should be evaluated using randomized trials comparing molecular assays as an add-on test versus conventional methods without the add-on test in neonates with suspected sepsis.

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Conflict of interest statement

TD: none. TD is an author of an included study, but they were not involved with the selection, data extraction or risk of bias assessment of that study.

DV: none. DV is an author of an included study, but they were not involved with the selection, data extraction or risk of bias assessment of that study.

TM: none. TM is an author of an included study, but they were not involved with the selection, data extraction or risk of bias assessment of that study.

JV: none.

ML: none. ML is a DTA editor, but was not involved with the editorial processing of this review.

CC: none.

MP: none. MP is an editor with Cochrane Neonatal, but was not involved with the editorial processing of this review.

Update of

References

References to studies included in this review

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García‐Gudiño 2018 {published data only}
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Li 2019 {published data only}
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Makhoul 2005 {published data only}
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Mancilla‐Ramirez 2017 {published data only}
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Massa‐Buck 2024 {published data only}
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Silva‐Junior 2016 {published data only}
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Straňák 2020 {published data only}
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Stranieri 2018 {published data only}
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Tirodker 2003 {published data only}
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References to studies excluded from this review

Akkaya 2017 {published data only}
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Ala‐Houhala 2018 {published data only}
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Albuquerque 2019 {published data only}
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Al‐Emran 2016b {published data only}
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Anand 2016 {published data only}
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Culbreath 2019 {published data only}
    1. Culbreath K, Melanson S, Gale J, Baker J, Li F, Saebo O, et al. Validation and retrospective clinical evaluation of a quantitative 16S rRNA gene metagenomic sequencing assay for bacterial pathogen detection in body fluids. Journal of Molecular Diagnostics 2019;21(5):913-23. [PMID: ] - PubMed
Dantuluri 2020 {published data only}
    1. Dantuluri KL, Konvinse KC, Crook J, Thomsen IP, Banerjee R. Human herpesvirus 6 detection during the evaluation of sepsis in infants using the FilmArray Meningitis/Encephalitis Panel. Journal of Pediatrics 2020;223:204-6. [PMID: ] - PubMed
Das 2015 {published data only}
    1. Das BK, Suri S, Nath G, Prasad R. Urine nested polymerase chain reaction in neonatal septicemia. Journal of Tropical Pediatrics 2015;61(4):295-300. [PMID: ] - PubMed
Davis 2015 {published data only}
    1. Davis J, Christie S, Fairley D, Coyle P, Tubman R, Shields MD. Performance of a novel molecular method in the diagnosis of late-onset sepsis in very low birth weight infants. PLOS One 2015;10(8):e0136472. [DOI: 10.1371/journal.pone.0136472] - DOI - PMC - PubMed
Decuypere 2016 {published data only}
    1. Decuypere S, Meehan CJ, Van Puyvelde S, De Block T, Maltha J, Palpouguini L, et al. Diagnosis of bacterial bloodstream infections: a 16S metagenomics approach. PLOS Neglected Tropical Diseases 2016;10(2):e0004470. [PMID: ] - PMC - PubMed
de Zoysa 2012 {published data only}
    1. Zoysa A, Edwards K, Gharbia S, Underwood A, Charlett A, Efstratiou A. Non-culture detection of Streptococcus agalactiae (Lancefield group B Streptococcus) in clinical samples by real-time PCR. Journal of Medical Microbiology 2012;61(Pt 8):1086-90. [PMID: ] - PubMed
Du Plessis 2021 {published data only}
    1. Du Plessis M, Gouveia L, Freitas C, Abera NA, Lula BS, Raboba JL, et al. The role of molecular testing in pediatric meningitis surveillance in southern and East African countries, 2008–2017. Journal of Infectious Diseases 2021;224:S194-S203. [PMID: ] - PMC - PubMed
Erdem 2021 {published data only}
    1. Erdem G, Kaptsan I, Sharma H, Kumar A, Aylward SC, Kapoor A, et al. Cerebrospinal fluid analysis for viruses by metagenomic next-generation sequencing in pediatric encephalitis: not yet ready for prime time? Journal of Child Neurology 2021;36(5):350-6. [PMID: ] - PubMed
Fatima 2017 {published data only}
    1. Fatima A, Bashir G, Wani T, Jan A, Kohli A, Khan MS. Molecular identification of Candida species isolated from cases of neonatal candidemia using polymerase chain reaction-restriction fragment length polymorphism in a tertiary care hospital. Indian Journal of Pathology & Microbiology 2017;60(1):61-5. [PMID: ] - PubMed
Fernandes 2020 {published data only}
    1. Fernandes JF, Laubscher F, Held J, Eckerle I, Docquier M, Grobusch MP, et al. Unbiased metagenomic next-generation sequencing of blood from hospitalized febrile children in Gabon. Emerging Microbes & Infections 2020;9(1):1242-4. [PMID: ] - PMC - PubMed
Firoozeh 2019 {published data only}
    1. Firoozeh F, Shiralinezhad A, Momen-Heravi M, Aghadavod E, Zibaei M. Rapid detection of pathogenic bacteria in whole blood samples using 23S rRNA PCR assays. Open Microbiology Journal 2019;13(1):101-5. [DOI: 10.2174/1874285801913010101] - DOI
Freedman 2022 {published data only}
    1. Freedman A, Mangold K, Price E, Ernst L. Pathogen-specific nucleic acid targets in umbilical cord tissue: correlations with neonatal blood culture and placental histology. Pediatric and Developmental Pathology 2022;25(2):223-4. [DOI: 10.1177/10935266221086454] - DOI
Gies  2016 {published data only}
    1. Gies F, Tschiedel E, Felderhoff-Müser U, Rath PM, Steinmann J, Dohna-Schwake C. Prospective evaluation of SeptiFast Multiplex PCR in children with systemic inflammatory response syndrome under antibiotic treatment. BMC Infectious Diseases 2016;16:378. [PMID: ] - PMC - PubMed
Golden 2004 {published data only}
    1. Golden SM, Stamilio DM, Faux BM, Dela Cruz WP, Shoemaker CT, Blackmon CL, et al. Evaluation of a real-time fluorescent PCR assay for rapid detection of Group B Streptococci in neonatal blood. Diagnostic Microbiology and Infectious Disease 2004;50(1):7-13. [PMID: ] - PubMed
Guiducci 2019 {published data only}
    1. Guiducci S, Moriondo M, Nieddu F, Ricci S, De Vitis E, Casini A, et al. Culture and real-time polymerase chain reaction sensitivity in the diagnosis of invasive meningococcal disease: does culture miss less severe cases? PLOS One 2019;14(3):e0212922. [PMID: ] - PMC - PubMed
Haddad‐Boubaker 2018 {published data only}
    1. Haddad-Boubaker S, Lakhal M, Fathallah C, Bouafsoun A, Kharrat M, Khemiri M, et al. Molecular diagnosis of bacterial meningitis by multiplex real time PCR in Tunisian children. Journal of Infection in Developing Countries 2018;12(4):235-43. [DOI: 10.3855/jidc.9650] - DOI - PubMed
Hasan 2020 {published data only}
    1. Hasan MR, Sundararaju S, Tang P, Tsui KM, Lopez AP, Janahi M, et al. A metagenomics-based diagnostic approach for central nervous system infections in hospital acute care setting. Scientific Reports 2020;10(1):11194. - PMC - PubMed
Hassan 2018 {published data only}
    1. Hassan JS, Salman AE, Obeid AS, Rhman TR. Isolation and identification of Serratia marcescens from suspected late neonatal sepsis in intensive care unit. International Journal of Pharmaceutical Quality Assurance 2018;9(1):286-90.
Hemmati 2021 {published data only}
    1. Hemmati N, Nikkhahi F, Javadi A, Eskandarion S, Marashi SM. Use of a new multiplex quantitative polymerase chain reaction based assay for simultaneous detection of Neisseria meningitidis, Escherichia coli k, 1 Streptococcus agalactiae, and Streptococcus pneumoniae. Iranian Journal of Microbiology 2021;13(4):464-9. [DOI: 10.18502/ijm.v13i4.6970] - DOI - PMC - PubMed
Hibberd 2016 {published data only}
    1. Hibberd PL, Qazi SA. Population-based novel molecular diagnostics to move the neonatal sepsis agenda forward. Pediatric Infectious Disease Journal 2016;35(5 Suppl 1):S1-2. [DOI: 10.1097/INF.0000000000001097] - DOI - PubMed
Howard 2021 {published data only}
    1. Howard AK, Claeys K, Biggs JM, Parbuoni KA, Johnson K, Luneburg P, et al. Performance of Verigene rapid diagnostic testing for detection of inpatient pediatric bacteremia. Journal of Pediatric Pharmacology and Therapeutics 2021;26(5):472-7. [DOI: 10.5863/1551-6776-26.5.472] - DOI - PMC - PubMed
Huber 2021 {published data only}
    1. Huber S, Weinberger J, Pilecky M, Lorenz I, Schildberger A, Weber V, et al. A high leukocyte count and administration of hydrocortisone hamper PCR-based diagnostics for bloodstream infections. European Journal of Clinical Microbiology & Infectious Diseases 2021;40(7):1441-9. - PubMed
Jabbar Salman 2018 {published data only}
    1. Jabbar Salman H, Hesnaa Saeed M, Nada Mohammed T, Abbas AA. Isolation and identification of bacterial species in neonatal sepsis using polymerase chain reaction-based 16S rRNA sequencing. Journal of Pharmaceutical Sciences and Research 2018;10(6):1508-10.
Jones 2010 {published data only}
    1. Jones V, Wilks M, Johnson G, Warwick S, Hennessey E, Kempley S, et al. The use of molecular techniques for bacterial detection in the analysis of gastric aspirates collected from infants on the first day of life. Early Human Development 2010;86(3):167-70. [PMID: ] - PubMed
Jordan 2005b {published data only}
    1. Jordan JA, Butchko AR, Durso MB. Use of pyrosequencing of 16S rRNA fragments to differentiate between bacteria responsible for neonatal sepsis. Journal of Molecular Diagnostics 2005;7(1):105-10. [PMID: ] - PMC - PubMed
Jordan 2009 {published data only}
    1. Jordan JA, Jones-Laughner J, Durso MB. Utility of pyrosequencing in identifying bacteria directly from positive blood culture bottles. Journal of Clinical Microbiology 2009;47(2):368-72. [PMID: ] - PMC - PubMed
Keij 2020 {published data only}
    1. Keij FM, Kornelisse RF, Tramper-Stranders GA, Allegaert K. Improved pathogen detection in neonatal sepsis to boost antibiotic stewardship. Future Microbiology 2020;15:461-4. - PubMed
Kelkar 2019 {published data only}
    1. Kelkar A, Christopher A, Doshi P, Nimbargi R, Mani NS. Standardisation of protocols for the diagnosis of neonatal sepsis by molecular methods. Research and Practice in Thrombosis and Haemostasis 2019;3:477-8.
Kim 2021 {published data only}
    1. Kim KM, Park JY, Park KU, Sohn YJ, Choi YY, Han MS, et al. Diagnostic evaluation of the BioFire meningitis/encephalitis panel: a pilot study including febrile infants younger than 90 days. Pediatric Infection and Vaccine 2021;28(2):92-100. [DOI: 10.14776/piv.2021.28.e9] - DOI
Koh 2018 {published data only}
    1. Koh LL, O'Rourke S, Brennan M, Clooney L, Cafferkey M, McCallion N, et al. Impact of a rapid molecular test for positive blood cultures from neonatal intensive care patients on clinical management: a retrospective audit. Irish Journal of Medical Science 2018;187(2):423-7. - PubMed
Kumar 2021 {published data only}
    1. Kumar R, Kumar P, Singh MK, Singh V, Singh SP, Goyal A. Molecular characterisation and profile of extended spectrum beta lactamase producing enterobacteriaceae isolates causing neonatal sepsis at a tertiary care center. Journal of Nepal Paediatric Society 2021;41(2):197-204.
Lafolie 2018 {published data only}
    1. Lafolie J, Labbé A, L'Honneur AS, Madhi F, Pereira B, Decobert M, et al. Assessment of blood enterovirus PCR testing in paediatric populations with fever without source, sepsis-like disease, or suspected meningitis: a prospective, multicentre, observational cohort study. Lancet Infectious Diseases 2018;18(12):1385-96. - PMC - PubMed
Lin 2022 {published data only}
    1. Lin GY, Lin CY, Chi H, Huang DT, Huang CY, Chiu NC. The experience of using FilmArray Meningitis/Encephalitis Panel for the diagnosis of meningitis and encephalitis in pediatric patients. Journal of Microbiology, Immunology and Infection 2022;55(6P2):1180-7. [DOI: 10.1016/j.jmii.2022.07.013] - DOI - PubMed
Liu 2020 {published data only}
    1. Liu T, Shi H, Liu F, Jiang Y. Application of metagenomic next-generation sequencing in detection of the pathogens in neonatal infectious diseases. Chinese Journal of Laboratory Medicine 2020;43(6):609-13.
Lucignano 2011 {published data only}
    1. Lucignano B, Ranno S, Liesenfeld O, Pizzorno B, Putignani L, Bernaschi P, et al. Multiplex PCR allows rapid and accurate diagnosis of bloodstream infections in newborns and children with suspected sepsis. Journal of Clinical Microbiology 2011;49(6):2252-8. [PMID: ] - PMC - PubMed
Lyons 2018 {published data only}
    1. Lyons TW, Cruz AT, Freedman SB, Nigrovic LE. Accuracy of herpes simplex virus polymerase chain reaction testing of the blood for central nervous system herpes simplex virus infections in infants. Journal of Pediatrics 2018;200:274-276.e1. - PubMed
Mahajan 2016 {published data only}
    1. Mahajan P, Kuppermann N, Mejias A, Suarez N, Chaussabel D, Casper TC, et al. Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. JAMA 2016;316(8):846-57. [DOI: 10.1001/jama.2016.9207] - DOI - PMC - PubMed
Makhoul 2007 {published data only}
    1. Makhoul IR, Sprecher H, Smolkin T, Sawaid R, Ben-David S, Sujov P, et al. Approach to term neonates born after maternal intrapartum fever and unknown maternal group B Streptococcus status: value of serum C-reactive protein and 16S rRNA gene PCR amplification. Pediatric Infectious Disease Journal 2007;26(11):1064-6. [PMID: ] - PubMed
May 2020 {published data only}
    1. May ML, Tozer S, Day R, Doyle R, Bernard A, Schlapbach LJ, et al. Polymerase chain reaction for human parechovirus on blood samples improves detection of clinical infections in infants. Molecular Biology Reports 2020;47(1):715-20. - PubMed
Messacar 2016 {published data only}
    1. Messacar K, Breazeale G, Robinson CC, Dominguez SR. Potential clinical impact of the film array meningitis encephalitis panel in children with suspected central nervous system infections. Diagnostic Microbiology and Infectious Disease 2016;86(1):118-20. - PMC - PubMed
Morrissey 2017 {published data only}
    1. Morrissey SM, Nielsen M, Ryan L, Al Dhanhani H, Meehan M, McDermott S, et al. Group B streptococcal PCR testing in comparison to culture for diagnosis of late onset bacteraemia and meningitis in infants aged 7–90 days: a multi-centre diagnostic accuracy study. European Journal of Clinical Microbiology & Infectious Diseases 2017;36(7):1317-24. - PubMed
Nambei 2016 {published data only}
    1. Nambei WS, Gamba EP, Gbangbangai E, Ouambita RM, Dalengat-Vogbia Z, Nana R, et al. Detection of the serogoups and serotypes causing bacterial meningitidis in Bangui, 2012. Medecine et Sante Tropicales 2016;26(3):302-7. - PubMed
Nassrallah 2021 {published data only}
    1. Nassrallah B, Bamberger E, Cohen S, Srugo I, Golan-Shany O, Shlonsky Y, et al. The yield of CSF molecular testing in febrile neonates. European Journal of Clinical Microbiology & Infectious Diseases 2021;40(7):1553-7. - PubMed
NCT03884894a {published data only}
    1. NCT03884894. Neonatal sepsis diagnosis: PCR commercial technique and blood culture. https://clinicaltrials.gov/study/NCT03884894 (first received 20 March 2019).
NCT03884894b {published data only}
    1. NCT03884894. Neonatal sepsis diagnosis: PCR commercial technique and blood culture. https://clinicaltrials.gov/study/NCT03884894 (first received 20 March 2019).
Nga Nguyen 2022 {published data only}
    1. Nga Nguyen TQ, Nguyen TV, Tran MD, Skinner A, Narchi H. Cerebrospinal fluid polymerase chain reaction in the diagnosis of neonatal bacterial meningitis: a single-center experience from Vietnam. Indian Pediatrics 2022;59(12):943-5. - PubMed
Obiero 2022 {published data only}
    1. Obiero CW, Gumbi W, Mwakio S, Mwangudzah H, Seale AC, Taniuchi M, et al. Detection of pathogens associated with early-onset neonatal sepsis in cord blood at birth using quantitative PCR. Wellcome Open Research 2022;7:3. [DOI: 10.12688/wellcomeopenres.17386.3] - DOI - PMC - PubMed
Okeke 2021 {published data only}
    1. Okeke IN, Ihekweazu C. The importance of molecular diagnostics for infectious diseases in low-resource settings. Nature Reviews. Microbiology 2021;19(9):547-8. - PMC - PubMed
Paioni 2020 {published data only}
    1. Paioni P, Barbey F, Relly C, Meyer Sauteur P, Berger C. Impact of rapid enterovirus polymerase chain reaction testing on management of febrile young infants < 90 days of age with aseptic meningitis. BMC Pediatrics 2020;20(1):166. - PMC - PubMed
Pandey 2021 {published data only}
    1. Pandey M, Xess I, Singh G, Kumar R, Mahapatra M, Jyotsna VP, et al. Conventional PCR as a reliable method for diagnosing invasive mucormycosis in resource-limited settings. Journal of Medical Microbiology 2021;70(5):-. [DOI: 10.1099/jmm.0.001370] - DOI - PubMed
Park 2019 {published data only}
    1. Park SE, Song D, Shin K, Nam SO, Ko A, Kong J, et al. Prospective research of human parechovirus and cytokines in cerebrospinal fluid of young children less than one year with sepsis-like illness: comparison with enterovirus. Journal of Clinical Virology 2019;119:11-6. - PubMed
Pintos 2021 {published data only}
    1. Pintos C, Mintegi S, Benito J, Aranzamendi M, Bonilla L, Gomez B. Blood enterovirus polymerase chain reaction testing in young febrile infants. Archives of Disease in Childhood 2021;106(12):1179-83. - PubMed
Ramos 2017 {published data only}
    1. Ramos JT, Villar S, Bouza E, Bergon-Sendin E, Perez Rivilla A, Collados CT, et al. Performance of a quantitative PCR-based assay and beta-d-glucan detection for diagnosis of invasive candidiasis in very-low-birth-weight preterm neonatal patients (CANDINEO study). Journal of Clinical Microbiology 2017;55(9):2752-64. - PMC - PubMed
Ray 2016 {published data only}
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Razlansari 2016 {published data only}
    1. Razlansari AA, Jamalidoust M, Ziyaeyan M, Shahian M, Moeini M, Asaei S, et al. Diagnosis of non-polio enteroviral infections in septic neonates by polymerase chain reaction assays. International Journal of Pharmaceutical Sciences and Research 2016;7(12):4956-62.
Saha 2019 {published data only}
    1. Saha S, Ramesh A, Kalantar K, Malaker R, Hasanuzzaman M, Khan LM, et al. Unbiased metagenomic sequencing for pediatric meningitis in Bangladesh reveals neuroinvasive chikungunya virus outbreak and other unrealized pathogens. MBio 2019;10(6):e0287719. - PMC - PubMed
Sahan 2020 {published data only}
    1. Sahan ZA, Hamed SL. Molecular detection of extended-spectrum β-lactamases-producer Serratia marcescens causing neonatal sepsis in Iraq. International Journal of Research in Pharmaceutical Sciences 2020;11(4):5803-8.
Samies 2019 {published data only}
    1. Samies N, Jariwala R, Boppana S, Pinninti S. Utility of surface and blood polymerase chain reaction assays in identifying infants with neonatal herpes simplex virus infection. Pediatric Infectious Disease Journal 2019;38(11):1138-40. - PubMed
Sasso 2016 {published data only}
    1. Sasso M, Chastang-Dumas E, Bastide S, Alonso S, Lechiche C, Bourgeois N, et al. Performances of four real-time PCR assays for diagnosis of pneumocystis Jirovecii pneumonia. Journal of Clinical Microbiology 2016;54(3):625-30. - PMC - PubMed
Savini 2018 {published data only}
    1. Savini V, Marrollo R, Verzulli S, Pontieri E, Fazii P, Creti R. Genexpert-negative group b streptococci detected by accelerate pheno(tm) system. Veterinary Microbiology 2018;217:64-5. - PubMed
Schmoch 2021 {published data only}
    1. Schmoch T, Westhoff JH, Decker SO, Skarabis A, Hoffmann GF, Dohna-Schwake C, et al. Next-generation sequencing diagnostics of bacteremia in pediatric sepsis. Medicine 2021;100(25):e26403. - PMC - PubMed
Shaat 2013a {published data only}
    1. Shaat SS, El Shazly SA, Badr EM, Barakat SS, Hashish MH. Role of polymerase chain reaction as an early diagnostic tool for neonatal bacterial sepsis. Journal of the Egyptian Public Health Association 2013;88(3):160-4. [DOI: 10.1097/01.EPX.0000441294.14692.4c] - DOI - PubMed
Shabani 2018 {published data only}
    1. Shabani A, Makvandi M, Samarbafzadeh A, Teimoori A, Rasti M, Karami C, et al. Echovirus 30 and coxsackievirus A9 infection among young neonates with sepsis in Iran. Iranian Journal of Microbiology 2018;10(4):258-65. - PMC - PubMed
Shang 2001 {published data only}
    1. Shang S, Chen Z, Yu X. Detection of bacterial DNA by PCR and reverse hybridization in the 16S rRNA gene with particular reference to neonatal septicemia. Acta Paediatrica 2001;90(2):179-83. [PMID: ] - PubMed
Sharma 2021 {published data only}
    1. Sharma S, Acharya J, Caugant DA, Banjara MR, Ghimire P, Singh A. Detection of Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae in culture negative cerebrospinal fluid samples from meningitis patients using a multiplex polymerase chain reaction in Nepal. Infectious Disease Reports 2021;13(1):173-80. - PMC - PubMed
Shaw 2017 {published data only}
    1. Shaw E, Bullivant J, Ridgeway E, Clark S, Pilling E. Absence of DNA polymerase chain reaction in neonatal blood cultures could lead to earlier discharge, better antibiotic stewardship and significant financial saving. Archives of Disease in Childhood 2017;102:A192-A-193.
Shen 2004 {published data only}
    1. Shen DX, Du J, Feng ZC. Rapid diagnosis of common pathogenic bacteria infection in newborn infants by 16SrDNA oligonucleotide array. Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics 2004;42(9):668-72. [PMID: ] - PubMed
Sinnar 2020 {published data only}
    1. Sinnar SA, Schiff SJ. The problem of microbial dark matter in neonatal sepsis. Emerging Infectious Diseases 2020;26(11):2543-8. - PMC - PubMed
Stranieri 2016 {published data only}
    1. Stranieri I, Kanunfre KA, Rodrigues JC, Yamamoto L, Nadaf MI, Palmeira P, et al. Usefulness of a 16S rDNA real-time PCR to monitor neonatal sepsis and to assist in medical decision to discontinue antibiotics. Journal of Maternal-Fetal & Neonatal Medicine 2016;29(13):2141-4. - PMC - PubMed
Suryani 2020 {published data only}
    1. Suryani UH, Rezano A, Sribudiani Y. Polymerase chain reaction multiplication for the detection of bacterial isolates causing neonatal sepsis. Open Access Macedonian Journal of Medical Sciences 2020;8:623-8.
Suzuki 2021 {published data only}
    1. Suzuki Y, Aizawa Y, Izumita R, Habuka R, Watanabe K, Saitoh A. PCR detection rates for serum and cerebrospinal fluid from neonates and young infants infected with human parechovirus 3 and enteroviruses. Journal of Clinical Virology 2021;135:104736. - PubMed
Tao 2022 {published data only}
    1. Tao Y, Yan H, Liu Y, Zhang F, Luo L, Zhou Y, et al. Diagnostic performance of metagenomic next-generation sequencing in pediatric patients: a retrospective study in a large children's medical center. Clinical Chemistry 2022;68(8):1031-41. [DOI: 10.1093/clinchem/hvac067] - DOI - PubMed
Tschiedel 2012 {published data only}
    1. Tschiedel E, Steinmann J, Buer J, Onnebrink JG, Felderhoff-Muser U, Rath PM, et al. Results and relevance of molecular detection of pathogens by SeptiFast – a retrospective analysis in 75 critically ill children. Klinische Padiatrie 2012;224(1):12-6. [PMID: ] - PubMed
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Wang 2022 {published data only}
    1. Wang ZX, Wu X, Xu J, Ye YZ, Han SZ, Ye LJ, et al. Value of metagenomic next-generation sequencing in the etiology diagnosis of bacterial meningitis in children. Zhonghua Er Ke za Zhi 2022;60(8):769-73. [DOI: 10.3760/cma.j.cn112140-20220317-00214] - DOI - PubMed
Yang 2021 {published data only}
    1. Yang Q, He B, Chen C, Wang H, Li W, Xue X, et al. A rapid, visible, and highly sensitive method for recognizing and distinguishing invasive fungal infections via CCP-FRET technology. ACS Infectious Diseases 2021;7(10):2816-25. - PubMed
Yu 2019 {published data only}
    1. Yu R, Zhou Q, Jiang S, Mei Y, Wang M. Combination of 16S rRNA and procalcitonin in diagnosis of neonatal clinically suspected sepsis. Journal of International Medical Research 2019;48(3):300060519892418. - PMC - PubMed
Yu 2020 {published data only}
    1. Yu R, Zhou Q, Jiang S, Mei Y, Wang M. Combination of 16S rRNA and procalcitonin in diagnosis of neonatal clinically suspected sepsis. Journal of International Medical Research 2020;48(3):300060519892418. - PMC - PubMed
Źródłowski 2018 {published data only}
    1. Źródłowski TW, Jurkiewicz-Badacz D, Sroka-Oleksiak A, Salamon D, Bulanda M, Gosiewski T. Comparison of PCR, fluorescent in situ hybridization and blood cultures for detection of bacteremia in children and adolescents during antibiotic therapy. Polish Journal of Microbiology 2018;67(4):479-86. - PMC - PubMed
Zurina 2021 {published data only}
    1. Zurina Z, Hoo NP, Amin-Nordin S, Joseph NM, Nunis MA. Diagnosis of neonatal meningitis: is it time to use polymerase chain reaction? Medical Journal of Malaysia 2021;76(1):101-3. - PubMed

References to ongoing studies

ChiCTR2100047120 {published data only}
    1. ChiCTR2100047120. Prospective study on the value of metagenomic second generation sequencing in the diagnosis and treatment of neonatal central nervous system infectious diseases. https://trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR2100047120 (first received 8 June 2021).
Dohna‐Schwake 2013 {published data only}
    1. Dohna-Schwake. Comparison of multiplex PCR assay for detection of bacterial and fungal DNA and blood cultures in children with suspected sepsis under antibiotic treatment. https://drks.de/search/en/trial/DRKS00004694/details (first registered 7 February 2013).
NCT05416918 {published data only}
    1. NCT05416918. Clinical value of metagenomic sequencing in neonatal sepsis. https://clinicaltrials.gov/study/NCT05416918 (first received 2 June 2022).
NCT05763680 {published data only}
    1. NCT05763680. Molecular culture for the diagnosis of neonatal sepsis. https://clinicaltrials.gov/study/NCT05763680 (first received 16 February 2023).
Vivek 2018 {published data only}
    1. Raju. A clinical study to find out ability of polymerase chain reaction test in detecting infection in neonates. https://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=24635 2018.

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References to other published versions of this review

Pammi 2015
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Pammi 2017
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