Systematic review on molecular detection of congenital and neonatal infections caused by TORCH and SARS-CoV-2 in newborns’ cerebrospinal fluid

Zimmerman, Suzana Ferreira; Bonon, Sandra Helena Alves; Marba, Sergio Tadeu Martins

doi:10.1590/1984-0462/2025/43/2023191

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Brasil

Revista Paulista de Pediatria

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Brasil

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Review Article • Rev. paul. pediatr. 43 • 2025 • https://doi.org/10.1590/1984-0462/2025/43/2023191 copy

Systematic review on molecular detection of congenital and neonatal infections caused by TORCH and SARS-CoV-2 in newborns’ cerebrospinal fluid

Revisáo sistemática sobre deteção molecular de infecções congênitas e neonatais causadas por TORCH e SARS-CoV-2 no líquido cefalorraquidiano de recém-nascidos

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To verify the use and identify advantages of molecular methods for congenital infections diagnosis in cerebrospinal fluid of neonates.

Data source:

The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO), under CRD42021274210. The literature search was performed in databases: PubMed, Virtual Health Library/ Latin American and Caribbean Center on Health Sciences Information (VHL/BIREME), Scopus, Web of Science, Excerpta Medica database (EMBASE), Cochrane, ProQuest, and EBSCOhost. The search was carried out from August to October 2021 and updated in December 2022, respecting the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The selection sequence was: 1) Duplicate title removal; 2) Examination of titles and abstracts; 3) Full-text retrieval of potentially relevant reports; and 4) Evaluation of the full text according to eligibility criteria by two independent authors. Inclusion criteria considered randomized and non-randomized control trials, longitudinal, cross-sectional, and peer-reviewed studies in humans, published in English, Spanish, Italian, and Portuguese, with newborns up to 28 days old who had congenital neuroinfections by toxoplasmosis, rubella, cytomegalovirus, herpes simplex (TORCH), and others such as Treponema pallidum, Zika, parvovirus B-19, varicella zoster, Epstein-Barr, and SARS-CoV2, diagnosed by polymerase chain reaction (PCR). Two evaluators extracted the following information: author, year of publication, nationality, subjects, study type, methods, results, and conclusion.

Data synthesis:

The most studied pathogen was herpes simplex. Several articles reported only nonspecific initial symptoms, motivating the collection of cerebrospinal fluid and performing PCR for etiological investigation.

Conclusions:

Molecular methods are effective to detect pathogen genomes in cerebrospinal fluid, which can impact clinical evolution and neurological prognosis.

Keywords:
Congenital toxoplasmosis; Congenital syphilis; Herpes simplex encephalitis virus; Congenital Zika syndrome; Polymerase chain reaction; Cerebrospinal fluid

Study	Country, Year	Subjects	Study type	Methods	Results and Conclusion
Anderson et al.¹1. Anderson NE, Powell KF, Croxson MC. A polymerase chain reaction assay of cerebrospinal fluid in patients with suspected herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 1993;56:520-5. https://doi.org/10.1136/jnnp.56.5.520 https://doi.org/10.1136/jnnp.56.5.520...	New Zealand, 1993	Patients with clinical HSV encephalitis	prospective	detection of HSV DNA with PCR in CSF	PCR is a highly specific test for HSV-1 and HSV-2 encephalitis in newborns
Czech-Kowalska et al.⁵5. Czech-Kowalska J, Jedlińska-Pijanowska D, Kasztelewicz B, Kłodzińska M, Pietrzyk A, Sarkaria E, et al. The limitations of cytomegalovirus DNA detection in cerebrospinal fluid of newborn infants with congenital CMV infection: a tertiary care neonatal center experience. Pediatr Infect Dis J. 2021;40:838-45. https://doi.org/10.1097/INF.0000000000003205 https://doi.org/10.1097/INF.000000000000...	Poland, 2021	168 infants with cCMV	retrospective and prospective	retrospective (2012–2015) and prospective (2016–2019)	PCR in CSF: 23 positive for CMV, all symptomatic
Davis et al.⁶6. Davis KL, Shah SS, Frank G, Eppes SC. Why are young infants tested for herpes simplex virus? Pediatr Emerg Care. 2008;24:673-8. https://doi.org/10.1097/PEC.0b013e318188773a https://doi.org/10.1097/PEC.0b013e318188...	USA, 2008	infants 0–60 days; 88 cases and 83 controls	case-control study	PCR in CSF; 1999–2004	HSV: 3,4% by PCR; seizure associated with decision to CSF HSV PCR
Jeyanthi et al.¹³13. Jeyanthi JC, Ong I, Guan YJ, Subramania KS, Cheng TK. Epidemiology and outcome in neonatal and pediatric herpes simplex encephalitis: a 13-year experience in a Singapore tertiary children’s hospital. J Pediatr Infect Dis. 2015;10:16-21. https://doi.org/10.1055/s-0035-1554972 https://doi.org/10.1055/s-0035-1554972...	Singapura, 2015	neonates with HSV in CNS	retrospective	PCR of HSV in CSF; 1998–2011	33% seizures, 44% vesicles
Kawada et al.¹⁴14. Kawada JI, Kimura H, Ito Y, Hoshino Y, Tanaka-Kitajima N, Ando Y, et al. Comparison of real-time and nested PCR assays for detection of herpes simplex virus DNA. Microbiol Immunol. 2004;48:411-5. https://doi.org/10.1111/j.1348-0421.2004.tb03530.x https://doi.org/10.1111/j.1348-0421.2004...	Japan, 2004	Neonates with HSV encephalitis	prospective	real-time PCR HSV compared with nested PCR in 109 CSF	Real-time PCR sensitivity: 100%; specificity: 99%
Kleines et al.¹⁵15. Kleines M, Scheithauer S, Schiefer J, Häusler M. Clinical application of viral cerebrospinal fluid PCR testing for diagnosis of central nervous system disorders: a retrospective 11-year experience. Diagn Microbiol Infect Dis. 2014;80:207-15. https://doi.org/10.1016/j.diagmicrobio.2014.07.010 https://doi.org/10.1016/j.diagmicrobio.2...	German, 2014	100 newborns, 2001–2012	retrospective	CSF PCR of HSV, VZV, EBV, CMV	Neonates: only CMV detected (4%)
Kurtz et al.¹⁶16. Kurtz J, Anslow P. Infantile herpes simplex encephalitis: diagnostic features and differentiation from non-accidental injury. J Infect. 2003;46:12-6. https://doi.org/10.1053/jinf.2002.1079 https://doi.org/10.1053/jinf.2002.1079...	United Kingdon, 2003	infants with HSV encephalitis	retrospective	CSF: HSV PCR were reviewed, follow-up 1996–1999	HSV PCR should be done in all neonates with encephalopathy
Malm and Forsgren¹⁷17. Malm G, Forsgren M. Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed. 1999;81:F24-9. https://doi.org/10.1136/fn.81.1.f24 https://doi.org/10.1136/fn.81.1.f24...	Sweden, 1999	36 neonatal HSV infections	retrospective	PCR in CSF; 1973–1996	in CNS: 29; seven had HSV-1 and 29 HSV-2
Melvin et al.²⁰20. Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Magaret A, Corey L, et al. Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr. 2015;166:827-33. https://doi.org/10.1016/j.jpeds.2014.11.011 https://doi.org/10.1016/j.jpeds.2014.11....	USA, 2015	neonates with HSV in CNS	retrospective	medical record review 1993–2012	HSV PCR in CSF: 70% of neonates with encephalitis
Mustonen et al.²³23. Mustonen K, Mustakangas P, Uotila L, Muir P, Koskiniemi M. Viral infections in neonates with seizures. J Perinat Med. 2003;31:75-80. https://doi.org/10.1515/JPM.2003.011 https://doi.org/10.1515/JPM.2003.011...	Finland/ UK, 2003	Neonates with seizures	prospective	PCR for: HSV-1 and 2, VZV 1995–1997	Only HSV-2 found in CSF samples of these neonates
Norero²⁴24. Norero X. Infecciones virales en neonatos febriles con sepsis clínica. Hospital del Niño. Panamá Diciembre 2013-2014. Pedátric Panamá. 2015;44:12-22.	Panama, 2015	febrile (60 neonates)	prospective descriptive	PCR of CSF; 2013 – 2014	2% CMV infection; none HSV in suspicion of sepsis
Parisi et al.²⁶26. Parisi SG, Basso M, Del Vecchio C, Andreis S, Franchin E, Dal Bello F, et al. Virological testing of cerebrospinal fluid in children aged less than 14 years with a suspected central nervous system infection: A retrospective study on 304 consecutive children from January 2012 to May 2015. Eur J Paediatr Neurol. 2016;20:588-96. https://doi.org/10.1016/j.ejpn.2016.04.002 https://doi.org/10.1016/j.ejpn.2016.04.0...	Italy, 2016	68 newborns, 2012 - 2015	retrospective	PCR for HSV/EBV/VZV/CMV/PvB-19	None of these pathogens detected in neonates’ CSF
Petel et al.²⁷27. Petel D, Barton M, Renaud C, Ouchenir L, Brophy J, Bowes J, et al. Enteroviral and herpes simplex virus central nervous system infections in infants < 90 days old: a Paediatric Investigators’ Collaborative Network on Infections in Canada (PICNIC) study. BMC Pediatrics. 2020;20:252. https://doi.org/10.1186/s12887-020-02151-4 https://doi.org/10.1186/s12887-020-02151...	Canada, 2020	younger than 90 days of age	cross-sectional retrospective	PCR in CSF, 2013–2014	Viral CNS infections more than bacterial in infants
Schleede et al.²⁹29. Schleede L, Bueter W, Baumgartner-Sigl S, Opladen T, Weigt-Usinger K, Stephan S, et al. Pediatric herpes simplex virus encephalitis: a retrospective multicenter experience. J Child Neurol. 2013;28:321-31. https://doi.org/10.1177/0883073812471428 https://doi.org/10.1177/0883073812471428...	German, 2013	Neonates with encephalitis	retrospective and prospective	HSV encephalitis diagnosed by PCR	difficulty to diagnose because of nonspecific early symptoms

Study	Country, Year	Subjects	Study type	Methods	Results and Conclusion
Belaz et al.²2. Belaz S, Gangneux JP, Dupretz P, Guiguen C, Robert-Gangneuxa F A. 10-year retrospective comparison of two target sequences, REP-529 and B1, for Toxoplasma gondii detection by quantitative PCR. J Clin Microbiol. 2015;53:1294-300. https://doi.org/10.1128/JCM.02900-14 https://doi.org/10.1128/JCM.02900-14...	France, 2015	41 suspicious congenital toxoplasmosis	Observational, longitudinal retrospective	PCR diagnosis from 2003 to 2013. All positive samples were reanalyzed with both gene targets in the same PCR. All samples from proven congenitally infected infants.	PCR positive for congenital toxoplasmosis in CSF and suggest that region should be adopted as part of the standardization
Cassaing et al.⁴4. Cassaing S, Bessières MH, Berry A, Berrebi A, Fabre R, Magnaval JF. Comparison between two amplification sets for molecular diagnosis of toxoplasmosis by real-time PCR. J Clin Microbiol. 2006;44:720-4. https://doi.org/10.1128/JCM.44.3.720-724.2006 https://doi.org/10.1128/JCM.44.3.720-724...	France, 2006	prenatal and neonatal diagnosis of toxoplasmosis	prospective study	Between June and October 2003, all samples for suspicion were tested	PCR method: sensitivity was confirmed in positive clinical samples including CSF (50%) PCR improved the performance of the diagnosis of toxoplasmosis
Olariu et al.²⁵25. Olariu TR, Remington JS, Montoya JG. Polymerase chain reaction in cerebrospinal fluid for the diagnosis of congenital toxoplasmosis. Pediatr Infect Dis J. 2014;33:566-70. https://doi.org/10.1097/INF.0000000000000256 https://doi.org/10.1097/INF.000000000000...	USA, 2014	infants ranged in age from 0–180 days, born from untreated mothers	retrospective	PCR in CSF for diagnosis of congenital toxoplasmosis. Studied infants, diagnosed clinically and serologically, noninfected, between 1993–2005	PCR in CSF: sensitivity varied by age group: 0–30 days = 60% VPP and specificity: 100% CSF PCR can contribute to the early confirmation of the diagnosis of congenital toxoplasmosis

Study	Country, Year	Subjects	Study type	Methods	Results and Conclusion
Araújo et al.⁷7. Araújo TV, Rodrigues LC, Ximenes RA, Miranda-Filho DB, Montarroyos UR, Melo AP, et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. Lancet Infect Dis. 2016;16:1356-63. https://doi.org/10.1016/S1473-3099(16)30318-8 https://doi.org/10.1016/S1473-3099(16)30...	Brazil, 2016	32 case patients (neonates with microcephaly) and 62 controls (neonates without microcephaly)	case-control study	January to May 2016 CSF samples of cases were tested for Zika virus by RT-PCR. Laboratory-confirmed Zika virus infection a positive RT-PCR result in neonates	80% mothers of cases had Zika virus infection while 64% mothers of controls 41% cases and none of controls had laboratory-confirmed Zika virus infection. Microcephaly epidemic is a result of congenital Zika virus infection
Araújo et al.⁸8. Araújo TV, Ximenes RA, Miranda-Filho DB, Souza WV, Montarroyos UR, Melo AP, et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: Final report of a case-control study. Lancet Infect Dis. 2018;18:328-36. https://doi.org/10.1016/S1473-3099(17)30727-2 https://doi.org/10.1016/S1473-3099(17)30...	Brazil, 2018	173 controls, 91 cases of neonates with microcephaly	case-control study	January to November 2016 CSF samples of cases tested for Zika virus, specific IgM and by quantitative RT-PCR	Cases: 43% positive for Zika virus and had cerebral abnormalities Association between microcephaly and congenital Zika virus infection was confirmed
Pomar et al.²⁸28. Pomar L, Vouga M, Lambert V, Pomar C, Hcini N, Jolivet A, et al. Maternal-fetal transmission and adverse perinatal outcomes in pregnant women infected with Zika virus: Prospective cohort study in French Guiana. BMJ. 2018;363:k4431. https://doi.org/10.1136/bmj.k4431 https://doi.org/10.1136/bmj.k4431...	French Guiana, 2018	305 newborns/fetuses from pregnant women with a laboratory-confirmed Zika virus infection during the epidemic period in French Guiana.	prospective	January to July 2016 Rate of maternal-fetal transmission of Zika virus CSF, signs of congenital Zika syndrome, severe complications or fetal loss. Associations between laboratory-confirmed infection and adverse fetal/neonatal outcomes	Positive Zika virus results were obtained from (57%) CSF. Maternal-fetal transmission seems to occur in approximately 1/4 of exposed fetuses and is associated with early adverse fetal/neonatal outcomes in 1/3 of infected fetuses

Study	Country, Year	Subjects	Study type	Methods	Results and Conclusion
Marangoni et al.¹⁸18. Marangoni A, Moroni A, Tridapalli E, Capretti MG, D’Antuono A, Biagi M, et al. Congenital syphilis surveillance. Microbiologia Medica. 2011;26:108-11. https://doi.org/10.4081/mm.2011.2368 https://doi.org/10.4081/mm.2011.2368...	Italy, 2011	165 newborn to 151 syphilis seropositive mothers with + RPR at birth	prospective surveillance	CSF analysis PCR, 2000 through 2010 prospective follow up	careful CSF examination allowed the identification and treatment of high-risk newborns
Marangoni et al.¹⁹19. Marangoni A, Moroni A, Tridapalli E, Capretti MG, Farneti G, Faldella G, et al. Antenatal syphilis serology in pregnant women and follow-up of their infants in northern Italy. Clin Microbiol Infect. 2008;14:1065-8. https://doi.org/10.1111/j.1469-0691.2008.02066.x https://doi.org/10.1111/j.1469-0691.2008...	Italy, 2008	133 infants Born to 119 syphilis seropositive mothers	prospective	six presumptive cases of congenital syphilis with IgM western blot positive results were analysed CSF, from 2000 through 2007	careful CSF examination allowed the identification and treatment of high-risk newborns
Michelow et al.²¹21. Michelow IC, Wendel Jr GD, Norgard MV, Zeray F, Leos NK, Alsaadi R, et al. Central nervous system infection in congenital syphilis. N Engl J Med. 2002;346:1792-8. https://doi.org/10.1056/NEJMoa012684 https://doi.org/10.1056/NEJMoa012684...	USA, 2002	148 infants were included whose mothers had syphilis during pregnancy	prospective	prospectively enrolled if born between 1989 and 1999	Treponema pallidum detected in CSF in 22% who had no prior antibiotic exposure. CNS infection was best predicted by IgM of serum or PCR of serum or blood. Only 35% of these infants had positive CSF PCR.

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[1] Corresponding author: E-mail: suzanafz@unicamp.br (S. F. Zimmerman)