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

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

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

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Sumário

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

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

Autoria SCIMAGO INSTITUTIONS RANKINGS

Objetivo: Verificar a utilização e identificar as vantagens dos métodos moleculares para diagnóstico de infecções congênitas no líquido cefalorraquidiano de neonatos.

Fontes de dados: A revisão foi registrada na base PROSPERO (International Prospective Register of Systematic Reviews) sob CRD42021274210. A busca bibliográfica foi realizada nas bases de dados PubMed, Biblioteca Virtual em Saúde/ Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde (BVS/BIREME), Scopus, Web of Science, Excerpta Medica database (EMBASE), Cochrane, ProQuest, e EBSCOhost. A busca foi feita no período de agosto a outubro de 2021 e atualizada em dezembro de 2022, respeitando as orientações do Preferred Reporting Items for Systematic Reviews e Meta-Analyises (PRISMA). A sequência da seleção dos estudos foi: 1) Remoção de duplicatas; 2) Exame de títulos e resumos; 3) Recuperação dos textos completos potencialmente relevantes; e 4) Avaliação do texto completo conforme critérios de elegibilidade por dois autores independentes. O critério de inclusão considerou ensaios clínicos randomizados e não randomizados, estudos longitudinais, transversais, revisados por pares, estudos em humanos, publicados em inglês, espanhol, italiano e português, com recém-nascidos de até 28 dias que sofreram neuroinfecções congênitas pelos agentes toxoplasmose, rubéola, citomegalovírus, herpes simples (TORCH), e outros como Treponema pallidum, Zika, parvovírus B-19, varicela zoster, Epstein-Barr, e SARS-CoV-2, diagnosticadas por reação em cadeia de polimerase (PCR). Dois avaliadores extraíram as seguintes informações: autor, ano de publicação, nacionalidade, sujeitos, tipo de estudo, métodos, resultados e conclusão.

Síntese dos dados: O patógeno mais estudado foi Herpes Simples. Muitos artigos relataram somente sintomas iniciais inespecíficos, motivando a coleta de líquido cefalorraquidiano e realização da PCR para investigação etiológica.

Conclusões: Os métodos moleculares são eficazes para detectar o genoma do patógeno no líquido cefalorraquidiano, o que pode impactar na evolução clínica e no prognóstico neurológico.

Palavras-chave:
Toxoplasmose congênita; Sífilis congênita; Vírus da encefalite herpes simples; Síndrome congênita de Zika; Reação em cadeia da polimerase; Líquido cefalorraquidiano

Study	Country, Year	Subjects	Study type	Methods	Results and Conclusion
Anderson et al.¹	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.⁵	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.⁶	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.¹³	Singapura, 2015	neonates with HSV in CNS	retrospective	PCR of HSV in CSF; 1998–2011	33% seizures, 44% vesicles
Kawada et al.¹⁴	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.¹⁵	German, 2014	100 newborns, 2001–2012	retrospective	CSF PCR of HSV, VZV, EBV, CMV	Neonates: only CMV detected (4%)
Kurtz et al.¹⁶	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 Forsgren¹⁷	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.²⁰	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.²³	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
Norero²⁴	Panama, 2015	febrile (60 neonates)	prospective descriptive	PCR of CSF; 2013 – 2014	2% CMV infection; none HSV in suspicion of sepsis
Parisi et al.²⁶	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.²⁷	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.²⁹	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.²	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.⁴	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.²⁵	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.⁷	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.⁸	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.²⁸	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.¹⁸	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.¹⁹	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.²¹	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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[TFN1] HSV: herpes simplex virus; DNA: deoxyribonucleic acid; PCR: polymerase chain reaction; CSF: cerebrospinal fluid; CMV: cytomegalovirus; cCMV: congenital cytomegalovirus; USA: United States of America; CNS: central nervous system; VZV: varicella zoster virus; EBV: Epstein-Barr virus; UK: United Kingdom.