Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective

Abstract

CONTEXT AND OBJECTIVE: Neonatal sepsis is associated with premature birth and maternal infection. Large-scale studies seek to define markers that identify neonates at risk of developing sepsis. Here, we examine whether the scientific evidence supports systematic use of polymorphism genotyping in cytokine and innate immunity genes, to identify neonates at increased risk of sepsis. DESIGN AND SETTING: Narrative literature review conducted at Fernandes Figueira Institute, Brazil. METHODS:The literature was searched in PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) and Cochrane Library. From > 400,000 references, 548 were retrieved based on inclusion/exclusion criteria; 22 were selected for detailed analysis after quality assessment. RESULTS:The studies retrieved addressed the impact of gene polymorphisms relating to immune mechanisms (most often TNF-a, LT-a, IL-6, IL-1β, IL-1ra, L-selectin, CD14 and MBL) or inflammatory mechanisms (ACE and angiotensin II receptors; secretory PLA2; and hemostatic factors). Despite initial reports suggesting positive associations between specific polymorphisms and increased risk of sepsis, the accumulated evidence has not confirmed that any of them have predictive power to justify systematic genotyping. CONCLUSIONS: Sepsis prediction through systematic genotyping needs to be reevaluated, based on studies that demonstrate the functional impact of gene polymorphisms and epidemiological differences among ethnically distinct populations. RESUMO CONTEXTO E OBJETIVO:A sepse neonatal está associada ao parto prematuro e à infecção materna. Estudos em grande escala buscam marcadores que identifiquem neonatos em risco de desenvolver sepse. Examinamos aqui se a evidência científica apoia o uso sistemático de genotipagem dos polimorfismos em genes de citocinas e imunidade inata, para identificar neonatos com risco elevado de sepse. TIPO DE ESTUDO E LOCAL:Revisão narrativa da literatura, Instituto Fernandes Figueira, Brasil. MÉTODOS: Busca online da literatura foi feita no PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) e Cochrane Library. De mais de 400.000 referências, 548 foram recuperadas com base nos critérios de inclusão/exclusão, e 22, selecionadas para análise detalhada após verificação da qualidade. RESULTADOS: Recuperamos estudos de impacto dos polimorfismos em genes relacionados com mecanismos imunes (mais frequentemente, TNF-a, LT-a, IL-6, IL-1β, IL-1ra, L-selectin, CD14, e MBL) ou inflamató-rios (ACE e receptores de angiotensina II; PLA2 secretória; fatores hemostáticos). Contrariando estudos que inicialmente sugeriram associação positiva entre polimorfismos específicos e risco aumentado de sepse, a evidência acumulada não confirmou, para qualquer deles, valor preditivo que justifique genotipagem sistemática para orientar antibioticoterapia. CONCLUSÕES: A...

Pathophysiology of Neonatal Sepsis

“…240 No mutations in specific domains of NLRs have been found in neonates with sepsis or NEC. 220,[231][232][233][241][242][243][244][245][246][247][248][249][250][251][252] The importance of NLRs in Listeria monocytogenes infections in neonates is unknown.…”

Fatores De Risco Para Sepse Neonatal Em Unidade De Terapia: Estudo De Evidência

“…Em consonância com os esses achados, um estudo realizado no Brasil identificou uma maior taxa de sepse neonatal precoce nos recém-nas¬cidos com idade gestacional entre 29 e 34 semanas e peso ≤ 1000 g. Esses resultados reforçam que a prematuridade e o baixo peso ao nascer constituem um fator importante para a sepse (13) . Ademais, uma investigação realizada na Ásia identificou que há associação entre o diagnóstico da sepse neonatal com a presença da hemocultura positiva, baixo peso ao nascer e prematuridade (14)(15) .…”

Clinical immunology Neonatal infections in Saudi Arabia: Association with cytokine gene polymorphisms

“…Some studies have reported an increase in the concentrations of these proinflammatory cytokines in systemic circulation in septic newborns [16][17][18][19][20], while others demonstrated similar or even lower levels in infected newborns compared to healthy newborns [21][22][23][24]. Such discrepancies in results among different studies could explain the different outcomes of sepsis seen in neonates [25]. Therefore, the variable of clinical evolution of neonatal sepsis is related to the individual variability in cytokine production and intensity of inflammation [25,26], which may be due to the variation of the genetic background of the patients [27].…”

“…Such discrepancies in results among different studies could explain the different outcomes of sepsis seen in neonates [25]. Therefore, the variable of clinical evolution of neonatal sepsis is related to the individual variability in cytokine production and intensity of inflammation [25,26], which may be due to the variation of the genetic background of the patients [27].…”