Previsão de desfechos relacionados a sepse em neonatos através da genotipagem sistemática de polimorfismos de genes da imunidade inata e inflamação: uma revisão narrativa e perspectiva crítica

Carvalho, Juliana Kilesse; Moore, Daniella Batalha; Luz, Ricardo Alves; Xavier-Elsas, Pedro Paulo; Gaspar-Elsas, Maria Ignez Capella

doi:10.1590/1516-3180.2013.1315519

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Sao Paulo Medical Journal

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Sumário

Narrative Review • Sao Paulo Med. J. 131 (05) • 2013 • https://doi.org/10.1590/1516-3180.2013.1315519 copiar

Previsão de desfechos relacionados a sepse em neonatos através da genotipagem sistemática de polimorfismos de genes da imunidade inata e inflamação: uma revisão narrativa e perspectiva crítica

Autoria SCIMAGO INSTITUTIONS RANKINGS

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:

Revis ão narrativa da literatura, Instituto Fernandes Figueira, Brasil. M ÉTODOS: 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-1 β, IL-1ra, L-selectin, CD14, e MBL) ou inflamatórios (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 previsão da sepse por meio de genotipagem sistemática precisa ser reavaliada, com base em estudos que demonstram o impacto funcional de polimorfismos gênicos e as diferenças epidemiológicas entre populações etnicamente distintas.

Neonatologia; Sepse; Citocinas; Predisposição genética para doença; Polimorfismo genético

Electronic search	Database	Filters	Search terms	Results
Search through NCBI (http://www.ncbi.nlm.nih.gov/pubmed)	PubMed	Limits: human, newborn, case control studies	(neonate OR premature OR VLBW OR LBW) AND (sepsis OR neonatal infections) AND (polymorphism OR polymorphisms OR genetic variability OR genotype)	Retrieved articles: 548Excluded articles: 526Included articles: 22
Search through Bireme-BVS (http://regional.bvsalud.org)	Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde)	Limits: human, newborn Major subject: genetic polymorphism
Search through Bireme-BVS (http://regional.bvsalud.org)	Cochrane Library	No limits
Search though Embase Biomedical Answers (http://embase.periodicos.saude.gov.br)	Embase (Excerpta Medica Database)	Limits: human, newborn infection
Search though SciELO (http://www.scielo.org)	SciELO (Scientific Electronic Library Online)	No limits
Last search date: September 18, 2012

Study	1	2	3	4	5	6	7
Aydemir et al.²¹	no	yes	yes	yes	yes	no	yes
Härtel et al.⁹	no	yes	yes	yes	yes	no	yes
Abu-Maziad et al.²²	no	yes	yes	yes	yes	no	no
Auriti et al.²³	no	yes	yes	yes	yes	no	yes
Koroglu et al.²⁴	no	yes	yes	yes	yes	no	yes
Spiegler et al.²⁵	no	yes	yes	yes	yes	no	yes
Abdel-Hady et al.²⁶	no	yes	yes	yes	yes	no	yes
Bertalan et al.²⁷	no	yes	yes	yes	yes	no	no
Reiman et al.²⁸	no	yes	yes	yes	yes	no	yes
Dzwonek et al.²⁹	no	yes	yes	yes	yes	no	yes
van Der Zwet et al.³⁰	no	yes	yes	no	no	no	yes
Schueller et al.³¹	no	yes	yes	yes	no	yes	yes
Derzbach et al.³²	no	yes	yes	yes	yes	no	no
Härtel et al.³³	no	yes	yes	yes	yes	no	yes
Baier et al.³⁴	no	yes	yes	yes	yes	yes	yes
Göpel et al.³⁵	no	yes	yes	yes	yes	no	yes
John Baier et al.³⁶	no	yes	yes	yes	yes	no	no
Hedberg et al.³⁷	no	yes	yes	yes	yes	no	no
Ahrens et al.³⁸	no	yes	yes	yes	yes	no	yes
Bessler et al.³⁹	no	yes	yes	yes	yes	no	yes
Harding et al.⁴⁰	yes	yes	yes	yes	yes	yes	yes
Treszl et al.⁴¹	no	yes	yes	yes	yes	no	yes

Questions (Q)	Aydemir et al.²¹	Härtel et al.⁹	Abu-Maziad et al.²²	Auriti et al.²³	Koroglu et al.²⁴	Spiegler et al.²⁵	Abdel-Hady et al.²⁶	Bertalan et al.²⁷	Reiman et al.²⁸	Dzwonek et al.²⁹	van Der Zwet et al.³⁰	Schueller et al.³¹	Derzbach et al.³²	Härtel et al.³³	Baier et al.³⁴	Göpel et al.³⁵	John Baier et al.³⁶	Hedberg et al.³⁷	Ahrens et al.³⁸	Bessler et al.³⁹	Harding et al.⁴⁰	Treszl et al.⁴¹
Q 1	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 2	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 3	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 4	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 5	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 6	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 10	no	yes	yes	yes	yes	yes	yes	yes	yes	yes	no	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	no
Q 11	no	no	no	yes	no	no	no	no	no	no	yes	no	no	no	no	no	no	no	no	no	no	no
Q 13	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 14	no	no	no	no	no	no	no	no	no	no	no	yes	no	no	yes	no	no	no	no	no	yes	no
Q 15	no	no	no	no	no	no	no	no	no	no	no	yes	no	no	yes	no	no	no	no	no	yes	no
Q 18	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 20	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 21	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	no	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 22	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 25	no	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes	no	yes	yes	yes	yes	yes	yes	yes	yes	yes	yes
Q 27	no	yes	yes	no	yes	no	no	no	yes	no	no	no	no	yes	yes	no	no	no	yes	no	yes	no

Down and Black checklist for assessing study quality. Q 1 = Is the hypothesis/aim/objective of the study clearly described?; Q 2 = Are the main outcomes to be measured clearly described in the Introduction or Methods section?; Q 3 = Are the characteristics of the patients included in the study clearly described?; Q 4 = Are the interventions of interest clearly described?; Q 5 = Are the distributions of principal confounders in each group of subjects to be compared clearly described?; Q 6 = Are the main findings of the study clearly described?; Q 7 = Does the study provide estimates of the random variability in the data for the main outcomes?; Q 8 = Have all important adverse events that may be a consequence of the intervention been reported?; Q 9 = Have the characteristics of patients lost to follow-up been described? Q 10 = Have actual probability values been reported (e.g. 0.035 rather than < 0.05) for the main outcomes except where the probability value is less than 0.001?; Q 11 = Were the subjects asked to participate in the study representative of the entire population from which they were recruited?; Q 12 = Were those subjects who were prepared to participate representative of the entire population from which they were recruited?; Q 13 = Were the staff, places, and facilities where the patients were treated, representative of the treatment the majority of patients receive?; Q 14 = Was an attempt made to blind study subjects to the intervention they have received?; Q 15 = Was an attempt made to blind those measuring the main outcomes of the intervention?; Q 16 = If any of the results of the study were based on "data dredging", was this made clear?; Q 17 = In trials and cohort studies, do the analyses adjust for different lengths of follow-up of patients, or in case-control studies, is the time period between the intervention and outcome the same for cases and controls?; Q 18 = Were the statistical tests used to assess the main outcomes appropriate?; Q 19 = Was compliance with the intervention/s reliable?; Q 20 = Were the main outcome measurements used accurate (valid and reliable)?; Q 21 = Were the patients in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited from the same population?; Q 22 = Were study subjects in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited over the same period of time?; Q 23 = Were study subjects randomized to intervention groups?; Q 24 = Was the randomized intervention assignment concealed from both patients and healthcare staff until recruitment was complete and irrevocable?; Q 25 = Was there adequate adjustment for confounding in the analyses from which the main findings were drawn?; Q 26 = Were losses of patients from follow-up taken into account?; Q 27 = Did the study have sufficient power to detect a clinically important effect where the probability value for a difference being due to chance is less than 5%? Note: Questions 7, 8, 9, 12, 16, 17, 19, 23, 24 and 26 were considered to be not applicable to the type of studies included in this in-depth review.

Author	Year	Country	Patients	Controls	Findings
Aydemir et al.²¹	2011	Turkey	31 preterm infants with fungal septicemia	30 preterm infants who had no invasive fungal infection	No association between codon 54 (B allele) polymorphism in exon 1 of the MBL gene and massive fungal sepsis
Hartel et al.⁹	2011	Germany	Cohort 1: 344 septic VLBW infants; Cohort 2: 555 septic VLBW infants	Cohort 1: 1600 non-septic VLBW infants; Cohort 2: 371 non-septic VLBW infants	No association between late onset sepsis and the SNP TNF- 308 G/A
Abu-Maziad et al.²²	2010	USA	79 preterm infants with sepsis	202 preterm infants without sepsis	TLR2, TLR5, IL-10 and PLA2G2A polymorphisms predispose to sepsis in preterm infants
Auriti et al.²³	2010	Italy	42 neonates with sepsis	85 neonates without infection	No association between the MBL2 genotypes and sepsis
Koroglu et al.²⁴	2010	Turkey	Proven sepsis: 11 preterm newborns; Clinical sepsis: 42 preterm newborns	57 preterm infants with no sepsis	No association between MBL polymorphism and culture-proven sepsis; however, a risk of clinical sepsis was shown
Spiegler et al.²⁵	2010	Germany	706 septic VLBW infants genotyped for ACE-ins/del genotype; 709 septic VLBW infants genotyped for ATR-1166A/C genotype	503 non-septic VLBW infants genotyped for ACE-ins/del genotype;495 non-septic VLBW infants genotyped for ATR-1166A/C genotype	No impact of any renin-angiotensin system SNPs; no association was found between the ATR-1166A/C genotype or ACE-ins/del genotype and neonatal sepsis
Abdel-Hady et al.²⁶	2009	Egypt	54 septic full-term neonates	70 non-septic matched full-term neonates	The IL-6 -174 and IL-10-1082 genotypes were not significantly different in neonates with bloodstream infections, compared with controls
Bertalan et al.²⁷	2008	Hungary	22 septic preterm neonates	103 non-septic preterm neonates	BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene were not associated with risk of sepsis
Reiman et al.²⁸	2008	Finland	11 septic preterm VLBW infants	96 non-septic preterm VLBW infants	Association between the IL-6-174 CC genotype and increased sepsis prevalence in VLBW infants
Dzwonek et al.²⁹	2008	England/ Poland	47 septic preterm infants	111 non-septic preterm infants	Analyses of the effect of MBL genotype in newborns of gestational age < 28 weeks and birth weight < 1000 g did not show a statistically significant association with sepsis
van der Zwet et al.³⁰	2008	Holland	Low MBL genotype: 8 septic neonates; Medium MBL genotype: 15 septic neonates; High MBL genotype: 41 septic neonates	Low MBL genotype: 30 non-septic neonates; Medium MBL genotype: 60 non-septic neonates High MBL genotype: 44 non-septic neonates	No relationship was found between MBL genotype and the risk of nosocomial sepsis
Schueller et al.³¹	2006	Germany	67 preterm infants (< 32 weeks of gestation) and early-onset sepsis	102 healthy newborns born after 32 weeks of gestation	No association between polymorphisms of TNF-308 and LTA +252 and early-onset sepsis in newborns with < 32 weeks of gestation.
Derzbach et al.³²	2006	Hungary	36 septic LBW infants	89 non-septic LBW infants	No association was found between the polymorphisms E-selectin Ser128Arg, P-selectin Thr715Pro, L-selectin Pro213Ser and the risk of sepsis
Hartel et al.³³	2006	Germany	198 septic VLBW infants	1008 non-septic VLBW infants	Higher rate of sepsis for carriers of factor XIII Val34Leu SNP
Baier et al.34	2006	Canada	148 septic VLBW infants	145 non-septic VLBW infants	The IL-6 -174C allele was associated with increased incidence of late bloodstream infection (BSI) in AA but not in Caucasian infants. The IL-10 -1082A allele was associated with increased incidence of late BSI. The CD14 -260 C/T SNP did not alter the overall risk of BSI in ventilated VLBW infants.
Göpel et al.³⁵	2006	Germany	97 VLBW infants who evolved with sepsis	320 non-septic VLBW infants	No association between sepsis and IL-6-174 genetic polymorphism
John Baier et al.³⁶	2005	Canada	149 septic VLBW infants	146 non-septic VLBW infants	The ACE I/D polymorphism did not have a significant effect on incidence of sepsis
Hedberg et al.³⁷	2004	USA	82 mechanically ventilated VLBW infants with late bacteremia	91 mechanically ventilated VLBW infants without late bacteremia	The TNF-308 G/A SNP had no influence on the incidence of either early or late bacteremia or fungemia
Ahrens et al.³⁸	2004	Germany	50 septic VLBW infants	306 non-septic VLBW infants	VLBW infants carrying the NOD2-3020ins C allele (n = 15) and the IL-6-174 G allele (n = 121) had a significantly higher rate of blood culture-proven sepsis.
Bessler et al.³⁹	2004	Israel	34 septic preterm LBW infants aged 24-35 weeks of gestation	61 non-septic preterm LBW infants aged 24-35 weeks of gestation	No impact of IL-1ra genetic polymorphism on early onset sepsis
Harding et al.⁴⁰	2003	England	51 septic preterm infants aged < 32 weeks of gestation.	106 non-septic preterm infants aged < 32 weeks of gestation.	Increased confirmed bacteriological sepsis with IL-6-174 GG allele
Treszl et al.⁴¹	2003	Hungary	33 septic VLBW neonates	35 non-septic VLBW neonates	TNF-308, IL-1β, IL-4 receptor α chain, IL-6 and IL-10 genes are not risk factors for sepsis in LBW infants

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[1] Address for correspondence: Maria Ignez Capella Gaspar Elsas Av. Rui Barbosa, 716 Laboratório de Fisiopatologia Humana Flamengo - Rio de Janeiro (RJ) - Brasil CEP 22250-020 E-mail: elsas@iff.fiocruz.br