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

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

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

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Neonatology; Sepsis; Cytokines; Genetic predisposition to disease; Polymorphism, genetic

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