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PEDIATRICS Vol. 112 No. 4 October 2003, pp. 800-803

Is Interleukin-6 –174 Genotype Associated With the Development of Septicemia in Preterm Infants?

David Harding, PhD*, Sukhbir Dhamrait, MD{ddagger}, Ann Millar, MD§, Steve Humphries, PhD{ddagger}, Neil Marlow, MD||, Andrew Whitelaw, MD and Hugh Montgomery, MD{ddagger}

* Department of Child Health, University of Bristol, Bristol, United Kingdom
{ddagger} Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London, United Kingdom
§ Lung Research Group, University of Bristol Medical School, Southmead Hospital, Bristol, United Kingdom
|| School of Human Development, University of Nottingham, Nottingham, United Kingdom
Neonatal Intensive Care Unit, University of Bristol Medical School, Southmead Hospital, Bristol, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Objective. Systemic infection affects one quarter of preterm infants. Defense from infection is in part mediated by the cytokine interleukin-6 (IL-6). We tested the hypothesis that the IL-6 –174 GG genotype, associated with lower IL-6 response to inflammation, is also associated with the development of septicemia in preterm infants.

Methods. The study group comprised 157 infants who were born at ≤32 weeks. Genotype distribution (34% [54] GG, 46% [72] GC, 20% [31] CC) and C allele frequency (0.43; 95% confidence interval [CI]: 0.37–0.48) were similar to the UK adult population. Among the patients who developed bacterially confirmed septicemia (n = 51 [33%]), there was a significantly higher prevalence of the IL-6 –174 GG genotype than that observed in those who did not develop infection (47% vs 28% for GG: odds ratio [OR]: 2.3; 95% CI: 1.1–4.5). This association remained statistically significant (OR: 2.7; 95% CI: 1.2–6.3) after multiple binary logistic regression adjustment for other significant predictors of the development of septicemia. Late infection alone was similarly associated with GG genotype (septicemia 47% vs no septicemia 29% for GG: OR: 2.2; 95% CI: 1.1–4.3).

Conclusions. Variation in the IL-6 gene seems to influence the defense against bacterial pathogens in the very preterm infant.

Key Words: interleukin-6 • polymorphism • infant • infection

Abbreviations: NICU, neonatal intensive care unit • IL-6, interleukin-6 • APIP, Avon Premature Infant Project • OR, odds ratio • CI, confidence interval

Systemic infection is an important cause of morbidity and mortality in intensive care units. This is particularly evident in the neonatal intensive care unit (NICU), where septicemia affects at least one quarter of infants during their hospital stay.1 Here, it is one of the most common causes of mortality, being responsible for fully 40% of late deaths.2 Immune system immaturity in the preterm infant is associated with a state of relative immunocompromise and subsequent elevated risk of bacterial infection. Interleukin-6 (IL-6) is a cytokine that plays a crucial role in the orchestration of the proinflammatory response and whose levels may be reduced in preterm (compared with term) infants.3–6 Although IL-6 activity does rise in response to infection,7 the lower IL-6 activity of the preterm infant thus might be associated with the susceptibility of preterm infants to septicemia.3–5 However, the association of any identified lower IL-6 levels with impaired outcome may or may not be causal. The recognized volatility of cytokine responses and the need to assess total IL-6 burden over time (rather than single levels) prevents "tightening" the demonstration of association. Even this, however, would fail to demonstrate causality. One way forward is the use of a genetic strategy. Such an approach is now widely accepted: a common functional variation is identified in the gene regulating synthesis of the agent in question. Association of that variation with a pathophysiologic phenotype goes a long way to demonstrate causality.

A common functional variant of the IL-6 gene has been reported, comprising a G/C substitution at position –174. The C allele is common in whites (UK frequency, 0.41; 95% CI: 0.38–0.43).8 Although basal (unstimulated/low-grade inflammatory) IL-6 levels seem G-allele related,8–10 the inflammatory rise in IL-6 levels seems strongly C allele dependent. Thus, IL-6 levels are C-allele related among adults with (inflammatory) aortic aneurysms,11 and after the inflammatory provocation of cardiopulmonary bypass12 and C-reactive protein levels (CRP) share this allele association.13,14 Among newborn infants, the C allele is associated with raised peripartum IL-6 levels,15 whereas in vitro, neonatal endotoxin-stimulated monocyte IL-6 production is also C-allele associated.15 Thus, the C allele seems associated with a greater rise in IL-6 levels as part of the acute inflammatory response and in certain disease states.

If lower basal IL-6 levels are in part responsible for the vulnerability of a preterm infant to infection, then the IL-6 –174 G allele and particularly the GG genotype would be expected to be associated with the development of septicemia after preterm birth. We tested this hypothesis by examining the relationship between IL-6 –174G>C genotype and the development of septicemia in a well-defined16 cohort of preterm infants who were born at or before 32 weeks’ gestation.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Both this study and the Avon Premature Infant Project (APIP)16 study from which samples were drawn (below) were approved by the appropriate ethics committees of Southmead Hospital, Bristol, and the United Bristol Health Care Trust. Parental assent was required for APIP (below) by the ethics committees but not for the gene-association study, as all data were rendered anonymous and stored separately from identifying information.

Patients
A large-scale cohort of premature infants who were subjected to prospective evaluation was sought to test the hypothesis. Subjects composed a well-defined group of infants who were representative of the local population already recruited to APIP, a prospective neonatal outcome study.16 These patients were born in 2 Bristol (UK) hospitals over a 30-month period between 1990 and 1993 at ≤32 weeks’ gestation. All survived to 2 years. Septicemia was defined prospectively during the original study as a clinical deterioration in the presence of a positive blood culture—a definition also suggested more recently by Stoll et al.17 Early septicemia was defined as septicemia occurring within 48 hours of delivery and late septicemia as that apparent 48 hours or more after delivery. Retrospective case note review was conducted to determine the temporal relationship between immunosuppressive pulmonary therapy (dexamethasone) and the development of septicemia, with reviewers blinded to the IL-6 data. Infants who were receiving dexamethasone when developing septicemia were excluded from primary analysis as were those who received their last dose of dexamethasone within 48 hours of developing systemic infection. Subsequent analysis was performed on all infants regardless of whether they received steroids or not.

IL-6 Genotyping
DNA was extracted from the blood stored on newborn metabolic screening (Guthrie) cards by boiling in sterile distilled water after heavy metal ion chelation.18 IL-6 genotypes were determined by polymerase chain reaction amplification of a 190-bp fragment of the IL-6 gene promoter region, incubation with the restriction endonuclease NlaIII, and separation of the digestion products using a microtiter array diagonal electrophoresis gel stained with 0.1% ethidium bromide, as previously described.8,11,12 Analysis was performed by 2 independent staff who were blinded to patient data, and inconsistencies were resolved by repeat genotyping.

Statistical Analysis
Data storage and statistical analysis were performed using SPSS for windows (v9.0). Categorical data were analyzed by {chi}2 and {chi}2 trend, and continuous data were analyzed by t test and Mann-Whitney U test as appropriate. Multiple binary logistic regression was used to determine factors associated with sepsis development and to determine (through adjustment for these) whether –174G>C genotype was an independent risk factor for the development of bacterially confirmed sepsis. Adjustment was also made for any effect of race. P < .05 was taken as statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The APIP study comprised 308 patients. Guthrie cards with any blood left could be located for 200 patients, on which DNA extraction was performed, and IL-6 genotype was successfully determined in 164 cases. Such a technical failure rate is considered acceptable for conventional genotyping methods from very small and old dried blood samples. One infant from each of 3 pairs of identical twins (determined by gender and IL-6 genotypes) was excluded randomly for the purposes of this study and after IL-6 genotyping. Four patients who developed septicemia while receiving immunosuppressant corticosteroids (dexamethasone) for chronic inflammatory lung disease were excluded a priori. The study group thus comprised 157 whose genotype distribution (54 [34.4%] GG, 72 [45.9%] GC, 31 [19.7%] CC) was as expected for Hardy-Weinberg proportions. The allele frequencies were similar to those reported in previous UK adult population samples8,11,12 and well term neonates.15 Infant baseline characteristics (Table 1) were independent of 174G>C genotype and also representative of the original APIP cohort overall.16


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  		TABLE 1. Characteristics of Study Group*

 
Fifty-one (33%) patients developed septicemia, 7 (4%) patients developed early septicemia, and late septicemia occurred at least once in 47 (30%) patients. Twenty-one (13%) patients had >1 episode of septicemia. There were 76 septicemic episodes in total, and the causative bacterial pathogens cultured are shown in Table 2. There were no cases of fungal sepsis. The prevalence of –174 GG genotype was greater among the 51 who developed bacterially confirmed septicemia (GG 47% [24]) than among those 106 who did not (GG 28% [30]; P = .021). The odds ratio (OR) for septicemia associated with GG genotype was 2.3 (95% confidence interval [CI]: 1.1–4.5) when compared with the GC+CC group (Table 3). Logistic regression identified gestational age, duration of initial ventilation (days), and length of hospitalization (days) as significant individual predictors of septicemia. The risk associated with GG genotype persisted even after adjustment for all of these factors (OR: 2.7; 95% CI: 1.2–6.3; P = .019; Table 3). The study group was relatively racially homogeneous, with all but 12 patients being white. The size of the risk effect was essentially unchanged when also adjusting for race (septicemia and GG genotype, P = .022; OR: 2.7; 95% CI: 1.2–6.4, after multiple logistic regression). Similarly, the unadjusted prevalence of –174 GG genotype was greater among those 47 who developed only late septicemia (GG 47% [22]) than among those 110 who did not (GG 29% [32]; P = .032; OR for late septicemia with GG genotype: 2.2; 95% CI: 1.1–4.3, compared with the GC+CC).


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  		TABLE 2. Pathogens and Septicemia*

 

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  		TABLE 3. Association of IL-6 -174 GG Genotype and Septicemia*

 
All 10 infants who received a course of dexamethasone to aid weaning from the ventilator also developed systemic infection at some point in their admission (6 in the study and 4 patients excluded a priori because of developing septicemia only when on steroid therapy). The 2 clinical states, chronic inflammatory lung disease requiring steroids and systemic infection, are strongly associated (P < .001). When all of the patients who received dexamethasone were excluded from analysis, the association between –174 GG genotype and the development of bacterially confirmed sepsis was maintained (septicemia and GG genotype, P = .017; OR: 2.8; 95% CI: 1.2–6.6, after multiple logistic regression analysis; Table 3).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This study suggests, for the first time, that IL-6 –174 GG genotype is associated with a >2-fold risk for the development of septicemia in the very preterm neonate. This effect remained statistically significant after adjustment for other significant predictive factors. These data suggest that IL-6 may be involved in protection from septicemia in the preterm infant. These findings may be relevant to other groups of patients who experience states of relative immunocompromise, such as the neutropenic, as basal IL-6 production enhances intracellular bacterial killing19 and may augment the rapid genesis of mature granulocytes.20 The association of genotype with sepsis per se is unlikely to be attributable to "survivor bias," given that allele frequencies were similar to those among healthy adults and term newborn infants.8,10,11,15 Additional support for this belief is provided by the fact that genotypes were in Hardy-Weinberg equilibrium.

We used a candidate gene-association approach to address a role for IL-6 expression in disease pathogenesis. An approach using assay of IL-6 levels was not taken for many reasons. First, an association of disease with levels cannot suggest causality. Second, IL-6 levels are highly volatile (even over minutes) and more so in the presence of inflammatory stimuli. Thus, "white noise" is a common feature of such cytokine studies, a problem only surmounted by very frequent sampling, with assessment of "area under curve" or total IL-6 burden. Such problems are additionally compounded by differences in temporal rise in IL-6 levels during sepsis; that IL-6 levels rise before the clinical picture of septicemia is apparent7 and that although the development of septicemia may be GG genotype dependent, the rise in IL-6 concentrations after an inflammatory stimulus is greater if CC genotype.11–14

It is interesting that Schluter et al21 failed to identify an association between IL-6 –174 genotype and the development of septicemia in adult surgical patients on intensive care units. However, the more complex environmental challenges faced by the adult—and the far greater range of underlying pathologies—leads to a whole spectrum of gene-environment interactions that differ both qualitatively and quantitatively. This effect will mask identification of an allele association with disease. In addition, diverse adult demographics, including age, will act as confounders, especially given that cytokine gene expression and its responsiveness vary with age.3–6,22

We could not demonstrate a significant co-dominant effect across genotypes with systemic infection, although a trend toward the development of systemic infection was noted across genotypes: of those patients who developed septicemia 18% [9] were CC genotype, 35% [18] were GC, and 47% [24] were GG (P = .063, {chi}2 for linear trend). It may be that this study was insufficiently powered to detect such co-dominance, and this issue should be addressed in future studies. Alternatively, the IL-6 response among those of CC and CG genotype may be similar, or a "threshold effect" of biological response to IL-6 may exist. Plasma IL-6 levels were not available in these children to explore these possibilities, and such measures could be included in future prospective studies notwithstanding the problems of obtaining meaningful data on plasma IL-6 levels in this setting (above).

This study was insufficiently powered to explore the relationship of genotype with type of pathogen cultured. However, the vast majority of pathogens were coagulase-negative staphylococci (Table 2), the most common nosocomial acquired pathogen on NICUs. Coagulase-negative staphylococcal infection, although often thought of as relatively benign, may result in the need for ventilation in up to 70% of cases24 and has been associated with the development of cerebral palsy after prolonged rupture of the fetal membranes.25 It is possible that IL-6 genotype, through predisposition to the development of systemic infection, may influence long-term neurodevelopmental progress after preterm birth.26 It is also possible that IL-6 genotype influenced some aspect of cardiorespiratory function, which then resulted in greater instrumentation and hence greater infection rates. However, it is likely that the C allele being associated with a greater rise in IL-6 levels as part of the acute inflammatory response11–14 would be associated with worse cardiorespiratory status in the early period after birth and thus that patients with a C allele would be more likely to have a greater usage of indwelling catheters. Presumably the strong association (P < .001) between chronic inflammatory lung disease requiring steroids and systemic infection is through a common susceptibility to each other: infection may increase the risk of prolonged ventilation or vice versa. Alternatively, there could be a common genetic susceptibility.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The IL6 –174 GG genotype is associated with the development of septicemia in extremely preterm infants, and we speculate that this is as a result of lower [GG] genotype encoded basal IL-6 production. These data support a role for IL-6 itself in mediating the host defense in the preterm neonate whether this finding is effected via the –174 G-C substitution or by haplotype variation linked to this polymorphism.27 These data hint at the potential for influencing outcome after therapeutic manipulation of IL-6 levels or activity. Future prospective studies should explore not only these possibilities but also the relationship among the development of septicemia, genotype, and IL-6 levels in preterm infants and how this relationship changes during infection. Future work should also explore the relationship between IL-6 genotype and the susceptibility to infection in other immunologically vulnerable patient groups. Until then, a causal association between levels of IL-6 expression and clinical outcome can only be inferred. This type of investigative strategy might also be extended to the study of the role of other cytokines in perinatal outcome, such as IL-1 and tumor necrosis factor-{alpha}.


   ACKNOWLEDGMENTS
 
This research was supported by awards from the Southmead Hospital Millennium Research Fund to Drs Harding, Millar, and Whitelaw; the British Heart Foundation (grants RG200015, SP98003, and FS01XXX) to Drs Humphries, Montgomery, and Dhamrait; and an Action Research project grant to Dr Marlow.

We thank Rosemary Greenwood, Statistician, Research and Development Unit, United Bristol Health Care Trust, for help and David Croke for methodologic advice.


   FOOTNOTES
 
Received for publication Aug 12, 2002; Accepted Jun 13, 2003.

Reprint requests to (D.H.) Department of Child Health, St Michael’s Hospital, Bristol, BS82JZ, United Kingdom. E-mail: david.harding{at}bristol.ac.uk


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics



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