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(Chest. 2005;128:1690-1698.)
© 2005 American College of Chest Physicians

Interleukin-10 Haplotype Associated With Increased Mortality in Critically Ill Patients With Sepsis From Pneumonia But Not in Patients With Extrapulmonary Sepsis*

Anan Wattanathum, MD; Sanjay Manocha, MD; Horacio Groshaus, MD; James A. Russell, MD and Keith R. Walley, MD

* From the Critical Care Research Laboratories, University of British Columbia, Vancouver, BC, Canada.

Correspondence to: Keith R. Walley, MD, Critical Care Research Laboratories, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6; e-mail: kwalley{at}mrl.ubc.ca


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To test the hypothesis that haplotypes of the interleukin (IL)-10 gene are associated with clinical outcomes, comparing critically ill patients with sepsis from pneumonia vs those with extrapulmonary sepsis.

Design: Genetic association study.

Setting: Medical/surgical ICUs in a tertiary-care, university-affiliated teaching hospital.

Patients: Of 550 white patients with sepsis, 158 had pneumonia as the principle cause of their sepsis and 392 had an extrapulmonary source of sepsis.

Measurements: Haplotypes of the IL-10 gene were defined by measurement of haplotype tag single-nucleotide polymorphisms (SNPs). Primary outcome was 28-day survival. Secondary outcomes were days alive and free of organ dysfunction.

Results: Three SNPs in the IL-10 gene (– 592 C/A, + 734 G/T, and + 3367 G/A) identified four major haplotypes: CGG, AGG, CTA, and CTG. Patients with pneumonia who carried one or two copies of the CGG haplotype had greater 28-day mortality (51.4%) than patients who did not carry this haplotype (29.1%, p = 0.007). Carriers of CGG had significantly more cardiovascular dysfunction (and use of vasopressors), renal dysfunction (and requirement of dialysis), hepatic dysfunction, and hematologic dysfunction (p < 0.05 in each case). In contrast, in patients with an extrapulmonary source of infection there was no significant association of the CGG haplotype (or any measured IL-10 genotype) with 28-day mortality or organ dysfunction.

Conclusions: The IL-10 haplotype – 592C/734G/3367G is associated with increased mortality and organ dysfunction in critically ill patients with pulmonary sepsis but not in similarly ill patients with extrapulmonary sepsis. Therefore, polymorphisms within the IL-10 gene may be predictors of outcome in patients with sepsis from pneumonia.

Key Words: haplotype • interleukin-10 • pneumonia • polymorphism • sepsis • 28-day mortality


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Interleukin (IL)-10 is an important antiinflammatory cytokine that plays a key role in sepsis and, particularly, in modulating the pulmonary inflammatory response. IL-10 is a potent endogenous antiinflammatory cytokine that decreases lung inflammation partly on the basis of tumor necrosis factor-{alpha} and IL-1ß inhibition.1 Alveolar macrophages, which play a prominent role in orchestrating the pulmonary inflammatory and immune responses,2 produce significant amounts of IL-10.34 In the setting of acute lung inflammation, IL-10 is a key regulator of the degree of inflammation. This has been demonstrated both by addition of exogenous IL-10 and by neutralization of endogenous IL-10 for a variety of pulmonary inflammatory stimuli.5678 These findings are supported by the clinical observation that decreased IL-10 concentration in BAL fluid (BALF) is associated with worse outcome in patients with the ARDS.9

The A allele of an IL-10 – 1082 A/G promoter region single-nucleotide polymorphism (SNP) is associated with decreased IL-10 production by peripheral blood mononuclear cells.101112 Thus, it was surprising that Reid and colleagues13 found no relationship between IL-10 genotype and mortality in 88 critically ill patients with multiple organ dysfunction syndrome. Similarly, Lowe et al14 found no association of IL-10 – 1082 A/G with outcome in sepsis in 67 critically ill patients. In contrast to these studies, the IL-10 – 1082 A allele was associated with an increased frequency of pneumonia in infants with respiratory syncytial virus infection.15 These and other apparently discordant results appear to contrast sepsis from pneumonia with extrapulmonary sepsis and have resulted in uncertainty regarding the role of IL-10 genotype in pneumonia and sepsis.1617 Discordant findings may also result from type 1 error due to relatively small sample sizes or possibly due to population admixture.18 A further potential confounder is that none of the currently reported SNPs are necessarily the causal or functional SNP. Rather, currently reported SNPs may be only in partial linkage disequilibrium with the causal SNP, possibly contributing to confusing or conflicting reports. Thus, a number of authors181920 have adopted a haplotype-based approach.

To address all of these issues, we first recruited a large consecutive cohort of critically ill patients with sepsis. Second, we limited the analysis to white subjects to minimize the confounding effects of population admixture. Third, we used a haplotype-based analytic approach. Then we tested the hypothesis that haplotypes of the IL-10 gene are associated with clinical outcomes in critically ill patients with pneumonia but not in those with extrapulmonary sepsis.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The Research Ethics Board of Providence Health Care and the University of British Columbia approved this study.

Patient Cohort
All patients admitted to the ICU of St. Paul’s Hospital between November 2000 and April 2003 were eligible for entry into this study. This ICU is a mixed medical/surgical ICU in a tertiary-care teaching hospital of the University of British Columbia. Patients were included in the study if they had sepsis as defined by having at least two of four criteria of the systemic inflammatory response syndrome and known or suspected infection.21 Systemic inflammatory response syndrome criteria are as follows: (1) fever (> 38°C) or hypothermia (< 36°C); (2) tachycardia (> 90 beats/min in the absence of ß-blockers); (3) tachypnea (> 20 breaths/min), PaCO2 < 32 mm Hg, or need for mechanical ventilation; and (4) leukocytosis (total leukocyte count > 12,000/µL) or leukopenia (< 4,000 /µL).21 Patients were included in this cohort on the calendar day on which the definition of sepsis was met. We only report the results for the white patients who were successfully genotyped in order to decrease the potential confounding influence of population admixture secondary to ethnic diversity, on associations between genotype and phenotype.18

Patients with sepsis were then classified into those with pneumonia and those with extrapulmonary sources as the primary infection. Pneumonia was defined as the presence of new or progressive pulmonary infiltrates on chest radiography and clinical signs of pneumonia, together with at least two of the following: (1) fever (> 38°C) or hypothermia (< 36°C), (2) leukocytosis (total leukocyte count > 12,000/µL) or leukopenia (< 4,000 /µL), and (3) purulent respiratory secretions.22

Clinical Phenotype
Our primary outcome variable was 28-day survival. Secondary outcome variables were days alive and free (see below) of cardiovascular, respiratory, renal, hepatic, hematologic, and neurologic organ system failure. Baseline demographics recorded included age, gender, medical or surgical diagnosis on ICU admission (according to APACHE [acute physiology and chronic health evaluation] III diagnostic codes),23 ICU admission APACHE II score, and presence of septic shock on ICU admission.

Organ Dysfunction
To measure organ dysfunction, raw clinical and laboratory variables were recorded using the worst or most abnormal value for each 24-h period, with the exception of Glasgow coma score, where the best possible score for each 24-h period was recorded. Missing data on the day of ICU admission was assigned a normal value and missing data after day 1 was substituted by carrying forward the value of the previous day. If any variable was never measured, it was assumed to be normal. Clinically significant organ dysfunction for each organ system was defined as present if there was evidence of at least moderate organ dysfunction using the Brussels criteria.24 To further evaluate cardiovascular, respiratory, and renal function, we also recorded during each 24-h period vasopressor use, mechanical ventilation, and renal support, respectively. Vasopressor use was defined as dopamine > 5 µg/kg/min or any dose of norepinephrine, epinephrine, phenylephrine, or vasopressin. Mechanical ventilation was defined as need for intubation and positive airway pressure (ie, T-piece and mask ventilation were not considered ventilation). Renal support was defined as hemodialysis, peritoneal dialysis, or any continuous renal support mode (eg, continuous venovenous hemodialysis).

To assess duration of organ dysfunction and to correct organ dysfunction scoring for deaths in the 28-day observation period, we calculated days alive and free of organ dysfunction as previously reported.25 Briefly, during each 24-h period for each variable, a score of 1 was assigned if the patient was alive and free of organ dysfunction (defined as normal or mild organ dysfunction). A score of 0 was assigned if the patient had organ dysfunction (moderate, severe, or extreme) or was not alive during that 24-h period. Thus, the lowest score possible for each variable was zero, and the highest score possible was 28. A low score was indicative of more organ dysfunction, as there would be fewer days alive and free of organ dysfunction.

Haplotypes and Selection of Haplotype Tag SNPs
The IL-10 gene is located on the long arm of human chromosome 1, between 1q31 and 1q32, and is highly polymorphic. In order to make a rational choice of haplotype tag SNPs (htSNPs) to genotype in our sepsis cohort, we first examined the diversity of IL-10 genotype as reported for white subjects by the Seattle SNPs Program for Genomic Applications (http://pga.mbt.washington.edu26) and by the University of Arizona Innate Immunity Program for Genomic Applications (http://innateimmunity.net). Using unphased white genotypic data from these sites, we inferred haplotypes using PHASE software2728 (available at: http://pga.mbt.washington.edu) [Fig 1 ] and ordered these haplotypes according to a phylogenetic tree using MEGA 2 software29 (Center for Evolutionary Functional Genomics, Biodesign Institute; Tempe, AZ; available at: http://www.megasoftware.net) [Fig 2 ]. This haplotype structure was inspected to choose htSNPs across the entire IL-10 gene (Fig 1).19 Three htSNPs (– 1082 A/G, – 592 C/A, and + 3367 G/A) were chosen, identifying four major haplotypes. IL-10 – 1082 A/G and – 592 C/A are previous reported promoter region SNPs.13141617 The previously reported – 819 SNP30 was not chosen since it is in complete linkage disequilibrium with the –592 SNP (disequilibrium coefficient, D’ = 1, r2 = 1, Fig 1).31 As a result of technical failure to design a primer and probe for the – 1082 A/G SNP, we chose + 734 G/T as an alternative SNP that is in complete linkage disequilibrium with – 1082 A/G (D’ = 1, r2 = 1, Fig 1).313233 Therefore, we genotyped – 592 C/A, + 734 G/T, and + 3367 G/A in our patient cohort.



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  		Figure 1.. Color haplotype diagram of the IL-10 gene derived from publicly available genotypes (http://pga.mbt.washington.edu and http://innateimmunity.net). Each column represents a polymorphic locus and is coded as blue (common allele of that SNP) or yellow (rare alleles of that SNP), as well as having the allele identities indicated within the squares. Each row represents one distinct haplotype inferred from genotype data. Three haplotype tag SNPs (highlighted in red), IL-10 – 592 C/A, IL-10 + 734 G/T, and IL-10 + 3367 G/A, distinguish between four major haplotype clades: CGG, AGG, CTA, and CTG. The top numbering system identifies the SNP relative positions based on published studies and also provided by CHIP Bioinformatics (http://snpper.chip.org).28 Inspection of this haplotype diagram shows that IL-10 – 1082 A/G is in complete linkage disequilibrium with + 734 G/T. RefSNP = reference SNP.

 


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  		Figure 2.. Haplotype (Hap) tree of IL-10 gene. Numbered branches represent distinct haplotypes. Haplotypes are clustered into clades CGG, AGG, CTA, and CTG by using SNP position – 592, + 734, and + 3367. Distances between branch ends represent evolutionary distances (see 5% scale bar) between haplotypes, based on the number of sequence differences.

 
Genotyping
DNA was extracted from peripheral blood samples using a QIAamp DNA Blood Maxi Kit (Qiagen; Mississauga, ON, Canada). SNP genotypes were determined using the 5' nuclease, or Taqman polymerase chain reaction method (Applied Biosystems; Foster City, CA).34

Statistical Analysis
A {chi}2 test was used to test for association between the observed haplotypes across the three SNPs (– 592 C/A, + 734 G/T, and + 3367 G/A) and the primary outcome, 28-day survival. This analysis identified the CGG haplotype as distinct from the others. Therefore, subsequent analysis grouped all other haplotypes and compared patients according to the number of copies of the CGG haplotype that they carried (zero, one, or two). Baseline descriptive characteristics were compared using {chi}2 tests for proportions and analysis of variance for continuous variables. The Cochrane-Armitage test was used to test for associations between the number of copies of the CGG haplotype and 28-day survival. For secondary outcomes, the {chi}2/Fisher Exact Test was used for categorical variables, and the Mann-Whitney U test was used for continuous variables. Finally, a multiple logistic regression model using the baseline characteristics gender, age, medical vs surgical diagnosis, ICU admission APACHE II score, and presence of septic shock on ICU admission was used to test whether the CGG haplotype was an independent predictor of mortality. A two-tailed p value of < 0.05 was chosen as statistically significant. The data were analyzed using statistical software (SPSS 11.5 for Windows; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 737 consecutively enrolled ICU patients with sepsis, 563 were white and, of these, 550 were successfully genotyped and included in this analysis. Of these, 158 patients had pneumonia as the principle cause of their sepsis and 392 patients had an extrapulmonary source of sepsis. At baseline, patients with sepsis from pneumonia or extrapulmonary sepsis had comparable age, severity of illness as measured by APACHE II, and prevalence of septic shock (Table 1 ). However, patients with sepsis from pneumonia were more frequently male and had a primary medical admitting diagnosis (most often pneumonia) than those with extrapulmonary sepsis (Table 1).


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  		Table 1.. Baseline Characteristics of Critically Ill Patients With Sepsis From Pneumonia or Extrapulmonary Sepsis*

 
Three SNPs in the IL-10 gene (– 592 C/A, + 734 G/T, and + 3367 G/A) identified four major haplotypes: CGG (– 592C/+ 734G/+ 3367G), AGG, CTA, and CTG. The frequencies of the haplotypes CGG, AGG, CTA, and CTG were 27.8%, 27.3%, 13.1%, and 31.8%, respectively, in the total cohort of 550 patients, and were not different in patients with pneumonia or in patients with extrapulmonary sepsis (Table 2 ).


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  		Table 2.. Genotype, Allele, and Haplotype Frequencies in Critically Ill Patients With Sepsis From Pneumonia or Extrapulmonary Sepsis

 
Sepsis From Pneumonia
The CGG haplotype was associated with significantly greater 28-day mortality in patients with pneumonia ({chi}2 = 11.12, p = 0.011, Fig 3 ). Therefore, subsequent analysis grouped all other haplotypes and compared patients according to the number of copies of the CGG haplotype that they carried (zero, one, or two). Patients carrying one or two copies of the CGG haplotype had significantly higher 28-day mortality than patients who did not carry the CGG haplotype (51.4% vs 29.1%, p = 0.007). Kaplan-Meier analysis of survival in patients with or without carrying the CGG haplotype confirmed that the carriers were significantly associated with lower survival (p = 0.005; Fig 4 ). After adjusting for other predictors of survival (age, gender, medical vs surgical diagnosis, APACHE II score on ICU admission, and septic shock on ICU admission) [Table 3 ] using a Cox proportional hazards model, the hazard of death associated with carrying the CGG haplotype was 2.0 (95% confidence interval for hazard ratio, 1.22 to 3.41, p = 0.006) [Table 4 ].



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  		Figure 3.. Twenty-eight–day mortality by haplotype of the IL-10 gene in critically ill patients having sepsis. *p = 0.011 for pulmonary sepsis, and p = 0.51 for extrapulmonary sepsis ({chi}2 test).

 


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  		Figure 4.. Kaplan-Meier analysis by IL-10 haplotype, showing that patients who carried at least one copy of the CGG haplotype had a lower survival rate (p = 0.005) than patients who did not carry the CGG haplotype for the entire 28-day observation period.

 

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  		Table 3.. Baseline Demographics by Haplotype of the IL-10 Gene in Critically Ill Patients With Sepsis From Pneumonia or Extrapulmonary Sepsis

 

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  		Table 4.. Hazard Ratios of Death and 95% Confidence Intervals From Cox Regression Analysis in Patients With Pneumonia

 
Patients carrying either one or two copies of the CGG haplotype had more cardiovascular dysfunction (p = 0.022) [and use of vasopressors, p < 0.05], more renal dysfunction (p = 0.024) [and use ofrenal support, p < 0.05], more hepatic dysfunction (p = 0.016), and more hematologic dysfunction (p = 0.009) [Table 5 ].


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  		Table 5.. Days Alive and Free of Organ Failure (of a Maximum of 28 Days) in Patients With Pneumonia Who Carried the CGG Haplotype*

 
Extrapulmonary Sepsis
There was no difference in 28-day mortality rate between haplotypes CGG, AGG, CTA, and CTG (p = 0.51, Fig 3) in patients with extrapulmonary sepsis. Similarly, there were also no significant associations between haplotype and days alive and free of cardiovascular, respiratory, renal, neurologic, hepatic, or hematologic dysfunction in patients with extrapulmonary sepsis.

SNP-Based Analysis
We tested for association between phenotype and each of the three SNPs: – 592 C/A, + 734 G/T, and + 3367 G/A of the IL-10 gene. The genotype and allele frequencies are shown in Table 2 and were not significantly different between pneumonia and extrapulmonary sepsis patients. There were no significant differences between the individual genotype of each SNP and baseline characteristics of age, gender, medical vs surgical diagnosis, APACHE II score on ICU admission, and septic shock on ICU admission in both populations.

We did not find any association between genotype of any individual polymorphism and 28-day mortality in patients with either pneumonia or extrapulmonary sepsis. Similarly, we did not find any association between individual genotype of each SNP and days alive and free of any organ dysfunction.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our key finding is that the IL-10 gene CGG haplotype (– 592C/+ 734G/+ 3367G) was significantly associated with increased 28-day mortality in critically ill patients who had sepsis from pneumonia. In support of this result, patients who carried the CGG haplotype had more organ dysfunction for the cardiovascular, renal, hepatic, and coagulation organ systems. In contrast, there was no relationship between the four major haplotypes of the IL-10 gene and outcome in critically ill patients with extrapulmonary sepsis.

Our finding of the relationship between the CGG haplotype and outcome in pneumonia patients is consistent with previous work.15 Inspection of Figure 1 reveals that our + 734 G allele is essentially equivalent to the – 1082 A allele. The + 734 G allele (and by inference, the – 1082 A allele) is contained within the CGG haplotype that we found to be associated with adverse outcome in pneumonia patients. Gentile et al15 reported that the IL-10 – 1082 A allele was associated with an increased frequency of pneumonia in infants with respiratory syncytial virus infection. Similarly, IL-10 – 1082 AA genotype was associated with severity of meningococcal disease and higher mortality in patients with acute renal failure.3536 In addition, Helminen et al found that susceptibility to Epstein-Bar virus infection (EBV) is associated with not only IL-10 –1082 A allele37 but also with the – 1082A/– 819C/– 592C haplotype.30 This haplotype is, again, equivalent to the – 592C/+ 734G/+ 3367G haplotype in our study (Fig 1). Consistent with these studies, our results implicate a role for the CGG haplotype in adverse outcome in sepsis from pneumonia, but not in extrapulmonary sepsis.

We did not find an association between haplotype and clinical phenotypes in the critically ill patients with extrapulmonary sepsis. Our results in this cohort of patients are also consistent with previous reports.13 Reid and colleagues13 found no relationship between IL-10 genotypes and mortality in critically ill patients with multiple organ dysfunction syndrome compared with the control group. Lowe and coworkers14 also found no difference in outcome in patients with sepsis by – 1082 genotype.

Why would there be a difference between pneumonia and extrapulmonary sepsis? One possible explanation is that IL-10 production and concentration is particularly compartmentalized in the lung. IL-10 is produced primarily by pulmonary alveolar macrophages. Donnelly and colleagues9 examined blood and BALF cytokine concentrations from patients with early onset ARDS. The IL-10 concentration in BALF was higher than in the blood. In addition, decreased BALF concentrations of IL-10 were associated with decreased survival in ARDS patients.9 These investigators suggest that IL-10 has its principal activity at the local pulmonary site of production rather than in the systemic circulation.9 In a murine pneumonia model, van der Poll and colleagues38 demonstrated increased IL-10 production in normal mice, and this response was largely compartmentalized in the lung. Interestingly, IL-10 therapy increased survival in both a rabbit Pseudomonas aeruginosa pneumonia model and also in a murine pneumococcal pneumonia model,39 while the results of exogenous administration of IL-10 in extrapulmonary experimental sepsis have been inconclusive.40 Taken together, these results indicate that IL-10 is a key regulator of degree of inflammation in the setting of acute lung infection or inflammation, but this response is highly compartmentalized. These observations may account for the differential association of IL-10 haplotype with outcome of pneumonia vs extrapulmonary sepsis.

The genetic control of IL-10 production has been extensively investigated in an effort to explain the association between genotype and production of the cytokine. The results, however, are not fully uniform. The majority of the published studies indicate that the A allele of the – 1082 A/G SNP (a component of our CGG and AGG haplotype) is associated with decreased production of IL-10 by peripheral blood mononuclear cells. Additionally, stimulated mononuclear cells from individuals homozygous for the – 1082A/– 819C/– 592C haplotype (which corresponds with our CGG haplotype) have a lower transcriptional activity, as measured by IL-10 messenger RNA level, than those with the – 1082A/– 819T/– 592A haplotype (which corresponds with the AGG haplotype of this study).41 Also consistent are the findings that the G allele, the GG genotype, and the – 1082G/– 819C/– 592C haplotype are associated with increased production of IL-10,101112 although not all reports are concordant.131442 Taken together, these data suggest that it is reasonable to postulate that the CGG haplotype in this study is associated with lower IL-10 production in sepsis from pneumonia and therefore contributes to the higher mortality and organ dysfunction, as supported by previous studies.4344

In some instances, differences between studies are accounted for by type 1 error: finding a statistically significant association when it does not actually exist. Important causes of type 1 error are small sample size and population admixture. Small sample sizes, undefined ethnicity,14 and population admixture13 are a major limitation of published IL-10 gene association studies in pneumonia and sepsis. Large patient populations, analysis limited to a particular ethnic group, and verification of no deviation from Hardy-Weinberg equilibrium (to rule out high degrees of population stratification) are important approaches for addressing the potential of type 1 error of association studies. In the pneumonia group, where we found an association between haplotype and outcome, each polymorphism that we measured was in Hardy-Weinberg equilibrium ({chi}2 = 0.36, p = 0.55 for the position – 592; {chi}2 = 1.53, p = 0.22 for the position + 734; and {chi}2 = 2.32, p = 0.13 for the position + 3367).

SNP analysis may also lead to confusing or conflicting reports that a haplotype-based analysis may clarify. Many investigators18192045 have suggested that haplotypes defined by common SNPs have important implications for mapping of disease genes based on association between causal mutations and the ancestral haplotypes on which they arose. Moreover, identifying haplotypes associated with adverse outcomes narrows the search for the causal polymorphism and may lead to a better strategy of predicting those patients who are at greatest risk of adverse outcome.

It is conceivable that IL-10 genotyping may prove to be clinically useful and cost-effective. That is, identifying patients having pneumonia who are at a high risk of organ dysfunction and mortality may influence management decisions where controversy currently exists, such as in deciding on admission to critical care units, use of steroids,46 or use of other therapeutic strategies such as activated protein C. For example, whether steroids should be used to treat patients with pneumonia and sepsis remains an unresolved issue. It is possible that some patients will benefit while others will not, depending on their individual genotypes. This and related hypotheses would need to be tested in future clinical trials. If proven, then genotyping would become an important addition to our current clinical practice. Since this type of genotyping can be done quickly and inexpensively, a cost-benefit analysis may support genotyping, as it has in other clinical circumstances.47 Therefore, genotyping this IL-10 haplotype in patients with sepsis from pneumonia may allow better risk stratification and tailoring specific therapies to a high-risk group.

Several limitations of this study should be considered. First, we did not measure IL-10 levels. Thus, the mechanism linking the IL-10 CGG haplotype with increased mortality cannot be determined. Second, we have not identified a specific causal SNP but, rather, a haplotype that contains the causal genetic variants. It is possible that this haplotype is linked (ie, in linkage disequilibrium) with other polymorphisms outside the IL-10 gene that play a causative role. We addressed possible type 1 error by limiting our analysis to a single ethnic group and by recruiting a large sample size. In addition, we minimized the potential impact of selection bias by enrolling consecutive patients into the study.

In conclusion, we have identified a major haplotype of the IL-10 gene that is differentially associated with outcome in pulmonary and extrapulmonary sepsis. We found no relationship between IL-10 haplotypes and outcome in critically ill patients who had extrapulmonary sepsis, similar to previous reports1314 in septic patients. In contrast, the IL-10 – 592C/734G/3367G haplotype was associated with increased mortality and organ dysfunction in critically ill patients with pneumonia, again consistent with a previous report.15 Our large cohort size and analysis limited to a single ethnicity suggests that this result is due to a true biological difference in the role of IL-10 in pulmonary vs extrapulmonary sepsis, and may account for some of the apparently inconsistent literature.


   Footnotes
 
Abbreviations: APACHE = acute physiology and chronic health evaluation; BALF = BAL fluid; htSNP = haplotype tag single-nucleotide polymorphism; IL = interleukin; SNP = single-nucleotide polymorphism

Keith R. Walley is a Michael Smith Foundation for Health Research Distinguished Scholar.

Supported by Canadian Institutes of Health Research.

Received for publication November 29, 2004. Accepted for publication March 11, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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