Introduction
Materials and methods
Search strategy and selection criteria
Data extraction
Quality assessment
Data synthesis
Results
Prucha[14] | Ramilo[17] | Tang-2[18] | Talwar[8] | Payen[19] | Pachot[22] | Prabhakar[9] | Calvano[10] | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Aims
| Diagnostic prediction | Diagnostic prediction | Diagnostic prediction | Diagnostic prediction | Functional analysis | Prognostic study | Prognostic study | Prognostic study | Functional analysis | Functional analysis | Combined analysis¥ | Functional analysis |
Study design
| Cross-sectional | Cross-sectional | Cross-sectional | Cross-sectional | Longitudinal | Longitudinal | Longitudinal | Cross-sectional | Longitudinal | Longitudinal | Longitudinal | Longitudinal |
Country
| Czech Rep.. | Australia | U.S.A. | Australia | U.S.A. | France | U.S.A. | France | U.S.A. | U.S.A. | U.S.A. | U.S.A. |
Total (n)
| 12 | 94 | 148 | 70 | 12 | 17 | 176 | 38 | 12 | 14 | 101 | 90 |
Mean Age (yr)
| 58.9 | 63.5 | 3.4 | 65.5 | 30 | 59 | 35.7 | 67 | (18 to 40)† | (18 to 40)† | 3.2 | 44 |
Clinical setting
| Adult ICU | Adult ICU | Pediatric wards | Adult ICU | University clinic | Adult ICU | Adult ICU | Adult ICU | University clinic | University clinic | Pediatric ICU | Trauma ICU |
Inclusion criteria
| Severe sepsis | Sepsis | Acute infection | Sepsis | Healthy volunteers | Septic shock | Post-trauma | Septic shock | Healthy volunteers | Healthy volunteers | Sepsis | SIRS |
Control group
| Surgical patients | SIRS patients | Healthy subjects | SIRS patients | Healthy subjects | Subjects at time zero | Non-septic patients | NA | Subjects at time zero | Healthy subjects | Non-septic patients | SIRS patients |
Prucha[14] | Ramilo[17] | Tang-2[18] | Talwar[8] | Payen[19] | Pachot[22] | Prabhakar[9] | Calvano[10] | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Experiment details
| ||||||||||||
Tissue used
| Whole blood | Neutrophils | PBMC | PBMC | PBMC | PBMC | PBMC | Whole blood | PBMC | Whole blood | Whole blood | Whole blood |
RNA extraction
| PAXGene | Ambion | Qiagen | Ambion | Qiagen | Qiagen | Qiagen | PAXGene | Qiagen | Qiagen | PAXGene | PAXGene |
Microarray platform
| Lab-Arraytor | In-house | Affymetrix | Affymetrix | Affymetrix | Lab-Arraytor | Affymetrix | Affymetrix | In-house | Affymetrix | Affymetrix | Affymetrix |
No. of genes or probe sets
| 340 | 18,664 | 14,500 | 54,675 | 12,623 | 340 | 54,613 | 14,500 | 18,432 | 33,000 | 54,675 | 54,675 |
Signature genes
| ||||||||||||
Sepsis vs. control
| 50 | 50 | 137 | 138 | 867 | 1,837 | 54 | 3,714 | 1,906 | 459 | ||
Survival vs. death
| 10 | 28 |
Prucha[14] | Ramilo[17] | Tang-2[18] | Talwar[8] | Payen[19] | Pachot[22] | Prabhakar[9] | Calvano[10] | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Data acquisition
| ||||||||||||
Tissue homogeneity of target samples | Low | High | High | High | High | High | High | Low | High | Low | Low | High |
Experiments follow miame criteria¶ | Yes | Yes | Yes | Yes | Not clear | Yes | Not clear | Not clear | Not clear | Not clear | Yes | Not clear |
Reporting of normalization method | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes |
Analytical issues
| ||||||||||||
Method for gene selection | t test | t test | Non-parametric test | t test | ANOVA | t test | Multiple | Not clear | Not clear | SAM | ANOVA and fold change | Non-parametric test |
Issue of variance estimation addressed | No | Yes | No | Yes | No | No | Not clear | Not clear | Not clear | Yes | No | No |
Comparison to other diagnostic markers | No | No | No | No | No | NA | Yes | Yes | No | No | No | Yes |
Correction for multiple testing | Yes | Yes | Yes | Yes | Yes | NA | Yes | Yes | No | Yes | Yes | Yes |
Reporting of classifier performance | No | Yes | No | Yes | NA | NA | No | Yes | NA | NA | Yes | NA |
Reporting of prediction accuracy | No | Yes | Yes | Yes | NA | NA | Yes | Yes | NA | NA | Yes | NA |
Validation of data
| ||||||||||||
Cross validation of signature genes | No | Yes | Yes | Yes | No | No | Yes | Yes | NA | No | Yes | Yes |
External validation in independent samples | No | Yes | Yes | Yes | No | No | Yes | Yes | NA | Yes | Yes | No |
Ratio of test/training sample size | NA | 1.14 | 2.00 | 1.00 | NA | NA | 0.50 | 0.23 | NA | 0.75 | 0.77 | NA |
Adjustment for confounders | No | Yes | Yes | No | NA | NA | No | No | No | NA | Yes | Yes |
Raw data made publicly available | No | Yes | Yes | Yes | Yes | Yes | No | No | No | No | Yes | No |
PCR validation | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | No | Yes |
Pathogen recognition
Pathogen recognition | Signal transduction | |
---|---|---|
Increase expression in toll-like receptor (TLR) pathway genes. | Increased expression in pathways genes associated with NF-k B, STAT, JAK and MAPKs. | |
Talwar[8] | Increase expression in TLR pathway genes. | Increased expression in genes associated with STAT, JAK and MAPKs pathways. |
Calvano[10] | Increase expression in TLR pathway genes and CD14 genes. | Increased expression in genes associated with STAT, NF-k B, CREB, JAK and MAPKs pathways. |
Prabhakar[9] | Increase expression in genes encoding for CD14 molecules. | Increased expression in genes associated with JAK pathway. |
Prucha[14] | Increased expression in genes associated with MAPKs pathway. | |
Reduced expression in pathways genes associated with NF-k B and MAPKs pathways. | ||
Tang-2[18] | Increase expression in TLR pathways genes. | Increased expression in genes associated with JAK, STAT and MAPKs pathways. |
Increased expression in genes associated with MAPKs pathway. | ||
Increase expression in TLR pathways genes. | Increased expression in genes associated with NF-k B STAT and MAPKs pathways. | |
Payen[19] | Increase expression in TLR pathways genes in survivors. | Greater expression of genes associated with MAPKs pathway in non-survivors. |
Pachot[22] | Increase expression in TLR pathways genes in survivors. | Greater expression of genes associated with MAPKs pathway in non-survivors. |
Inflammatory response
Timing | Gene-expression | Overall effect | Changes in inflammatory and immune genes | |
---|---|---|---|---|
Pre-sepsis (12 to 36 hrs prior to the diagnosis) | ↑394 genes and ↓65 genes | Activation of host response to infection. | Increased expression of genes associated with pro-inflammatory cytokines (IL-1, IL-18), immune cell receptor signalling (IFNR, IL-10RA, TNFSF) and T cell differentiation (IFNGR, IL-18R, IL-4R). | |
Activation of counter-regulatory mechanism that limits the pro-inflammatory response. | Increased expression of genes that limit pro-inflammatory cytokines (SOCS3). | |||
Talwar[8] | Early Sepsis (0 to 24 hrs) | ↑439 genes and ↓428 genes | Activation of host response to infection. | Increased expression of genes associated with cytokines (IL-1R, CCR1, CCR2, IL-17) and S100 calgranulins (S100A12, S100A11, S100A9, S100A8). Increased expression of genes associated with arachidonate metabolites (ALOX5) and anti-pathogen oxidases (CYBA, SOD) |
Activation of counter-regulatory mechanism that limits the pro-inflammatory response. | Increased expression of anti-inflammatory cytokines (IL-1RA, IL-10R) and reduced expression of pro-inflammatory genes (TNFSFR). | |||
Repression of immune cells and host defence, including antigen presentation by phagocytes. | Reduced expression of genes associated with T cells, cytotoxic lymphocytes and natural killer cells (T cell receptor, CD86, IL-2 receptor, TNFRSF7, CD160, cathepsin, CCR7, CXCR3, CD80). Reduced expression in MHC class II genes. | |||
Calvano[10] | Early Sepsis (0 to 24 hrs) | ↓ more than 1,857 (>50%)¶ | Activation of host response to infection. | Increased expression of genes associated with pro-inflammatory cytokines (TNF, IL-1, IL-1A, IL-1B, IL-8, CXCL1, CXCL10). |
Increased expression of genes associated with superoxide-producing activities and cell-cell signalling. | ||||
Activation of counter-regulatory mechanism that limits the pro-inflammatory response. | Increased expression of genes that limit the inflammatory response (SOSC3, IL1-RAP, IL1-R2, IL10 and TNFRSF1A). | |||
Repression of immune cells and host defence, including antigen presentation by phagocytes. | Reduced expression of genes associated with immune response in lymphocytes (TNFRSF7, CD86, CD28, IL-7R, lL-2RB).Reduced expression in MHC class II genes. | |||
Prabhakar[9] | Early Sepsis (0 to 24 hrs) | ↑31 genes and ↓23 genes | Activation of host response to infection. | Increased expression of pro-inflammatory genes (IL-1B, TRAIL) and S100 calgranulins. Increased expression of genes associated arachidonate metabolites (ALOX5, SOD). |
Activation of counter-regulatory mechanism that limits the pro-inflammatory response. | Increased expression of genes associated with cytokine suppression (SOCS1, SOCS3). | |||
Reduced antigen presentation by phagocytes. | Reduced expression in MHC class II genes. | |||
Prucha[14] | Late-sepsis (1 to 5 days) | ↑19 genes and ↓31 genes | Diminished pro-inflammatory response. | Increase expression of pro-inflammatory genes (IL-18, S100A8, S100A12), but reduced expression in others (TNF, IL8RA, CASP5, IL-6ST). |
Enhanced anti-inflammatory response. | Increased expression of anti-inflammatory genes (TGFβ1). | |||
Reduced lymphocyte function and antigen presentation by phagocytes. | Reduced expression of genes associated with lymphocyte function (IL-16, CD69, CD8, CD36, CX3CR1). Reduced expression in MHC class II genes. | |||
Late-sepsis (1 to 5 days) | ↑35 genes and ↓15 genes | Diminished pro-inflammatory response. | Reduced expression of pro-inflammatory genes (TNF, IL8RA, CASP5) | |
Reduced immune cell function. | Reduced expression of genes that modulate immune cell activation (IL-16, CD69, CD8, CD36). | |||
Tang-2[18] | Late-sepsis (1 to 5 days) | ↑105 genes and ↓33 genes | Diminished pro-inflammatory response. | Reduced expression of pro-inflammatory genes (TNFSF8), S100 calgranulins S100A8) and IL-4 pathway. |
Increased anti-inflammatory response. | Increased expression of anti-inflammatory genes (IL-10RB, TGFβ1). | |||
Reduced antigen presentation by phagocytes. | Reduced expression in MHC class II genes. | |||
Late-sepsis (1 to 5 days) | ↑862 gene and ↓1,283 genes (Day 1) | Activation of both pro-inflammatory and anti-inflammatory response. | Increased expression of both pro-inflammatory (IL-1 and IL-6) and anti-inflammatory (IL-10, TGFβ1) genes. Increased expression of genes associated with receptor signalling and granulocyte colony stimulating factor. | |
↑1,072 gene and ↓1,432 genes (Day 3) | Repression of immune cells and host defence, including antigen presentation by phagocytes. | Reduced expression of genes associated with antigen presentation, immune cell activation, IL-8 and IL-4 pathways. | ||
Reduced expression in MHC class II genes. | ||||
Late sepsis (1 to 5 days) | 1,837 genes | Unclear as only a small subset of genes are available for analysis. | Increased expression of pro-inflammatory genes (IL-1beta, NAIP, CEACAM8, and the alpha-defensins). | |
Payen[19] | Recovery (>5 days) | ↑1 gene and ↓3 genes (survivors). | Ongoing immuno-suppression throughout the 28-day study period. | In survivors, there was a progressive reduction in the expression of genes associated with S100 calgranulins (S100A8 and S100A12) and T cell activation (IL-3RA). |
↑29 gene and ↓7 genes (non-survivors). | Greater extent of immuno-suppression in non-survivors. | In non-survivors, there was an even greater reduction in the expression of genes associated with immune cell activation (CXCL14, CD180, CD244, CCR6 and CD84). In the same patients, there was also an increase expression of apoptosis genes (PPARG, DAP3 and HBXIP) and anti-inflammatory genes (PAFAH1B1 and IL-4R). | ||
Survival is accompanied with recovery of some immune functions. | Recovery of MHC class II gene (CD74) in survivors occurs on day 28. | |||
Pachot[22] | Recovery (>5 days) | ↑18 genes (survivors) and ↑10 genes (non-survivors) | Survival in sepsis is associated with restoration of immune function. | In survivors, there was an increased expression of genes in modulating T cell activation and receptor signalling (ILRB2, CXC31, TRDD3, TIAM1, FYN). |
Experimental sepsis
Discussion
Conclusions
Key messages
-
Sepsis-related inflammatory changes are highly variable on a transcriptional level.
-
These changes are not consistent with the established model of sepsis, where a biphasic pro-inflammatory and anti-inflammatory process is thought to underpin the host response.