Genetic influence on bloodstream infections and sepsis

International Journal of Antimicrobial Agents 32S (2008) S44–S50

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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Genetic influence on bloodstream infections and sepsis Oliver Kumpf a , Ralf R. Schumann b,∗ a b

Robert-Rössle-Klinik, Department for Surgery and Surgical Oncology, Charité University Medical Center, Berlin, Germany Institute for Microbiology and Hygiene, Charité University Medical Center, Dorotheenstr. 96, 10117 Berlin, Germany

a r t i c l e

i n f o

Keywords: Bloodstream infection Sepsis Genetic predisposition Single nucleotide polymorphism SNP Toll-like receptors TLRs Cytokines

a b s t r a c t Bloodstream infections (BSIs) are a major burden in health care today, associated with considerable morbidity, mortality and costs. They are either caused by direct influx of pathogens via devices into the blood (primary BSI) or by bacterial spillover from infected distant organs (secondary BSI). The recognition of invading microbes by sensing of conserved molecular patterns is pivotal for the host in staging an adequate immune response to eradicate the pathogen. Moreover, a balanced immune response is crucial to avoid over inflammation followed by additional damage to the host. This complex host response pattern is controlled by soluble proteins and cellular receptors, which have recently been found to contain substantial individual genetic variations. Single nucleotide polymorphisms have been shown to affect susceptibility to and the course of numerous diseases. A large number of genes and their products are involved in the host reaction to BSIs, and genetic variation in these molecules alters the frequency and course of these events. Here we summarise recent findings on genetic variations in molecules of the innate immune system and other systems as well as their connection with susceptibility to BSIs and sepsis and the way the host stages a beneficial response to infection. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Individual genetic variation and infection Recent studies, particularly after elucidation of the human genome, have revealed that genetic variations of the individual have a major role in susceptibility to diseases, including those that are generally not viewed as inherited diseases. Many inherited diseases, such as cystic fibrosis or blood clotting disorders, are termed monogenetic diseases because one genetic variation causes a protein change that results in a lack of function and therefore creates a disorder state. In addition to these relatively rare diseases, however, a number of more frequent diseases, termed ‘polygenetic’, might be caused by a combination of factors, including genetic variations, that increase the risk for the disease. Evidence has accumulated over the last years that these polygenetic diseases include the most frequent causes of death in the Western world, such as cardiovascular diseases, malignant diseases, and acute and chronic inflammatory diseases [1]. Although environmental factors and nutrition as well as the presence of microorganisms have clear roles in the pathogenesis of these diseases, large individual differences in the course of disease and susceptibility exist, which are a result of genetic variations of the host [2]. Following elucidation of the human genome in 2003, a large number of individual genetic mutations have been described. These

∗ Corresponding author. Tel.: +49 30 4505 24141; fax: +49 30 4505 24941. E-mail address: [email protected] (R.R. Schumann).

mutations may be due to polymorphisms leading to an exchange of single nucleic acids within the genetic code. Many different single mutations may occur and most of them are rare and differ completely from individual to individual. Similar mutations that occur in >1% of a normal population are termed single nucleotide polymorphisms (SNPs). SNPs can be located in either a coding or non-coding region of a gene; SNPs located in a coding region can be silent (not affecting the code for an amino acid) or may cause a non-synonymous change of amino acids potentially leading to an altered protein conformation. Some non-synonymous changes may also lead to a loss or change of function of the protein that the gene codes for (known as a functional SNP), which may have implications for disease susceptibility. Whilst the majority of the genome of a given species is identical between its members, individual variations in the sequence of ca. 0.01% of the genome exist. The human genome of every individual contains approximately ten million SNPs [3], which relates to, on average, 300 SNPs per gene [4]. Most of these SNPs have already been reported in public databases, although only a small number have been functionally analysed [5]. Genetic analysis is used to map genetic disease loci to positions within the human genome in order to then decipher the functional relevance of the gene loci and to find out about disease aetiology. Gene association studies measure the deviation of genetic variations from the random occurrence of SNPs in unrelated individuals (also known as linkage disequilibrium mapping) in order to identify genes potentially involved in disease pathology [6]. It is generally thought that mutations do not occur randomly

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within the genome but rather depend on the particular genomic region as well as on selective pressure [7]. Because of this selective pressure, the genes that encode proteins involved in immunity or disease resistance might have a higher number of functionally relevant polymorphisms in groups of patients carrying the respective diseases. 2. Bloodstream infections (BSIs) and host factors: general overview BSIs are present when viable bacteria are diagnosed inside the vasculature and if they are proven by microbiological means. Pathogenicity and virulence are factors associated with the pathogen itself and are important in terms of the probability and severity of an infection [8]. Of course, prevention of bacteraemia by hygiene measures and early changing of indwelling catheters remains key to limiting BSIs and their consequences [9]. Moreover, early detection, identification and susceptibility testing of the microorganism followed by adequate antibiotic chemotherapy is crucial for limiting the consequences of a BSI [10]. However, numerous host factors have been identified that lead to a variation in both susceptibility to and the course of BSI. The risk for BSI is of course increased during inherited and acquired immunodeficiencies caused by either underlying infections (i.e. human immunodeficiency virus (HIV)) or immunosuppressive therapy during cancer treatment or transplantation. The continuous presence of indwelling devices such as venous catheters for different therapeutic purposes adds to these factors and leads to primary BSIs. Bacterial spillover from infection of a local site or an organ system into the bloodstream is less frequent and leads to so-called secondary BSIs (Fig. 1) [11]. Independent of the cause, this systemic occurrence of pathogens frequently leads to generalised inflammation, sepsis and septic shock and thus increases the risk for end organ damage [12]. Furthermore, septic embolism may occur and lead to severe complications, including septic thrombophlebitis, endocarditis and other ‘metastatic’ infections such as abscesses, osteomyelitis or endophthalmitis. Both containment of a local infection and the systemic reaction pattern of the host are governed by complex defence systems involving a large number of cell types, receptors and soluble proteins. Besides the coagulation and complement systems, the innate immune system is the central network for initiating the host response. BSIs, like other systemic disturbances of the homeostasis of the organism furthermore induce a constitutive reaction termed the acute phase reaction, which is defined by the release of a number of acute phase proteins mainly from the liver [13]. Mechanisms involved in the reaction to pathogens, which is crucial for the host to mount the appropriate response to eradicate them, include sensing via the Toll-like receptors (TLRs) and others, the release of cytokines, and activation of immune cells and the coagulation system, to name only a few [14]. Recent risk association studies were able to show that inherited factors in all these systems play at least in part a role in the response to infections, including BSIs. The system to classify the risk for septic complication has recently been modified in that the genetic predisposition of the individual has been included (the PIRO system; Table 1) [15]. 3. Host control of primary and secondary bloodstream infections Systemic influx of bacteria or yeast through the lumen of a catheter (primary BSI) is potentially most dangerous as several levels of the normal defence system, such as the skin barrier and the innate immune system of the subcutaneous tissue, are bypassed by

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insertion of the catheter. Here the systemic reaction of the host to a given mass of bacteria or bacterial patterns, with cytokine release by blood leukocytes and responsive cells of the peripheral organs, will lead to systemic inflammation and shock. Individual variations in this reaction pattern owing to genetic differences of the individual might either be beneficial or detrimental. This reaction complex includes receptors, signalling cascades and cytokine networks, which can all be influenced by genetic variation. Furthermore, the regulation of large systemic response networks, including the acute phase response, the stress-hormone axis, the neuroendocrine reaction and long-term dampening of the immune reaction, are potentially related to inherited genetic variations. Primary BSI caused by contamination of catheters or by skin bacteria entering the bloodstream along the catheter are also characterised by an artificial situation. The defence of the skin is circumvented by the puncture and many bacteria have an advantage in growing along the plastic material. Still, the local defence mechanism of the subcutaneous tissue may be active here in limiting the spread of bacteria into the bloodstream. Thus, genetic variations within the host genes involved in local defence, as mentioned for secondary BSI, may be involved here too. A genetic predisposition that influences susceptibility to and the course of secondary BSI and sepsis involves the defence of pathogens on the skin surface and in the subcutaneous tissue. In these circumstances, recognition of microbes through pathogen recognition receptors as well as local inflammatory mechanisms to attract migrating and locally present immune cells to contain these microbes are as important as parts of the coagulation system. The primary goal of these reaction patterns is to limit local infection and avoid systemic spread. Encapsulation, abscess formation and local activation of the blood clotting cascade are important events in order to contain a given infection. Individual genetic variations in these systems may thus influence the incidence of secondary BSI. Similar to primary BSI, secondary BSI will also cause a systemic reaction through pathogens that eventually succeeded in entering the bloodstream. Finally, chronic infections may lead to a weakening of the immune system, i.e. due to the release of antiinflammatory factors [16]. Thus, genetic influences on these factors are also involved in the influx of pathogens into the bloodstream causing secondary infections. 4. Single nucleotide polymorphisms and bloodstream infection (Table 2) 4.1. Pathogen sensing and signal transduction Pattern recognition receptors have recently been discovered and a concept has arisen focusing on microbial ‘patterns’ associated with pathogens. Numerous studies have been performed to link these receptors to disease phenotypes, although many of these were not specifically designed to identify risk factors for BSIs and it seems obvious that a risk factor for nosocomial infections itself should also be predictive of BSIs. TLRs are key cellular receptors for initiation of the inflammatory response that recognise invading microbes and are an integral component of the innate immune system [58,59]. Because of their importance in both the innate immune response and the induction of adaptive immunity, TLRs are currently at the centre of both basic research and drug development. Two groups of TLRs exist: one group is expressed on the surface of immune cells and recognises components of microbial cell walls such as lipopolysaccharide (LPS) of Gram-negative bacteria (TLR4) and lipopeptides (TLR2/TLR1 or TLR2/TLR6) or microbial proteins such as flagellin (TLR5) and protozoan profilin (TLR11); the other group of TLRs is expressed within the cell and recognises certain nucleic acids, such as single-stranded

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Fig. 1. Bloodstream infections (BSIs) and potential influence of host factors. (A) Primary BSIs: mechanisms, host response and genetic variation. Primary BSIs can be caused either by (i) a direct influx of bacteria via catheters (rare) or (ii) via the exterior catheter surface (frequent, mainly Gram-positive cocci). In (ii), host factors of the subcutaneous tissue may limit this infection. If not, microorganisms spread via the bloodstream. Host factors involved in containing and limiting the infection are listed, and genetic variation may thus influence susceptibility to BSI. (B) Secondary BSIs: failed containment of infection, potential genetic influence. A local primary infection can be contained by the local host defence mechanisms listed. If these fail, a secondary BSI occurs and the potential genetic factors of the host are similar to the primary BSI. TNF␣, tumour necrosis factor-alpha; IL, interleukin; TLR, Toll-like receptor; MBL, mannan-binding lectin; ICAM, intercellular adhesion molecule; PAI-1, plasminogen activator inhibitor-1; LBP, lipopolysaccharide-binding protein.

or double-stranded RNA (TLR7/TLR8 and TLR3, respectively), or CpG-rich DNA (TLR9) in specific cellular compartments. These microbial compounds recognised by the TLR system have also been termed pathogen-associated molecular patterns (PAMPs), although they are not only expressed by pathogens but also by commensal microorganisms [60]. Among the genes involved in immune recognition, several non-synonymous SNPs have been described in the genes encoding the TLRs and the signalling molecules associated with these receptors [61]. Some of these genetic variations have been functionally analysed in in vitro overexpression systems, comparing the function of the normal and the mutant variant.

4.2. Single nucleotide polymorphisms in Toll-like receptor 4 Studies addressing TLRs mainly involved bacterial recognition through TLR4 and TLR2 variations. The influence of SNPs in TLR4 in either in vitro or clinical studies showed relevance of the Asp299Gly/Thr399Ile SNP. Carriers of this SNP had reduced airway reactivity upon inhalation with LPS [62]. Although some studies showed relevance of the co-segregated Asp299Gly/Thr399Ile SNP in Gram-negative infections, others were not able to confirm this [22–24]. However, the Asp299Gly haplotype alone was relevant with regard to sepsis severity and susceptibility to Gram-negative infections [63]. Moreover, in vitro stimulation of blood cells failed

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Table 1 The PIRO concept of sepsis classification. P

Predisposing factors

Innate: genetic polymorphisms and deficiencies of immune response genes affecting innate immune response, coagulation system, complement receptors, Toll-like receptors and intracellular signalling Acquired: burns, trauma, acquired immunodeficiencies

I

Infection

Site, quantity, intrinsic virulence, and local vs. systemic infection due to specific microbial pathogens

R

Response

Differential responses based on hyperresponsiveness vs. hyporesponsiveness–immunosuppression; response modifiers such as alcohol, age, sex, nutritional status, diabetes, other pre-existing diseases and physiological status of host

O

Organ dysfunction

Number, severity and pattern of organ dysfunctions in response to systemic infection; primary vs. secondary organ injury; and organ injury due to sepsis vs. pre-existing organ dysfunction

to show relevance of the Asp299Gly/Thr399Ile SNP [64,65]. Genetic variation of TLR4 showed an influence on the risk for BSI with Candida but there is no clear evidence that TLR4 is involved in the sensing of pathogenic fungi [66]. There are co-molecules associated with TLR4 sensing, including MD-2, CD14 and LPS-binding protein (LBP). In all these molecules mutations or SNPs have been described. A coding mutation in MD-2 influenced LPS-induced tumour necrosis factor-alpha (TNF␣) release in vitro but showed no

clinical influence [27]. Variations regarding CD14 have been shown to increase the risk of sepsis [19,67]. However, other studies could not confirm these results in patients with Gram-negative bacteraemia [23]. LBP SNPs were studied as part of association studies and there were also conflicting results with regard to sepsis [25]. However, one recent cohort study could confirm an increased risk of infection and death with variants in certain haplotypes following stem cell transplantation [26].

Table 2 Single nucleotide polymorphisms (SNPs) and bloodstream infections (BSIs) or sepsis. Function

Molecule (genetic variant)

Effect on sepsis or BSI

Reference

Microbial sensing

TLR1 (I602S) (TLR2 subfamily) TLR2 (Arg753Thr) TLR6 (TLR2 subfamily) TLR4 (Asp299Gly, Thr399Ile)

[17,18] [19–21] [17] [22–24]

CD14 (−159) LPS sensing MD-2 (−103) LPS sensing

No association with sepsis Association with Gram-positive infection No association with sepsis; increased risk for aspergillosis Association with Candida BSI; sepsis; Gram-negative septic shock Gender-specific association with sepsis. Bacteraemia after stem cell transplantation and death from Gram-negative bacteraemia Tendency towards higher mortality. Conflicting results Decreased cytokine release. No influence on sepsis studied

Signalling

IRAK-4 (mutation) IRAK-1 (haplotype) TIRAP/Mal (Ser180Leu) I␬B

Severe infections in childhood Increased mortality in sepsis Pneumococcal BSI, protection if heterozygous Protective effect of two promoter SNPs

[28] [29] [30] [31]

Cytokine (pro-inflammatory)

TNF␣ (−308)

[23,32–34]

IL-1␣ IL-6 (−174) MIF IFN␥

Association not clear. Early studies suggest higher risk when homozygous Association not clear Association not clear Higher mortality in homozygous carriers with meningococcal sepsis No association with sepsis C-allele confers increased risk of shock Influence on sepsis in African–Americans Association with sepsis (DD allele, homozygous)

Cytokine (anti-inflammatory)

IL-10 (−592 and −1082) IL-1RA (intron 2, IL-1RN*) TGF␤ superfamily genes and IGFR1 SNPs

Association with sepsis (DD allele, homozygous) Higher mortality in homozygous carriers Risk association with bacteraemia in sickle cell anaemia

[42,43] [44] [45]

Coagulation

PAI-1 (4G/4G) TAFI (Thr325Ile) Factor V (506; ‘Leiden’) Fibrinogen-␤

Higher rate of septic shock in meningitis Higher risk of death in meningitis Smaller risk of sepsis (heterozygous) Protective haplotype (GAA)

[46] [47] [48] [49,50]

Other factors

ACE (I/D polymorphism) Caspase-12 (Csp12-L) Fc␥Rec-IIa l-ficolin I␬B HSP-70 MBL (‘low-producing’ MBL2 coding alleles) CEACAM1

No association with sepsis Increased risk for sepsis (African–American) Association with septic shock No association with sepsis Protective effect of two promoter SNPs No association with sepsis Association with Candida BSI No association with sepsis

[51] [52] [51,53] [54] [31] [55] [19,56] [57]

LBP (Pro436Leu) and SNP 6878, SNP 17002, LBP (−788)

TNF␣ (−376) TNF-␣R IL-1␤ (−511)

[25,26]

[23,24,19] [27]

[35] [35] [36,37]

[38,39] [40] [41]

TLR, Toll-like receptor; LBP, LPS-binding protein; LPS, lipopolysaccharide; TNF␣, tumour necrosis factor-alpha; TNF-R, TNF receptor; IL, interleukin; MIF, macrophage inhibitory factor; IFN␥, interferon-gamma; IL-1RA, IL-1 receptor agonist; TGF, transforming growth factor; IGF1R, insulin-growth factor receptor 1; PAI-1, plasminogen activator inhibitor 1; TAFI, thrombin-activatable fibrinolysis inhibitor; ACE, angiotensin-converting enzyme; Fc␥Rec-IIa, Fc gamma receptor IIa; HSP, heat shock protein; MBL, mannan-binding lectin; CEACAM, carcinoembryonic antigen-related cell adhesion molecules.

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4.3. Single nucleotide polymorphisms in the Toll-like receptor 2 family and infections A functionally relevant SNP that occurs in European populations as frequently as 10% has been described for TLR2. This mutant involves the exchange of arginine at position 753 with glutamine (Arg753Gln) and is located within the TIR domain of TLR2 [20]. The most prominent Gram-positive bacterium shown to induce inflammation through TLR2 is Staphylococcus aureus. It has been proposed that the Arg753Gln TLR2 SNP predisposes individuals to S. aureus infections; however, a larger study concluded that this is not the case [20,21]. Another promoter SNP of TLR2 at position –16933 was associated with an increased prevalence of sepsis and Gram-positive bacteraemia [19]. TLR2 forms a heterodimer with either TLR1 or TLR6, and SNPs of both genes have also been identified. Immunocompromised patients who have received bone marrow transplantation are very susceptible to invasive aspergillosis caused by Aspergillus spp., and in a first small study a correlation of these dangerous infections with TLR1 and TLR6 SNPs was found [17]. 4.4. Variations in intracellular signalling of Toll-like receptors Intracellular signal transduction involves several steps, including numerous adaptor molecules and intracellular kinases. A SNP in the TLR4 adaptor TIRAP/Mal was associated with pneumococcal infection. Heterozygous carriers of the Ser180Leu SNP had decreased risk of a severe course of disease [30]. A SNP in a downstream kinase (IRAK-1) was also associated with increased risk for pneumococcal sepsis [29]. A functional relevant mutation in IRAK-4 was described and the patient showed repeated severe infections, elucidating the importance of affected genes in this signalling system [28]. A further enzyme related to the signalling pathway of TLRs is the intracellular kinase I␬B. A recently discovered SNP in this gene showed an association with pneumococcal infections, conferring protection for carriers of this variation [31]. 5. Cytokine response Cytokines play a major role both in innate immunity and in the organisation of an orchestrated response to local and generalised infections. In general there exists a distinction between pro- and anti-inflammatory cytokines. However, many have both properties, mainly depending on the time course of the events [14]. A number of variations in cytokine genes have been reported in gene association studies. TNF␣ is a prototypical pro-inflammatory cytokine. Three promoter polymorphisms in the TNF␣ gene have been described (−238, −308 and −376), and particularly the −308 SNP has been studied extensively. An association with sepsis severity and outcome following different inflammatory insults was found repeatedly, with a tendency towards increasing levels of TNF␣ and therefore a stronger inflammatory response [32,33,68]. This is considered a factor contributing to sepsis severity and finally results in increased mortality [34]. However, these results have not been confirmed in recent studies [23,35]. Another pro-inflammatory cytokine is interleukin (IL)-1 (isoforms ␣ and ␤). An IL-1␣ polymorphisms was described for intron 6 (‘variable number tandem repeats’, 46 bp) but this variation of IL-1␣ failed to show an association with sepsis [36]. However, an IL-1␤ polymorphism in the promoter region (−511) was associated with worse outcome in meningococcal disease [37]. IL-6 is also regarded as a pro-inflammatory cytokine although it exerts its function on a broader base, also possessing antiinflammatory properties by activating dampening mechanisms of

the acute phase response. In patients with systemic inflammatory response syndrome (SIRS), mortality was increased in relation to existing IL-6 haplotypes [69]. For the IL-6 promoter polymorphism (−174), evidence is accumulating that presence of the C-allele is associated with increased risk of septic shock [38,39]. Other factors involved in the inflammatory response in acute infection were recently studied. Macrophage inhibitory factor (MIF) showed increased risk of severe forms of sepsis in African–American patients [70]. SNPs in interferon-gamma (IFN␥), although predominately involved in host defence for viral infections, were described as a risk factor for sepsis following trauma [41]. Furthermore, for IL-8, which is a chemokine with chemoattractant function for neutrophilic granulocytes, an association with infections has been revealed but no association with sepsis has yet been published [71]. As mentioned above, anti-inflammatory cytokines are also important in acute infection since they provide control of the inflammatory process and therefore protect the host from its detrimental effects. IL-10 and transforming growth factor-beta (TGF␤) are considered the most important anti-inflammatory cytokines [72]. These cytokines, among others, are involved in the dampening of inflammation. Association studies of IL-10 SNPs (−592 and −1082) showed a higher risk for carriers of the respective mutations [42,43]. However, a haplotype analysis of the highly variable 10.G microsatellite region of the gene promoter had no influence on the severity of sepsis [73]. IL-1 receptor antagonist (IL-1RA) is also involved in the control of the activity by competitively inhibiting IL-1 receptors. Homozygous carriers of a common SNP in this gene show lower IL-1RA levels in vitro and have a worse outcome [44]. 6. Genetic variants in effectors related to the innate immune response As pointed out earlier, the containment of localised infection is necessary to protect the host from generalised inflammation. Molecular systems in this context involve the coagulation system and vascular elements such as adhesion molecules and factors associated with the cellular response and therefore killing and eradication of pathogens. A close evolutionary relationship has been described for the coagulation system. This close relationship is frequently observed, since patients with severe infection have marked alterations in this system. Therefore, inherited variations associated with infections and sepsis have been described for coagulation factors such as plasminogen activator inhibitor-1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), fibrinogen and factor 5. Studies on genetic variation in PAI-1 have been associated with clinical variables in severe meningococcal infection [46]. For a SNP in the TAFI gene the outcome for meningitis was negatively influenced in homozygous carriers [47]. Furthermore, a protective haplotype has been described for fibrinogen-␤ gene variants [49]. A weak protective effect for the heterozygous carriers of factor V (506, ‘Leiden’ mutation), which is associated with a procoagulatory effect and the risk of thrombosis, has been reported [48]. Further molecules with a variety of functions, such as angiotensin-converting enzyme (ACE), Fc gamma receptor IIa (Fc␥Rec-IIa) [50], l-ficolin, heat shock proteins (HSPs) and caspases, are additionally involved in the infection response. They were also studied for the influence of polymorphisms on the respective phenotypes. ACE, which is involved in the regulation of vascular tone, has been a risk factor for pulmonary failure. However, a recent study could not confirm a proposed influence on sepsis severity or mortality [51]. Leukocyte Fc␥ receptors confer potent cellular effector functions in leukocytes [74]. For variation in Fc␥Rec-IIa there have been reports of altered risk in meningococcal meningitis and septic shock due to meningococcal disease [50,53]. l-Ficolin, which is part of a variety of pattern recognition molecules, binds lipoteichoic

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acid of Gram-positive bacteria and activates the lectin pathway of complement. However, polymorphisms in the coding gene were not associated with pneumococcal disease [54]. Another pattern recognition molecule is mannan-binding lectin (MBL). A SNP in this gene conferred higher susceptibility to major infections probably through a low-producer haplotype in immunocompromised children following myeloablative chemotherapy for haematological malignancies [56,75]. Critically ill sepsis patients were also affected [19]. HSPs are molecules with cell protection properties. They are also involved as danger signals in inflammatory processes. However, risk association studies for SNPs in these important proteins were unable to show altered risk with regard to sepsis, although the course after major trauma was negatively influenced [55]. Very recently a SNP in caspase-12 (involved in cytokine maturation and apoptosis) has been shown to confer a risk increase for septic shock in patients of African–American descent [52]. Patients carrying this variant were producing a full-length caspase proenzyme (Csp12-L), which leads to impaired cytokine release upon in vitro stimulation. Patients producing a truncated protein (Csp12S) were rather protected. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in adhesion of bacteria in the nasopharyngeal tract and is a binding protein for pathogens involved in meningitis. SNPs in this gene have been studied and a functional change in the protein was described but no clinical study has yet been performed [57]. 7. Conclusion With the completion of the Human Genome Project and with large projects such as HapMap listing SNPs in public databases, one of the current tasks of biomedical research is to link this information of individual genetic variations with disease susceptibility. For BSIs, individual variations in the response pattern exist and currently several areas of genetic variations are being investigated, such as microbial recognition receptors, cytokines and coagulation. One of the goals of these studies is to identify certain individual genetic compositions and clearly associate them with the risk for BSI in order to mount or decrease prophylactic measures individually. This goal currently has not been met, as large multigenetic studies are still missing and several of the smaller studies are still contradictory. Numerous SNPs have been described in the host response systems involved, and gene association studies have linked some of these SNPs to BSI susceptibility. However, the results are currently far from being conclusive. The future indeed may lie in the investigation of a combination of SNPs in these host defence systems. The authors of this review have recently found that a combination of SNPs in the TLRs and the subsequent signalling system leads to a profound change in host response and subsequent sepsis susceptibility. With genotyping techniques becoming more and more advanced and with the cost decreasing, larger studies in the future may lead to a clearer picture of the individual variation in response patterns leading to a change in susceptibility to and course of BSIs. Acknowledgments RRS thanks the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)) for financial support. Funding: No funding sources. Competing interests: None declared. Ethical approval: Not required. References [1] Thomson G, Esposito MS. The genetics of complex diseases. Trends Cell Biol 1999;9:M17–20.

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