[Functional requirements of patient data management systems in intensive care medicine]. / Funktionelle Anforderungen an Patientendatenmanagementsysteme in der Intensivmedizin.

BACKGROUND: As part of the German government's digitization initiative, the paper-based documentation that is still present in many intensive care units is to be replaced by digital patient data management systems (PDMS). In order to simplify the implementation of such systems, standards for basic functionalities that should be part of basic configurations of PDMS would be of great value. PURPOSE: This paper describes functional requirements for PDMS in several categories. METHODS: Criteria for standardized data documentation were defined by the authors and derived functional requirements were classified into two priority categories. RESULTS: Overall, general technical requirements, functionalities for intensive care patient care, and additional functionalities for PDMS were defined and prioritized. DISCUSSION: Using this paper as a starting point for a discussion about basic functionalities of PDMS, it is planned to develop and obtain consensus on definitive standards with representatives from medical societies, medical informatics and PDMS manufacture.

Quality indicators in intensive care medicine for Germany - fourth edition 2022.

The measurement of quality indicators supports quality improvement initiatives. The German Interdisciplinary Society of Intensive Care Medicine (DIVI) has published quality indicators for intensive care medicine for the fourth time now. After a scheduled evaluation after three years, changes in several indicators were made. Other indicators were not changed or only minimally. The focus remained strongly on relevant treatment processes like management of analgesia and sedation, mechanical ventilation and weaning, and infections in the ICU. Another focus was communication inside the ICU. The number of 10 indicators remained the same. The development method was more structured and transparency was increased by adding new features like evidence levels or author contribution and potential conflicts of interest. These quality indicators should be used in the peer review in intensive care, a method endorsed by the DIVI. Other forms of measurement and evaluation are also reasonable, for example in quality management. This fourth edition of the quality indicators will be updated in the future to reflect the recently published recommendations on the structure of intensive care units by the DIVI.

Automated Monitoring of Adherence to Evidenced-Based Clinical Guideline Recommendations: Design and Implementation Study.

BACKGROUND: Clinical practice guidelines are systematically developed statements intended to optimize patient care. However, a gapless implementation of guideline recommendations requires health care personnel not only to be aware of the recommendations and to support their content but also to recognize every situation in which they are applicable. To not miss situations in which recommendations should be applied, computerized clinical decision support can be provided through a system that allows an automated monitoring of adherence to clinical guideline recommendations in individual patients. OBJECTIVE: This study aims to collect and analyze the requirements for a system that allows the monitoring of adherence to evidence-based clinical guideline recommendations in individual patients and, based on these requirements, to design and implement a software prototype that integrates guideline recommendations with individual patient data, and to demonstrate the prototype's utility in treatment recommendations. METHODS: We performed a work process analysis with experienced intensive care clinicians to develop a conceptual model of how to support guideline adherence monitoring in clinical routine and identified which steps in the model could be supported electronically. We then identified the core requirements of a software system to support recommendation adherence monitoring in a consensus-based requirements analysis within the loosely structured focus group work of key stakeholders (clinicians, guideline developers, health data engineers, and software developers). On the basis of these requirements, we designed and implemented a modular system architecture. To demonstrate its utility, we applied the prototype to monitor adherence to a COVID-19 treatment recommendation using clinical data from a large European university hospital. RESULTS: We designed a system that integrates guideline recommendations with real-time clinical data to evaluate individual guideline recommendation adherence and developed a functional prototype. The needs analysis with clinical staff resulted in a flowchart describing the work process of how adherence to recommendations should be monitored. Four core requirements were identified: the ability to decide whether a recommendation is applicable and implemented for a specific patient, the ability to integrate clinical data from different data formats and data structures, the ability to display raw patient data, and the use of a Fast Healthcare Interoperability Resources-based format for the representation of clinical practice guidelines to provide an interoperable, standards-based guideline recommendation exchange format. CONCLUSIONS: Our system has advantages in terms of individual patient treatment and quality management in hospitals. However, further studies are needed to measure its impact on patient outcomes and evaluate its resource effectiveness in different clinical settings. We specified a modular software architecture that allows experts from different fields to work independently and focus on their area of expertise. We have released the source code of our system under an open-source license and invite for collaborative further development of the system.

Sedation, sleep-promotion, and non-verbal and verbal communication techniques in critically ill intubated or tracheostomized patients: results of a survey.

BACKGROUND: The aim of this survey was to describe, on a patient basis, the current practice of sedation, pharmacologic and non-pharmacologic measures to promote sleep and facilitation of communication in critically ill patients oro-tracheally intubated or tracheostomized. METHODS: Cross-sectional online-survey evaluating sedation, sleep management and communication in oro-tracheally intubated (IP) or tracheostomized (TP) patients in intensive care units on a single point. RESULTS: Eighty-one intensive care units including 447 patients (IP: n = 320, TP: n = 127) participated. A score of ≤ -2 on the Richmond Agitation Sedation Scale (RASS) was prevalent in 58.2% (IP 70.7% vs. TP 26.8%). RASS -1/0 was present in 32.2% (IP 25.9% vs. TP 55.1%) of subjects. Propofol and alpha-2-agonist were the predominant sedatives used while benzodiazepines were applied in only 12.1% of patients. For sleep management, ear plugs and sleeping masks were rarely used (< 7%). In half of the participating intensive care units a technique for phonation was used in the tracheostomized patients. CONCLUSIONS: The overall rate of moderate and deep sedation appears high, particularly in oro-tracheally intubated patients. There is no uniform sleep management and ear plugs and sleeping masks are only rarely applied. The application of phonation techniques in tracheostomized patients during assisted breathing is low. More efforts should be directed towards improved guideline implementation. The enhancement of sleep promotion and communication techniques in non-verbal critically ill patients may be a focus of future guideline development.

Does adherence to a quality indicator regarding early weaning from invasive ventilation improve economic outcome? A single-centre retrospective study.

OBJECTIVES: To measure and assess the economic impact of adherence to a single quality indicator (QI) regarding weaning from invasive ventilation. DESIGN: Retrospective observational single-centre study, based on electronic medical and administrative records. SETTING: Intensive care unit (ICU) of a German university hospital, reference centre for acute respiratory distress syndrome. PARTICIPANTS: Records of 3063 consecutive mechanically ventilated patients admitted to the ICU between 2012 and 2017 were extracted, of whom 583 were eligible adults for further analysis. Patients' weaning protocols were evaluated for daily adherence to quality standards until ICU discharge. Patients with <65% compliance were assigned to the low adherence group (LAG), patients with ≥65% to the high adherence group (HAG). PRIMARY AND SECONDARY OUTCOME MEASURES: Economic healthcare costs, clinical outcomes and patients' characteristics. RESULTS: The LAG consisted of 378 patients with a median negative economic results of -€3969, HAG of 205 (-€1030), respectively (p<0.001). Median duration of ventilation was 476 (248; 769) hours in the LAG and 389 (247; 608) hours in the HAG (p<0.001). Length of stay (LOS) in the LAG on ICU was 21 (12; 35) days and 16 (11; 25) days in the HAG (p<0.001). LOS in the hospital was 36 (22; 61) days in the LAG, and within the HAG, respectively, 26 (18; 48) days (p=0.001). CONCLUSIONS: High adherence to this single QI is associated with better clinical outcome and improved economic returns. Therefore, the results support the adherence to QI. However, the examined QI does not influence economic outcome as the decisive factor.

Presentation of ethical criteria during medical decision-making for critically ill patients: a mixed methods study.

Background: Every medical decision is based on balancing medical knowledge, ethical considerations, and patient preferences. Previous surveys have mainly covered the ethical knowledge of medical staff. The aim of this study is to evaluate the feasibility of an innovative concept regarding how ethical criteria are applied to clinical decision-making during critical illness. Methods: An online survey including a short case vignette was carried out at a university hospital among physicians specialising in intensive care medicine in Germany. After free text responses regarding further required case information, the participants were asked to rank decision criteria during the course of the case vignette. A qualitative evaluation was performed by two independent investigators, based on a transcription into categories. This was followed by a quantitative analysis of ranked criteria. Results: Our analysis has shown that doctors are initially inclined to consider medical information when making treatment decisions. When complications occur, ethical values are more often included in the decision-making. The qualitative evaluation reveiled that the patient's will was consistently regarded as the leading criterion for decision-making. In the quantitative evaluation, patient's well-being, quality of life, and patient autonomy were rated as the most important decision criteria. Economic factors were ranked least important. Conclusion: A mixed methods approach is able to reflect the complexity of ethical reasoning within the medical decision-making process, suggesting the feasibility of this concept. Clinical trial registration: The study was registered under DRKS-ID: DKRS00011905 (April 2017).

A Genetic Variation of Lipopolysaccharide Binding Protein Affects the Inflammatory Response and Is Associated with Improved Outcome during Sepsis.

LPS binding protein (LBP) is an important innate sensor of microbial cell wall structures. Frequent functionally relevant mutations exist and have been linked to influence susceptibility to and course of bacterial infections. We examined functional properties of a single nucleotide polymorphism resulting in an exchange of phenylalanine to leucine at position 436 of LBP (rs2232618) and compared the frequent variant of the molecule with the rare one in ligand binding experiments. We then stimulated RAW cells with bacterial ligands in the presence of serum obtained from individuals with different LBP genotypes. We, furthermore, determined the potential effects of structural changes in the molecule by in silico modeling. Finally, we analyzed 363 surgical patients for this genetic variant and examined incidence and course of sepsis following surgery. We found that binding of LBP to bacterial ligands was reduced, and stimulation of RAW cells resulted in an increased release of TNF when adding serum from individuals carrying the F436L variant as compared with normal LBP. In silico analysis revealed structural changes of LBP, potentially explaining some of the effects observed for the LBP variant. Finally, patients carrying the F436L variant were found to be similarly susceptible for sepsis. However, we observed a more favorable course of severe infections in this cohort. Our findings reveal new insights into LPS recognition and the subsequent activation of the innate immune system brought about by LBP. The identification of a genetic variant of LBP influencing the course of sepsis may help to stratify individuals at risk and thus reduce clinical complications of patients.

[Quality Assurance in Intensive Care Medicine: Peer Reviews and Quality Indicators]. / Qualitätssicherung in der Intensivmedizin: Peer Reviews und Qualitätsindikatoren.

Goal-oriented quality management in health care is an essential tool to provide good medical practice and treatment. It aims at a patient-centred case management with high transparency of structural and clinical process aspects, as well as patient outcome. An objective and comprehensive description of clinical care includes the use of quality indicators. However, the appliance of those indicators falls short, when the evaluation of quality is not followed by recommendations for improvement.As a highly specified area in health care provided in hospitals, intensive care medicine is characterized by complex interprofessional and multidisciplinary approaches. In addition, critical care units are an expensive resource. In order to provide an economic and yet high quality patient care, treatments should be evidence-based, and cost-drivers must be analysed for their effectiveness on patient-outcome.Various methods of quality assurance allow for a formative evaluation of intensive care units by peer reviews, including the use of quality indicators. This article focuses on peer review systems currently applied in German hospitals, and particularly describes quality indicators that have been established by DIVI (German Interdisciplinary Society of Intensive Care and Emergency Medicine). It also addresses the need for a professional dialogue between equal partners. This has to accompany each peer review that aims at an improvement in quality of critical patient care.

The future development of intensive care quality indicators - a methods paper.

Introduction: Medical quality indicators (QI) are important tools in the evaluation of medical quality. Their development is subject to specific methodological requirements, which include practical applicability. This is especially true for intensive care medicine with its complex processes and their interactions. This methods paper presents the status quo and shows necessary methodological developments for intensive care QI. For this purpose, a cooperation with the Association of the Scientific Medical Societies' Institute for Medical Knowledge Management (AWMF-IMWi) was established. Methodology: Review of published German manuals for QI development from guidelines and narrative review of quality indicators with a focus on evidence and consensus-based guideline recommendations. Future methodological adaptations of indicator development for improved operationalization, measurability and pilot testing are presented, and a development process is proposed. Results: The development of intensive care quality indicators in Germany is based on an established process. In the future, additional evaluation criteria (QUALIFY criteria) will be applied to assess the evidence base. In addition, a continuous exchange between the national steering committee of the DIVI responsible for QI development and guideline development groups involved in intensive care medicine is planned. Conclusion: Intensive care quality indicators will have to meet improved methodological requirements in the future by means of an improved development process. Future QI development is intended to improve the structure of the development process, with a focus on scientific evidence and a link to guideline projects. This is intended to achieve the goal of a broad application of QI and to further evaluate its relevance for patient outcome and performance of institutions.

Quality indicators in intensive care medicine for Germany - third edition 2017.

Quality improvement in medicine is depending on measurement of relevant quality indicators. The quality indicators for intensive care medicine of the German Interdisciplinary Society of Intensive Care Medicine (DIVI) from the year 2013 underwent a scheduled evaluation after three years. There were major changes in several indicators but also some indicators were changed only minimally. The focus on treatment processes like ward rounds, management of analgesia and sedation, mechanical ventilation and weaning, as well as the number of 10 indicators were not changed. Most topics remained except for early mobilization which was introduced instead of hypothermia following resuscitation. Infection prevention was added as an outcome indicator. These quality indicators are used in the peer review in intensive care, a method endorsed by the DIVI. A validity period of three years is planned for the quality indicators.

Rapid molecular diagnosis of infective aortic valve endocarditis caused by Coxiella burnetii.

We describe a case of Q-fever endocarditis with severe destruction of the aortic valve with perivalvular abscess formation and cardiac failure. The patient needed urgent operative treatment and postoperative critical care. All specimens sent for microbiological examination were negative. Molecular analysis, including fluorescence in situ hybridization of aortic valve tissue combined with PCR and sequencing, led to the correct diagnosis and to appropriate anti-infective treatment. The patient subsequently recovered from complex cardiovascular surgery. This is the first report on Q-fever endocarditis that was rapidly diagnosed using these methods.

Early deep sedation is associated with decreased in-hospital and two-year follow-up survival.

INTRODUCTION: There is increasing evidence that deep sedation is detrimental to critically ill patients. The aim of this study was to examine effects of deep sedation during the early period after ICU admission on short- and long-term survival. METHODS: In this observational, matched-pair analysis, patients receiving mechanical ventilation that were admitted to ICUs of a tertiary university hospital in six consecutive years were grouped as either lightly or deeply sedated within the first 48 hours after ICU admission. The Richmond Agitation-Sedation Score (RASS) was used to assess sedation depth (light sedation: -2 to 0; deep: -3 or below). Multivariate Cox regression was conducted to investigate the impact of early deep sedation within the first 48 hours of admission on in-hospital and two-year follow-up survival. RESULTS: In total, 1,884 patients met inclusion criteria out of which 27.2% (n = 513) were deeply sedated. Deeply sedated patients had longer ventilation times, increased length of stay and higher rates of mortality. Early deep sedation was associated with a hazard ratio of 1.661 (95% CI: 1.074 to 2.567; P = 0.022) for in-hospital survival and 1.866 (95% CI: 1.351 to 2.576; P < 0.001) for two-year follow-up survival. CONCLUSIONS: Early deep sedation during the first 48 hours of intensive care treatment was associated with decreased in-hospital and two-year follow-up survival. Since early deep sedation is a modifiable risk factor, this data shows an urgent need for prospective clinical trials focusing on light sedation in the early phase of ICU treatment.

The course of gastric cancer following surgery is associated with genetic variations of the interleukin-1 receptor antagonist and interleukin-1ß.

BACKGROUND: Inflammation, especially the cytokine response of the IL-1 family, has been shown to influence susceptibility to gastric cancer. In addition, several other pro-inflammatory cytokines have been demonstrated to influence metastasis and resistance to chemotherapy. Therefore, genetic variations within these genes may not only affect susceptibility but also influence the outcome of gastric cancer patients. A limited number of studies showed indeed an association of IL-1ß and IL-1RN variations with survival of gastric cancer patients. However, results are inconsistent, possibly because of different patient cohorts and different therapies. METHODS: In this retrospective cohort study we genotyped 154 patients with gastric cancer for IL-1ß and IL-1RN variations. Patients had undergone pathologically proven R0 resection and had received no additional adjuvant treatment. RESULTS: We show here a protective association with disease-free survival for both heterozygous genotypes, IL-1ß SNP C-511T (rs16944) and IL-1RN VNTR. The combination of both heterozygous genotypes is the strongest predictor independent of UICC stage. CONCLUSION: Genetic variations in the IL-1ß and IL-1RN genes influence disease progression in gastric cancer. Screening for these genetic variations might help to stratify therapies for gastric cancer patients in the future.

Voluntary peer review as innovative tool for quality improvement in the intensive care unit--a retrospective descriptive cohort study in German intensive care units.

INTRODUCTION: Quality improvement and safety in intensive care are rapidly evolving topics. However, there is no gold standard for assessing quality improvement in intensive care medicine yet. In 2007 a pilot project in German intensive care units (ICUs) started using voluntary peer reviews as an innovative tool for quality assessment and improvement. We describe the method of voluntary peer review and assessed its feasibility by evaluating anonymized peer review reports and analysed the thematic clusters highlighted in these reports. METHODS: Retrospective data analysis from 22 anonymous reports of peer reviews. All ICUs - representing over 300 patient beds - had undergone voluntary peer review. Data were retrieved from reports of peers of the review teams and representatives of visited ICUs. Data were analysed with regard to number of topics addressed and results of assessment questionnaires. Reports of strengths, weaknesses, opportunities and threats (SWOT reports) of these ICUs are presented. RESULTS: External assessment of structure, process and outcome indicators revealed high percentages of adherence to predefined quality goals. In the SWOT reports 11 main thematic clusters were identified representative for common ICUs. 58.1% of mentioned topics covered personnel issues, team and communication issues as well as organisation and treatment standards. The most mentioned weaknesses were observed in the issues documentation/reporting, hygiene and ethics. We identified several unique patterns regarding quality in the ICU of which long-term personnel problems und lack of good reporting methods were most interesting Conclusion: Voluntary peer review could be established as a feasible and valuable tool for quality improvement. Peer reports addressed common areas of interest in intensive care medicine in more detail compared to other methods like measurement of quality indicators.

The crystal structure of lipopolysaccharide binding protein reveals the location of a frequent mutation that impairs innate immunity.

Lipopolysaccharide (LPS) binding protein (LBP) is an acute-phase protein that initiates an immune response after recognition of bacterial LPS. Here, we report the crystal structure of murine LBP at 2.9 Å resolution. Several structural differences were observed between LBP and the related bactericidal/permeability-increasing protein (BPI), and the LBP C-terminal domain contained a negatively charged groove and a hydrophobic "phenylalanine core." A frequent human LBP SNP (allelic frequency 0.08) affected this region, potentially generating a proteinase cleavage site. The mutant protein had a reduced binding capacity for LPS and lipopeptides. SNP carriers displayed a reduced cytokine response after in vivo LPS exposure and lower cytokine concentrations in pneumonia. In a retrospective trial, the LBP SNP was associated with increased mortality rates during sepsis and pneumonia. Thus, the structural integrity of LBP may be crucial for fighting infections efficiently, and future patient stratification might help to develop better therapeutic strategies.

The German quality indicators in intensive care medicine 2013--second edition.

Quality indicators are key elements of quality management. The quality indicators for intensive care medicine of the German Interdisciplinary Society of Intensive Care Medicine (DIVI) from the year 2010 were recently evaluated when their validity time expired after two years. Overall one indicator was replaced and further three were in part changed. The former indicator I "elevation of head of bed" was replaced by the indicator "Daily multi-professional ward rounds with the documentation of daily therapy goals" and added to the indicator IV "Weaning and other measures to prevent ventilator associated pneumonias (short: Weaning/VAP Bundle)" (VAP = ventilator-associated pneumonia) which aims at the reduction of VAP incidence. The indicator VIII "Documentation of structured relative-/next-of-kin communication" was refined. The indicator X "Direction of the ICU by a specially trained certified intensivist with no other clinical duties in a department" was also updated according to recent study results. These updated quality indicators are part of the Peer Review in intensive care medicine. The next update of the quality indicators is due in 2016.

Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts.

INTRODUCTION: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. METHODS: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. RESULTS: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. CONCLUSIONS: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.

Genetic variation in innate immunity pathways and their potential contribution to the SIRS/CARS debate: evidence from human studies and animal models.

The lack of a causal and successful treatment for sepsis has led to a re-evaluation of the condition's pathophysiology. The failure of anti-inflammatory strategies has implied compensatory immunosuppression to play a central part in fatal clinical cases. While searching for novel therapeutic strategies, the question arose whether pro-inflammation (systemic inflammatory response syndrome, SIRS) or anti-inflammation (compensatory anti-inflammatory response syndrome, CARS) are dominant in sepsis, and may be counteracted by therapeutic measures. Here we ask whether in a given organism--man or mouse--the lack of any functional protein involved in this cascade may help in understanding the events. In humans, genetic variations exist, and some of them have functional consequences altering the inflammatory response to pathogens. In mice, knockout animals were created, which may assist us in understanding the SIRS/CARS cascade. Here we summarize data on genetic variations in the TLR- and cytokine system and their influence on course of infectious diseases and sepsis. In addition, we summarize animal experiments and conclude that both cascades may be needed for containing infection. Imbalances in both the pro- and anti-inflammatory system may be harmful. Thus, interventional strategies have to be introduced carefully, and in the future genetic profiling may be needed in order to tailor therapies in the best way.

Low frequency of the TIRAP S180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy.

BACKGROUND: The Toll-like receptors (TLRs) mediate innate immunity to various pathogens. A mutation (S180L) in the TLR downstream signal transducer TIRAP has recently been reported to be common in Europeans and Africans and to roughly half the risks of heterogeneous infectious diseases including malaria, tuberculosis, bacteremia, and invasive pneumococal disease in heterozygous mutation carriers. METHODS: We assessed the TIRAP S180L variant by melting curve and RFLP analysis in 1095 delivering women from malaria-endemic Ghana, as well as in a further 1114 individuals participating in case control studies on sepsis and leprosy in Germany, Turkey and Bangladesh. RESULTS: In Ghana, the TIRAP S180L polymorphism was virtually absent. In contrast, the mutation was observed among 26.6%, 32.9% and 12% of German, Bangladesh and Turkish controls, respectively. No significant association of the heterozygous genotype with sepsis or leprosy was observed. Remarkably, homozygous TIRAP 180L tend to increase the risk of sepsis in the German study (P = 0.04). CONCLUSION: A broad protective effect of TIRAP S180L against infectious diseases per se is not discernible.

Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.

Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.