Complement System Part I – Molecular Mechanisms of Activation and Regulation

Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins and the membrane attack complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly we will discuss the development and benefits of therapies using complement inhibitors

Complement System Part II: Role in Immunity

International audienceThe complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target

Incidence of postoperative nosocomial endophthalmitis: results of an eight-year prospective surveillance programme in a university hospital in France

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Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1

Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in in vitro and in vivo models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, in vitro and in vivo, compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4—known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Sociocognitive determinants of self-reported compliance with standard precautions: Development and preliminary testing of a questionnaire with French health care workers

International audienceBackground Inconsistent compliance of health care workers with standard precautions has already been documented. The objective of this study was to develop a questionnaire to investigate the sociocognitive determinants of compliance with standard precautions based on the theory of planned behavior. Methods To construct the Standard Precautions Questionnaire (SPQ), items were selected using a systematic review of literature and semistructured interviews with 54 health care workers. Thirty-five items were selected for a draft questionnaire. These questionnaires were sent to 649 health care workers in 3 medical specialties (pediatrics, geriatrics, and intensive care) in a French University hospital. A total of 331 valid questionnaires were analyzed. Results Factor analysis yielded a final 7-factor solution with an explained variance of 66.51%, with 24 items. The 7 dimensions were the following: attitude toward standard precautions, social influence facilitating organization, exemplary behavior of colleagues, organizational constraints, individual constraints, and intention to perform standard precautions. Some differences were observed between medical specialties on attitude toward standard precautions, social influence, and individual constraints. Conclusion The SPQ met the conditions of reliability and validity in accordance with psychometric demands and could be used to evaluate attitudes and intention to perform standard precautions among medical and nursing staff

The impact of a patient’s social status on the cost of vaginal deliveries: an observational study in a French university hospital

International audienceINTRODUCTION:We aimed to assess the association between a patient's social status and the cost of stay for a single uncomplicated vaginal delivery. Currently, few data have been reported.MATERIAL AND METHODS:We conducted an observational study with data retrieved from the medical and administrative databases of a university hospital in North-West France. We included all patients admitted in 2014 and classified in either Diagnosis-Related Group (DRG) « Single uncomplicated vaginal deliveries in a primiparous patient » or DRG « Single uncomplicated vaginal deliveries in a multiparous patient ». Criteria defining poor social status were: a specific healthcare benefit in relation to low income or for foreign undocumented patients, and/or a consultation with a social worker during the hospital stay except if no social problem was diagnosed. We compared the cost of stay between patients with poor social status and patients with good social status using a multivariate median regression stratified on parity, and adjusted for age, gestational age and neonatal hospitalization.RESULTS:Among 686 primiparous patients, 21% had poor social status, which was associated with an increase in the median cost of stay (+€475; 95% CI [+334 to +616]), mostly explained by a 1-day increase in the median length of stay.Among 899 multiparous patients, 29% had poor social status, which was not associated with the cost of stay.DISCUSSION:Social status had an impact on the cost of vaginal deliveries in primiparous patients. Our findings suggest a need to redefine the DRG classification according to patients' social status

Surgical Site Infection in Endometriosis Surgery Is a Rare Complication: Results of a Single Center's Prospective Surveillance of Eight Hundred Ninety-Six Procedures

International audienceBACKGROUND:There are no studies reporting the rate of surgical site infection (SSI) after surgery for endometriosis, although this information is valuable when discussing the most appropriate treatment strategy with the patient.METHODS:We conducted a prospective cohort study in a university hospital and regional reference center for endometriosis. We sought to measure the rate of SSI after endometriosis surgery using prospective SSI post-discharge surveillance data and the hospital information system via an ad hoc algorithm using both diagnosis and procedure code classifications.RESULTS:Among 896 consecutive endometriosis surgical procedures, we identified 365 procedures with involvement of the gastrointestinal tract, defined as the deep invasive procedure (DIP) group, 107 procedures with involvement of an ovary, and 424 other procedures. Twelve SSI (all organ/space infections) were observed, all in the DIP group, corresponding to an overall SSI incidence of 1.3% 95% confidence interval (CI) 0.7-2.3, and an SSI incidence in the DIP group of 2.8%, 95% CI 1.5-4.9. The median delay between the procedure and the SSI was 6.5 days (range, 3-23). At least one micro-organism was found in 10 patients (four Escherichia coli, four Enterobacter cloacae, three Enteroccus faecalis, two Bacteroides fragilis, one Pseudomonas aeruginosa, one Candida albicans).CONCLUSION:A low overall rate of SSI after surgery for endometriosis was observed. Nevertheless, procedures with involvement of the intestinal tract were at risk of SSI