Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Characterizing the B cell response and understanding the mechanism of action of vedolizumab in ulcerative colitis and chronic HIV-1 infection

La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique intestinale (MICI) qui est caractérisée par l’inflammation chronique du rectum et/ou du côlon. Bien que l’idée qu’il existe une réponse immunitaire exagérée contre le microbiote intestinal soit communément acceptée, la physiopathologie est encore insuffisamment connue. Parmi les dysfonctions immunitaires, il existe des arguments en faveur d’un dérèglement de la biologie des lymphocytes B. A l’aide de plusieurs techniques (dont la cytométrie en flux, le single-cell RNA sequencing et le single-cell BCR sequencing), nous avons mis en évidence des modifications marquées des populations plasmocytaires coliques chez des patients avec RCH, dont une augmentation de l’expression des IgG et IgA1 et une diminution en IgA2 associées à l’accroissement de la proportion des plasmocytes à durée de vie courte. Ce turnover accru se reflétait dans la circulation sanguine par l’élévation des plasmablastes ?7+ à tropisme intestinal, associé à l’activité de la maladie et à la survenue de complications. Notre second travail s’intéressait au mécanisme d’action du vedolizumab (anti-?4?7), traitement couramment utilisé dans les MICI et prometteur pour le VIH. Dans une cohorte de patients atteints à la fois de MICI et du VIH, mous avons mis en évidence un impact majeur sur les follicules lymphoïdes intestinaux avec une absence d’effet significatif sur la fréquence des lymphocytes T effecteurs de la lamina propria. Cette découverte, décrite pour la première fois chez l’homme, ouvre de nouvelles perspectives quant au mécanisme d’action du vedolizumab dans les MICI et le VIH.Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) that leads to chronic inflammation of the rectum and the colon. Even though it is commonly accepted that it results from an exaggerated immune response toward the gut microbiota, the pathophysiology is still not fully understood. Among immune defects, many evidences exist supporting a disturbed B cell system, including the presence of (auto-)antibodies and the infiltration of the lamina propria by plasma cells. Using multiple advanced techniques including single-cell RNA sequencing and single-cell BCR sequencing we extensively characterized the B cell compartment in the blood and the intestinal mucosa of UC patients. We found that the colonic plasma cells phenotype was skewed toward an increased expression of IgG and IgA1 and an increased proportion of short-lived plasma cells. This increased turnover was reflected in the blood by the expansion of ?7+ plasmablasts, which correlated with disease activity and predicted disease course. Our second work focused on the mechanism of action of vedolizumab, a monoclonal antibody targeting the ?4?7 integrin, for both IBD and HIV. In a unique cohort of patients with concomitant IBD and HIV, we unexpectedly found that memory T cells within the lamina propria were not significantly affected. Conversely, lymphoid aggregates, mostly in the terminal ileum were massively impacted. These findings are being further explored and may change the paradigm regarding the mechanism of action of vedolizumab

Etude de la biologie des lymphocytes B et du mécanisme d'action du vedolizumab dans la rectocolite hémorragique et au cours de l'infection chronique à VIH

Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) that leads to chronic inflammation of the rectum and the colon. Even though it is commonly accepted that it results from an exaggerated immune response toward the gut microbiota, the pathophysiology is still not fully understood. Among immune defects, many evidences exist supporting a disturbed B cell system, including the presence of (auto-)antibodies and the infiltration of the lamina propria by plasma cells. Using multiple advanced techniques including single-cell RNA sequencing and single-cell BCR sequencing we extensively characterized the B cell compartment in the blood and the intestinal mucosa of UC patients. We found that the colonic plasma cells phenotype was skewed toward an increased expression of IgG and IgA1 and an increased proportion of short-lived plasma cells. This increased turnover was reflected in the blood by the expansion of ?7+ plasmablasts, which correlated with disease activity and predicted disease course. Our second work focused on the mechanism of action of vedolizumab, a monoclonal antibody targeting the ?4?7 integrin, for both IBD and HIV. In a unique cohort of patients with concomitant IBD and HIV, we unexpectedly found that memory T cells within the lamina propria were not significantly affected. Conversely, lymphoid aggregates, mostly in the terminal ileum were massively impacted. These findings are being further explored and may change the paradigm regarding the mechanism of action of vedolizumab.La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique intestinale (MICI) qui est caractérisée par l’inflammation chronique du rectum et/ou du côlon. Bien que l’idée qu’il existe une réponse immunitaire exagérée contre le microbiote intestinal soit communément acceptée, la physiopathologie est encore insuffisamment connue. Parmi les dysfonctions immunitaires, il existe des arguments en faveur d’un dérèglement de la biologie des lymphocytes B. A l’aide de plusieurs techniques (dont la cytométrie en flux, le single-cell RNA sequencing et le single-cell BCR sequencing), nous avons mis en évidence des modifications marquées des populations plasmocytaires coliques chez des patients avec RCH, dont une augmentation de l’expression des IgG et IgA1 et une diminution en IgA2 associées à l’accroissement de la proportion des plasmocytes à durée de vie courte. Ce turnover accru se reflétait dans la circulation sanguine par l’élévation des plasmablastes ?7+ à tropisme intestinal, associé à l’activité de la maladie et à la survenue de complications. Notre second travail s’intéressait au mécanisme d’action du vedolizumab (anti-?4?7), traitement couramment utilisé dans les MICI et prometteur pour le VIH. Dans une cohorte de patients atteints à la fois de MICI et du VIH, mous avons mis en évidence un impact majeur sur les follicules lymphoïdes intestinaux avec une absence d’effet significatif sur la fréquence des lymphocytes T effecteurs de la lamina propria. Cette découverte, décrite pour la première fois chez l’homme, ouvre de nouvelles perspectives quant au mécanisme d’action du vedolizumab dans les MICI et le VIH

Why is SARS-CoV-2 infection more severe in obese men? The gut lymphatics – Lung axis hypothesis

International audienceConsistent observations report increased severity of SARS-CoV-2 infection in overweight men with cardiovascular factors. As the visceral fat possesses an intense immune activity, is involved in metabolic syndrome and is at the crossroad between the intestines, the systemic circulation and the lung, we hypothesized that it plays a major role in severe forms of SARS-CoV-2 infection. SARS-CoV2 presents the ability to infect epithelial cells of the respiratory tract as well as the intestinal tract. Several factors may increase intestinal permeability including direct enterocyte damage by SARS-CoV2, systemic inflammatory response syndrome (SIRS) and epithelial ischemia secondary to SARS-CoV2- associated endothelial dysfunction. This increase permeability further leads to translocation of microbial components such as MAMPs (microbial-associated molecular pattern), triggering an inflammatory immune response by TLR-expressing cells of the mesentery fat (mostly macrophages and adipocytes). The pro-inflammatory cytokines produced by the mesentery fat mediates systemic inflammation and aggravate acute respiratory distress syndrome (ARDS) through the mesenteric lymph drainage

Topological Modelling of Deep Ulcerations in Patients with Ulcerative Colitis

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I-FABP is decreased in COVID-19 patients, independently of the prognosis.

BackgroundSevere acute respiratory syndrome caused by the novel coronavirus (SARS-CoV-2) is frequently associated with gastrointestinal manifestations. Herein we evaluated the interest in measuring the intestinal fatty acid-binding protein (I-FABP), a biomarker of intestinal injury, in COVID-19 patients.MethodsSerum I-FABP was analyzed in 28 consecutive patients hospitalized for a PCR-confirmed COVID-19, in 24 hospitalized patients with non-COVID-19 pulmonary diseases, and 79 patients admitted to the emergency room for abdominal pain.ResultsI-FABP serum concentrations were significantly lower in patients with COVID-19, as compared to patients with non-COVID-19 pulmonary diseases [70.3 pg/mL (47-167.9) vs. 161.1 pg/mL (88.98-305.2), respectively, p = 0.008]. I-FABP concentrations in these two populations were significantly lower than in patients with abdominal pain without COVID-19 [344.8 pg/mL (268.9-579.6)]. I-FABP was neither associated with severity nor the duration of symptoms. I-FABP was correlated with polymorphonuclear cell counts.ConclusionsIn this pilot study, we observed a low I-FABP concentration in COVID-19 patients either with or without gastrointestinal symptoms, of which the pathophysiological mechanisms and clinical impact remain to be established. Further explorations on a larger cohort of patients will be needed to unravel the molecular mechanism of such observation, including the effects of malabsorption and/or abnormal lipid metabolism

The Appendix Orchestrates T-Cell Mediated Immunosurveillance in Colitis-Associated CancerSummary

Background & Aims: Although appendectomy may reduce colorectal inflammation in patients with ulcerative colitis (UC), this surgical procedure has been suggested to be associated with an increased risk of colitis-associated cancer (CAC). Our aim was to explore the mechanism underlying the appendectomy-associated increased risk of CAC. Methods: Five-week-old male BALB/c mice underwent appendectomy, appendicitis induction, or sham laparotomy. They were then exposed to azoxymethane/dextran sodium sulfate (AOM/DSS) to induce CAC. Mice were killed 12 weeks later, and colons were taken for pathological analysis and immunohistochemistry (CD3 and CD8 staining). Human colonic tumors from 21 patients with UC who underwent surgical resection for CAC were immunophenotyped and stratified according to appendectomy status. Results: Whereas appendectomy significantly reduced colitis severity and increased CAC number, appendicitis induction without appendectomy led to opposite results. Intratumor CD3+ and CD8+ T-cell densities were lower after appendectomy and higher after appendicitis induction compared with the sham laparotomy group. Blocking lymphocyte trafficking to the colon with the anti-α4β7 integrin antibody or a sphingosine-1-phosphate receptor agonist suppressed the inducing effect of the appendectomy on tumors’ number and on CD3+/CD8+ intratumoral density. CD8+ or CD3+ T cells isolated from inflammatory neo-appendix and intravenously injected into AOM/DSS-treated recipient mice increased CD3+/CD8+ T-cell tumor infiltration and decreased tumor number. In UC patients with a history of appendectomy, intratumor CD3+ and CD8+ T-cell densities were decreased compared with UC patients without history of appendectomy. Conclusions: In UC, appendectomy could suppress a major site of T-cell priming, resulting in a less efficient CAC immunosurveillance

Tofacitinib as salvage therapy for 55 patients hospitalised with refractory severe ulcerative colitis: A GETAID cohort

International audienceSummary Background Up to 25% of patients with ulcerative colitis (UC) will require hospitalization for severe flare. In patients hospitalised for severe flare, who previously experienced multiple drug failures, including steroids and anti‐TNF agents, new quick‐acting medical options are needed. Tofacitinib is effective in refractory UC and has a rapid onset of action. Aim To evaluate effectiveness and safety of tofacitinib as rescue therapy in patients hospitalised for UC flare. Methods We conducted an observational and multicentre study with both retrospective and prospective collections in 14 GETAID centres. The primary objective was to assess the survival without colectomy following tofacitinib initiation in patients hospitalised for a UC flare. We determined rates of clinical response, clinical remission, and steroid‐free clinical remission at week 6 and week 14 and safety. Results Fifty‐five patients were included (49 with prior infliximab failure and 19 previously exposed to ciclosporin). With a median follow‐up of 6.5 months (interquartile range [IQR] [3‐12.3]), rate of colectomy‐free survival was estimated at 78.9% (95 CI [68.5‐90.9]) and 73.6% (95 CI [61.9‐87.3]) at 3 and 6 months, respectively. Rates of clinical response, clinical remission and steroid‐free clinical remission were 60%, 45.5% and 37.5% at week 6 and 41.8%, 34.5% and 32.7% at week 14. Regarding safety, no death was observed, three patients withdrew tofacitinib due to adverse events. Two herpes zoster infections occurred in patients aged over 60 years old. No venous thrombotic or major adverse cardiovascular events occurred. Conclusion Tofacitinib appears as a promising option in patients hospitalised with a UC flare but needs further validation in controlled trials