Update on the management of acute pancreatitis

Purpose of reviewThis review provides insight into the recent advancements in the management of acute pancreatitis.Recent findingsModerate fluid resuscitation and Ringer's lactate has advantages above aggressive fluid resuscitation and normal saline, respectively. A normal "on-demand"diet has a positive effect on recovery from acute pancreatitis and length of hospital stay. A multimodal pain management approach including epidural analgesia might reduce unwarranted effects of opiate use. A more targeted use of antibiotics is starting to emerge. Markers such as procalcitonin may be used to limit unwarranted antibiotic use. Conversely, many patients with infected necrotizing pancreatitis can be treated with only antibiotics, although the optimal choice and duration is unclear. Delay of drainage as much as is possible is advised since it is associated with less procedures. If drainage is required, clinicians have an expanding arsenal of interventional options to their disposal such as the lumen-apposing metal stent for transgastric drainage and (repeated) necrosectomy. Immunomodulation using removal of systemic cytokines or anti-inflammatory drugs is an attractive idea, but up to now the results of clinical trials are disappointing. No additional preventive measures beside non-steroidal anti-inflammatory drugs (NSAIDs) can be recommended for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.SummaryMore treatment modalities that are less invasive became available and a trend towards less aggressive treatments (fluids, starvation, interventions, opiates) of acute pancreatitis is again emerging. Despite recent advancements, the pathophysiology of specific subgroup phenotypes is still poorly understood which reflects the disappointing results of pharmacological and immunomodulatory trials

Early laboratory biomarkers for severity in acute pancreatitis; A systematic review and meta-analysis

Background/Objectives: Acute pancreatitis is complicated by local and systemic complications in 20–30% of the patients. Accurate prediction of severity may be important for clinical decision making. Our aim is to identify and compare the accuracy of laboratory biomarkers that predict severity and complications in adult patients. Methods: Medline, EMBASE, Web of Science and Cochrane Library (1993 to August 2020) were searched for studies with an unselected population of patients with acute pancreatitis, that contains accuracy data for ≥1 laboratory biomarker(s) and/or APACHE-II score for the prediction of a patient outcomes of interest during the first 48 h of admission. The primary outcome is moderate severe or severe acute pancreatitis (MSAP/SAP). Secondary outcomes are severe acute pancreatitis, pancreatic necrosis and organ failure. Risk of bias was assed using QUADAS-2. Biomarkers extracted from ≥3 unique sources, were analyzed using hierarchical summary receiver operating characteristic (HSROC) and bivariate model analysis. Results: In total, 181 studies were included in the qualitative analysis reporting on 29 biomarkers. For the primary outcome at admission, summary sensitivities and specificities were, respectively, 87% (95% CI 69–95%) and 88% (95% CI 80–93%) for IL-6 at a threshold of >50 pg/ml, 72% (95% CI 64–79%) and 76% (95% CI 67–84%) for an APACHE-II score of ≥8, and 53% (95% CI 35–71%) and 82% (95% CI 74–88%) for CRP >150 mg/l. HSROC curve analysis confirmed these results. Conclusion: This study indicates superiority of IL-6 for the early prediction of MSAP/SAP and may be used for to guide clinical decision making

Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate

Objective: The gut microbiota are the main source of infections in necrotising pancreatitis. We investigated the effect of disruption of the intestinal microbiota by a Western-type diet on mortality and bacterial dissemination in necrotising pancreatitis and its reversal by butyrate supplementation. Design: C57BL/6 mice were fed either standard chow or a Western-type diet for 4 weeks and were then subjected to taurocholate-induced necrotising pancreatitis. Blood and pancreas were collected for bacteriology and immune analysis. The cecum microbiota composition of mice was analysed using 16S rRNA gene amplicon sequencing and cecal content metabolites were analysed by targeted (ie, butyrate) and untargeted metabolomics. Prevention of necrotising pancreatitis in this model was compared between faecal microbiota transplantation (FMT) from healthy mice, antibiotic decontamination against Gram-negative bacteria and oral or systemic butyrate administration. Additionally, the faecal microbiota of patients with pancreatitis and healthy subjects were analysed. Results: Mortality, systemic inflammation and bacterial dissemination were increased in mice fed Western diet and their gut microbiota were characterised by a loss of diversity, a bloom of Escherichia coli and an altered metabolic profile with butyrate depletion. While antibiotic decontamination decreased mortality, Gram-positive dissemination was increased. Both oral and systemic butyrate supplementation decreased mortality, bacterial dissemination, and reversed the microbiota alterations. Paradoxically, mortality and bacterial dissemination were increased with FMT administration. Finally, patients with acute pancreatitis demonstrated an increase in Proteobacteria and a decrease of butyrate producers compared with healthy subjects. Conclusion: Butyrate depletion and its repletion appear to play a central role in disease progression towards necrotising pancreatitis

Intravenous delivery of HIV-based lentiviral vectors preferentially transduces F4/80+ and Ly-6C+ cells in spleen, important target cells in autoimmune arthritis

Contains fulltext : 118684.pdf (publisher's version ) (Open Access)Antigen presenting cells (APCs) play an important role in arthritis and APC specific gene therapeutic targeting will enable intracellular modulation of cell activity. Viral mediated overexpression is a potent approach to achieve adequate transgene expression levels and lentivirus (LV) is useful for sustained expression in target cells. Therefore, we studied the feasibility of lentiviral mediated targeting of APCs in experimental arthritis. Third generation VSV-G pseudotyped self-inactivating (SIN)-LV were injected intravenously and spleen cells were analyzed with flow cytometry for green fluorescent protein (GFP) transgene expression and cell surface markers. Collagen-induced arthritis (CIA) was induced by immunization with bovine collagen type II in complete Freund's adjuvant. Effect on inflammation was monitored macroscopically and T-cell subsets in spleen were analyzed by flow cytometry. Synovium from arthritic knee joints were analyzed for proinflammatory cytokine expression. Lentiviruses injected via the tail vein preferentially infected the spleen and transduction peaks at day 10. A dose escalating study showed that 8% of all spleen cells were targeted and further analysis showed that predominantly Ly6C+ and F4/80+ cells in spleen were targeted by the LV. To study the feasibility of blocking TAK1-dependent pathways by this approach, a catalytically inactive mutant of TAK1 (TAK1-K63W) was overexpressed during CIA. LV-TAK1-K63W significantly reduced incidence and arthritis severity macroscopically. Further histological analysis showed a significant decrease in bone erosion in LV-TAK1-K63W treated animals. Moreover, systemic Th17 levels were decreased by LV-TAK1-K63W treatment in addition to diminished IL-6 and KC production in inflamed synovium. In conclusion, systemically delivered LV efficiently targets monocytes and macrophages in spleen that are involved in autoimmune arthritis. Moreover, this study confirms efficacy of TAK1 targeting in arthritis. This approach may provide a valuable tool in targeting splenic APCs, to unravel their role in autoimmune arthritis and to identify and validate APC specific therapeutic targets

Over- and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis:An Observational Multicenter Study

OBJECTIVE: The use and impact of antibiotics and the impact of causative pathogens on clinical outcomes in a large real-world cohort covering the entire clinical spectrum of necrotizing pancreatitis remain unknown. SUMMARY BACKGROUND DATA: International guidelines recommend broad-spectrum antibiotics in patients with suspected infected necrotizing pancreatitis. This recommendation is not based on high-level evidence and clinical effects are unknown. METHODS: This study is a post-hoc analysis of a nationwide prospective cohort of 401 patients with necrotizing pancreatitis in 15 Dutch centers (2010-2019). Across the patient population from time of admission to 6 months post admission, multivariable regression analyses were used to analyze (1) microbiological cultures and (2) the antibiotic use. RESULTS: Antibiotics were started in 321/401 patients (80%) administered at a median of 5 days (P25-P75: 1-13) after admission. Median duration of antibiotics was 27 days (P25-P75: 15-48). In 221/321 patients (69%) infection was not proven by cultures at time of initiation of antibiotics. Empirical antibiotics for infected necrosis provided insufficient coverage in 64/128 patients (50%) with a pancreatic culture. Prolonged antibiotic therapy was associated with Enterococcus infection (OR1.08 [95%CI 1.03-1.16], P=0.01). Enterococcus infection was associated with new/persistent organ failure (OR3.08 [95%CI 1.35-7.29], P<0.01) and mortality (OR5.78 [95% CI 1.46-38.73], P=0.03). Yeast were found in 30/147 cultures (20%). DISCUSSION: In this nationwide study of patients with necrotizing pancreatitis, the vast majority received antibiotics, typically administered early in the disease course and without a proven infection. Empirical antibiotics were inappropriate based on pancreatic cultures in half the patients. Future clinical research and practice must consider antibiotic selective pressure due to prolonged therapy, coverage of Enterococcus and yeast. Improved guidelines on antimicrobial diagnostics and therapy could reduce inappropriate antibiotic use and improve clinical outcomes

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Contains fulltext : 51057.pdf (publisher's version ) (Closed access)Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity