Endoscopy management algorithms: role of cyanoacrylate glue injection and self-expanding metal stents in acute variceal haemorrhage

Mortality from acute variceal bleeding (AVB) has improved markedly over the last 2–3 decades due to increased specialisation and standardisation of medical and endoscopic practice culminating in the production of consensus guidance based on expert opinion. Nonetheless, despite greater exposure, training and endoscopic practices, 30-day mortality still remains high at around 30%. This is a reflection of the high morbidity with liver disease, and limited endoscopic experience and/or endoscopic techniques used by the majority of general endoscopists. Clinical necessity defines our drive for further endoscopic innovation to improve ‘best practice’ and, therefore, clinical outcomes accordingly. Sclerotherpy, variceal band ligation and/or rescue balloon tamponade have been entrenched in most treatment algorithms over the decades. However, in recent years and albeit limited to specialised liver centres, cyanoacrylate glue injection therapy (for oesophageal and gastric varices), and the placement of a self-expanding metallic stent for oesophageal varices have begun to offer improved endoscopic care in experienced hands. Yet even in specialised centres, their application is sporadic and operator dependent. Here, we discuss the evidence of these newer endoscopic approaches, and hope to propose their inclusion in endoscopic therapy algorithms for ‘best practice’ management of AVB in all appropriately supported endoscopy units

Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

Background/aims: Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown. Methods/design: We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively. Results: In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments. Conclusions: In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients

Byrsonima crassifolia

Angiosperm

Eradication of Staphylococcus aureus Biofilm Infection by Persister Drug Combination

Staphylococcus aureus can cause a variety of infections, including persistent biofilm infections, which are difficult to eradicate with current antibiotic treatments. Here, we demonstrate that combining drugs that have robust anti-persister activity, such as clinafloxacin or oritavancin, in combination with drugs that have high activity against growing bacteria, such as vancomycin or meropenem, could completely eradicate S. aureus biofilm bacteria in vitro. In contrast, single or two drugs, including the current treatment doxycycline plus rifampin for persistent S. aureus infection, failed to kill all biofilm bacteria in vitro. In a chronic persistent skin infection mouse model, we showed that the drug combination clinafloxacin + meropenem + daptomycin which killed all biofilm bacteria in vitro completely eradicated S. aureus biofilm infection in mice while the current treatments failed to do so. The complete eradication of biofilm bacteria is attributed to the unique high anti-persister activity of clinafloxacin, which could not be replaced by other fluoroquinolones including moxifloxacin, levofloxacin, or ciprofloxacin. We also compared our persister drug combination with the current approaches for treating persistent infections, including gentamicin + fructose and ADEP4 + rifampin in the S. aureus biofilm infection mouse model, and found neither treatment could eradicate the biofilm infection. Our study demonstrates an important treatment principle, the Yin–Yang model, for persistent infections by targeting both growing and non-growing heterogeneous bacterial populations, utilizing persister drugs for the more effective eradication of persistent and biofilm infections. Our findings have implications for the improved treatment of other persistent and biofilm infections in general

Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease

Intestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.We analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.In ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.In ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the 'leaky' gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients

Blockade of PD1 and TIM3 Restores Innate and Adaptive Immunity in Patients With Acute Alcoholic Hepatitis

BACKGROUND &amp; AIMS: Susceptibility to bacterial infection is a feature of alcohol-related liver disease (ALD). Programmed cell death 1 (PDCD1, also known as PD1), the T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3, also known as hepatitis A virus cellular receptor 2, HAVCR2) and their respective ligands-CD274 (also known as PDL1) and galectin-9-are inhibitory receptors that regulate the balance between protective immunity and host immune-mediated damage. However, their sustained hyper-expression promotes immune exhaustion and paralysis. We investigated the role of these immune inhibitory receptors in driving immune impairments in patients with ALD.METHODS: In a prospective study, we collected blood samples from 20 patients with acute alcoholic hepatitis (AAH), 16 patients with stable advanced alcohol-related cirrhosis (ARC), and 12 healthy individuals (controls). Whole blood or peripheral blood mononuclear cells were assessed for expression of PD1, PDL1, TIM3, galectin-9, and toll-like receptors (TLRs) on subsets of innate and adaptive immune effector cells. We measured antibacterial immune responses to lipopolysaccharide (endotoxin) using ELISpot assays, and used flow cytometry to quantify cytokine production, phagocytosis and oxidative burst in the presence or absence of blocking antibodies against PD1 or TIM3.RESULTS: Antibacterial innate and adaptive immune responses were greatly reduced in patients with AAH, compared with controls, whereas patients with ARC had less-severe dysfunctions in innate immune effector cells and preserved functional T-cell responses. Fewer T cells from patients with AAH produced interferon-γ (IFNγ) in response to LPS, compared with controls. Furthermore, patients with AAH had greater numbers of IL10-producing T cells, and reduced levels of neutrophil phagocytosis and oxidative burst in response to Escherichia coli stimulation, compared to controls. T cells from patients with AAH, but not ARC, expressed higher levels of PD1 and PDL1, or TIM3 and galectin-9, than T cells from controls. Antibodies against PD1 and TIM3 restored T-cell production of IFNγ, reduced the numbers of IL10-producing T cells, and increased neutrophil antimicrobial activities. Circulating levels of endotoxin in plasma from patients with AAH caused over expression of immune inhibitory receptors on T cells via TLR4 binding to CD14+ monocytes.CONCLUSIONS: Antibacterial immune responses are impaired in patients with AAH. Lymphocytes from these patients express high levels of immune inhibitory receptors, produce lower levels of IFNγ, and have increased IL10 production due to chronic endotoxin exposure. These effects can be reversed by blocking PD1 and TIM3, which increase the antimicrobial activities of T cells and neutrophils.</p