1 / 36

Immune dysfunction and s epsis in a cute on chronic liver failure

Immune dysfunction and s epsis in a cute on chronic liver failure. Dr Harry Antoniades MRC Clinician Scientist & Senior Lecturer in Hepatology. What is the scale of the problem ?.

blaise
Download Presentation

Immune dysfunction and s epsis in a cute on chronic liver failure

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Immune dysfunction and sepsis in acute on chronic liver failure Dr Harry Antoniades MRC Clinician Scientist & Senior Lecturer in Hepatology

  2. What is the scale of the problem ? “An 88% rise in age-standardised mortality from chronic liver disease, the only one of the major diseases which is still increasing, of which alcohol-related liver disease is one of the primary causes, along with viral hepatitis. Cirrhosis deaths are rising in England while falling in most other EU countries” NCEPOD report; Atlas for liver care for England; March ’13 Source; National Statistics 2007 Leon et al Lancet ‘06

  3. Acute on chronic liver failure (ACLF) • Definition • Acute deterioration of pre-existing, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multi-system organ failure. EASL-AASLD consensus Olson et al., Hepatology 2011 • CANONIC study - defining ACLF grades according to organ failure & mortality • - multicentre trial, including1443 patients with acute decompensationMoreau et al., Gastroenterology 2013 * Creatinine 132 μmol/L

  4. Background - ACLF vs. decompensated cirrhosis • Characteristics of ACLF • previously good or stable liver function • acute deterioration over a short period • induced by a precipitating event • resulting in organ failure and high risk of death • potentially reversible Jalan et al., J Hepatol, 2012

  5. Background - ACLF vs. decompensated cirrhosis • precipitating events: • infection • GI bleeding • surgery / trauma • alcoholic hepatitis, PVT, ... Jalan et al., J Hepatol, 2012 • Characteristics of ACLF • previously good or stable liver function • acute deterioration over a short period • induced by a precipitating event • resulting in organ failure and high risk of death & potentially reversible

  6. Admissions for organ support in cirrhosis: “ACLF” ICU series of consecutive patients • n=143 Hepatology 2001:34;255-61 • n=420 Chest 2004;126;1598-03 • n=312 Ali Pharm Ther 2006:23;883-93 • n=111 J ClinGast 2003;37:251-7 Welch et al J Health Science Research & Policy 2008;13S2:40-44

  7. ACLF in ICU; Prognosis Study Year n Mortality Zimmerman et al 1996 117 63% Hepatology 1996;23:193-1401 Zauner et al 1996 198 52% ICM 1996;22:559-63 Wehler et al 2001 143 46% Hepatology 2001;34:255-61 Aggarawal et al 2001 582 49% Chest 2001;119:1489-97 Tsai et al 2003 111 65% J Clin Gastro;37:251-257 Arabi et al 2004 129 74% E J Gastro Hep 2004;16(3):333-9 Gildea et al 2004 420 44% Chest 2004;96(4):1232-6 Cholongitas et al2006 312 65% Alim Pharm Ther 2006;23:883-893 Fang et al 2008 111 81% Neph Dial Trans 2008;23(6):1961-9 Junea et al 2009 104 42% J Crit Care 2009;24(3):387-93

  8. Sepsis in cirrhosis • Bacterial infections in cirrhosis: • leading cause morbidity/mortality in cirrhosis • 15-35% of hospitalised cirrhotic patients vs 5-7% general population (Verbake et al; Crit Care ‘11) • 50% mortality rate increase patients with sepsis* • increased susceptibility to secondary infections • increased frequency of extra-hepatic organ failure & requirement for organ support • Delisting from listing transplant *Bajaj et al; Hepatology’12 ‘14; Karvellas et al; Crit Care Med ‘10 ; Moreau et al, Gastro ‘13

  9. Infections in cirrhosis and ACLF • Frequency • hospitalised cirrhotic patients - 32-34% • hospitalised cirrhotic patients with GI bleeding - 45% • vs. hospitalised patients overall 5-7% • Sites of first infections • SBP - 22-25% • UTI - 20-28% • pneumonia – 8-15% 4. Gut infections • Pathogens • gram-negative (E. coli, Klebsiellaspp) • gram-positive (Streptococcus pneumonia, Staphyloccocusaureus) • Fungi • C Difficile Tandon, Sem Liver Disease, 2008 Borzio et al., Dig Liver Dis, 2001 Moreau et al; Gastro ‘13 Baja et al, Hepatology ‘12 Moreau et al, Gastro ‘13 FernándezJ et al., Hepatology’02 Karvellas et al; Crit Care Med ‘10 Bonnel et al., Clin Gastro Hepatol’11 Baja et al; Hepatology ‘12

  10. ACLF precipitating factors: Infection • Common in ACLF 40-50% hospital admissions of cirrhotics 20-40% develop nosocomial infections SIRS criteria for sepsis unreliable in cirrhotic patients (present in 57-70% infected patients) Infection confers poor outcome Levesque E et al. J Hepatology 2012, n = 377

  11. Infection & variceal bleeding • High incidence of infections in cirrhotics with variceal bleeding (20% at admission; 50% during first few days) • Meta-analysis reduction in infection (45% vs 14%) and mortality (24% vs 15%) with antibiotic prophylaxis (Bernard et al, Hepatology‘99) • Infection is associated with failure to control bleeding & variceal re-bleeding (Goulis et al Lancet 1999; Hou et al Hepatology ‘04) • Antibiotic prophylaxis associated lower incidence early variceal re-bleeding (Hou et al, Hepatology‘04) • Cochrane analysis : evidence base for antibiotics 8 trials (864 cases) Significant decrease mortality (RR 0.73) and incidence of bacterial infection (RR 0.4)

  12. Infection and Alcoholic Hepatitis: • >50% AH develop sepsis during admission • Mechanisms conferring susceptibility largely unknown • Infection increases mortality in AH Louvet et al. Gastroenterology 2009

  13. ACLF: Renal failure • Most data extrapolated from advanced cirrhotics; • Emerging data in ACLF • Causes: multifactorial Infection (46%) Hypovoloameia (32%) HRS (13%) Parenchymal nephropathy (9%) Drug-induced (7.5%) Creatinine >133 n=562 Martin-Llahi et al, Gastro ‘11

  14. Infection triggers development of organ failure & ACLF • 35% with proven infection required organ support (n=507) • Infection triggered organ failure (ACLF) increased mortality rate • Independent predictors of 30-day survival • Admission MELD score • Low albumin • Infection triggered organ failure (>2) • High WCC/CRP • Secondary/recurrent infections Liver dysfunction SIRS responses Immune dysfunction/ immunosuppression Bajaj et al; Hepatology’12 & Hepatology ‘14

  15. Secondary infections in ACLF confers poor outcome • Secondary infections: • 28% hospitalised patients • Associated wit high mortality (53% vs 20%) & independent of admission MELD • Commoner in patients with MODS/shock • Associated with noscomial first infection Predictors of 30-day survival Bajaj et al; Hepatology ‘12

  16. SIRS confers poor outcome in cirrhotics irrespective of infection 0-1 2 3-4 Culture +vein 40 and 42% survivors vs non-survivors Cazzaninga et al; J Hep 2009 Shawrcross et al; J Hep 2011

  17. Infection, SIRS and cirrhosis • 30-50% infections remain “culture negative” in cirrhosis • Patients with decompensated liver disease exhibit “partial SIRS responses” • SIRS in cirrhosis is “atypical”: • Reduced baseline PMN count • Elevated baseline HR (hyperdynamic circulation) • Baseline hyperventilation due to encephalopathy • Blunted elevation in body temperature • SIRS criteria and biomarkers (e.g. CRP, procalcitonin) DO NOT differentiate infectious vs non-infectious driven SIRS

  18. Pathophysiology • Not fully understood • Important to understand to allow for best interventions and improve prognosis • Multisystem disorder • Hepatic - reduction in liver synthetic function, raised bilirubin - histologically: cell death, loss of cellular actin - raised portal pressures (especially in sepsis, AH) • Baseline hyperdynamic circulation with effective intravascular depletion • Activation of R-A-A/ADH • Gut-liver axis dysfunction & bacterial translocation • Hepatic and peripheral Immune dysfunction

  19. Pathophysiology: Gut-liver-systemic axis dysfunction Selvapatt et al, Intensive Care Medicine ; In press

  20. Bacterial translocation: a pathogenic factor in development of sepsis • Migration of viable microorganisms from gut lumen to mesenteric lymph nodes & extra-intestinal sites • Pathogenic mechanism of “culture-negative” sepsis (30-50%) • SBP and other infections • Activation of innate immune & systemic inflammatory responses • Circulatory bacterial DNA is a biomarker for translocation of bacteria in cirrhosis Verbake et al; Crit Care ‘11. Bellot et al; LivInt ‘12

  21. Bacterial translocation in cirrhosis • Prevalence of circulating bacterial DNA with severity of liver disease : • Child’s A: 3.8% • Child’s B: 8% • Child’s C: 30% • Positive ascitic and peripheral bact DNA associated with worse outcome in culture negative decompensated liver disease • Child-Pugh score more predictive of presence of bact DNA vs portal hypertension • Associated with circulatory dysfunction/↑ intrahepatic resistance • Bact DNA+: low MAP, SVR, ↑ pro-inflammatory cytokines, PRA renal dysfunction (Frances et al Hepatology ‘08; Bellot et al Hepatology) Cirera et al; J Hep’01 Such et al; Hepatology ‘02 Zapater et al; Hepatology ‘08

  22. Bacterial translocation in ACLF –King’s College cohort • n-=20, preliminary cohort ACLF • Overall MR 50% • Median MELD: 24 • Median SOFA: 14.5 • Only 1/20 culture-positive • All on broad spectrum antimicrobials Patel et al, unpublished data

  23. liver Immune dysfunction: failure of hepatic clearance of pathogens pathogens • Multiple postulated mechanisms: • Immunological: • - Kupffer cell activation & RES dysfunction • & reduced bacterial clearance • - Sequestration/recruitment of immune cells • - Opsonisation deficiency (complement) • -  albumin production – increased NO, LPS, reduced PGE2 binding • Anatomical: • Static : porto-systemic shunting • Dynamic: sinusoidal endothelial dysfunction (intrahepatic resistance) shunting RES bacterial products gut - bacterial flora - gut permeability - local immune response Verbake et al; Crit Care ‘11; Selvapatt et al; Intensive Care Med, In press; O’Brien et al Nat Med ‘14

  24. Impaired systemic immune responses: mechanism for secondary/recurrent infections? Bonnel et al., Clin Gastro Hepatol, 2011

  25. Immune dysfunction in ACLF I • Lymphocytes: • Numerical reducation in CD4+, CD8+ • Expansion suppressive T regulatory cells • Polymorphonuclear leukocytes: • Abnormalities in neutrophil adherence • Impaired chemotaxis of white cells • Impaired phagocytosis and intracellular killing by neutrophils* * Shawcross et al; Hepatology’08 Shawcross et al; Hepatology ‘12 Dong t al, LivInt ‘13; Yang et al J Trans Med ‘12

  26. n=12 n=14 n=37 n=9 n=8 Immune dysfunction in ACLF II Reduced monocyte activation/tolerance to LPS Impaired phagocytosis E.Coli/S.Aureus HLA-DR Reduced pathogen clearance • LPS-evoked • TNF-a Bernsmeier et al, EASL ‘14 Wasmuth et al, J Hep ‘05; Berry et al, Intensive care Med ‘11

  27. Novel therapies for ACLF or are they not so novel? • Very little progress over past 20-30 years in management per se • Advances in critical care support but little impact on outcome • Emergence of multi-drug resistance & increased frequency in C.Difficle • Key unmet need in patients with liver disease: • Novel approaches to established therapies • Biomarkers –targeting early detection of infection • Novel therapies to targeting immune failure

  28. Albumin : re-orientating the indication as a therapy for infection? • ATTIRE study (UK): • PGE2- suppresses TNF-a • Albumin binds PGE2 – • restores TNF-a responses • Standard of care for prevention renal/circulatory dysfunction in SBP (metanalysis4 RCT [n=288]; Salerno et al ClinGastHep ‘13) • Controversy in use to improve outcome in non-SBP induced sepsis: • Guevara et al (n=110): improvement in renal/circulatory dysfunction/MR • Thevenot et al (ALB-CIRINF studyn=191): no improvement in renal function or mortality O’Brien et al, Nat Med ‘14

  29. N-acetylcysteine in alcoholic hepatitis?immune-modulatory role • 174 patients 11 centres France • Steroids ± NAC (5 days 150 mg/kg) • NAC group mortality benefit at 1 month : • trend at 2 and 6 mnths • Decreased infections in NAC group • Decreased HRF at 2 and 6 mnths Nguyen-Khac et al, NEJM ‘11

  30. Corticosteroids in ACLF: immunmodulatoryvsimmunosuppressive “Low dose” hydrocortisone may augment immune function • Controversy regarding use of hydrocortisone in cirrhosis with organ failure • High incidence of adrenal insufficiency (>60% patients) • 3 main studies: • Arabi et al, CMAJ ’10 • Fernandez et al, Hepatology ‘06 • Marik et al, Crit Care Med ’05 • Improvement in vasopressor requirments; variable mortality benefit • Imunmodulatory effects in ACLF unknown Keh et al, Am J RespirCrit Care Med ‘03

  31. Immuno-stimulatory therapies in ACLF G-CSF therapy in ACLF: n=47; mostly ETOH, HBV G-CSF at a dose of 5 mcg/kg subcutaneously, 12 doses over a period of 1 month (daily doses for the first 5 days and then every third day), Increase CD34+ progenitor responses/hepatic regeneration Improve neutrophil function/prevent sepsis No differences in sepsis during study period; only on follow-up Garg et al; Gastro ‘12

  32. Conclusions • ACLF is multisystem disorder with high short mortality 35-50% • Sepsis is commonest trigger for evolution to organ failure & 4-fold increase in mortality • Sepsis, SIRS responses & extra-hepatic organ failure confer poor outcome • Bacterial translocation of gut-derived organisms • pathogenic factor for seeding of microbes/sepsis development • “culture-negative sepsis” in cirrhosis • Activation of SIRS responses • Circulatory/hepatic endothelial dysfunction

  33. Conclusions • Important to identify early and Rx with goal directed therapy (as in sepsis) may improve outcome • Early treatment prior to or to offset the progression of organ failure- abrogate infection triggered inflammatory cascade in decompensated cirrhosis • “Top-down” approach rather than conventional “top-up” • Always think about sepsis as a cause of admission or deterioration following admission

  34. Future avenues for hospital care

  35. liver Circulation Immuneparesis Early predictive biomarkers of infection  Bacterial products ccytokine secretion Hepatic regeneration Albumin therapy RES Phagocytosis Oxidative burst LPS tolerance/PGE2 shunting pathogens • Impaired clearance • Production of opsonins • Albumin Immune cells Immunomonitoring Immune modulatory therapies migration bacterial products pathogens pathogens Reduction in microbial gut translocation bacterial products gut Impaired immune responses Microbial seeding/translocation - bacterial flora - gut permeability - local immune response sites of infection

  36. Conclusions • Thank you for your attention • Questions?

More Related